Oxidative Stress in Disease and Aging: Mechanisms and Therapies 2018View this Special Issue
Review Article | Open Access
Arnold N. Onyango, "Cellular Stresses and Stress Responses in the Pathogenesis of Insulin Resistance", Oxidative Medicine and Cellular Longevity, vol. 2018, Article ID 4321714, 27 pages, 2018. https://doi.org/10.1155/2018/4321714
Cellular Stresses and Stress Responses in the Pathogenesis of Insulin Resistance
Insulin resistance (IR), a key component of the metabolic syndrome, precedes the development of diabetes, cardiovascular disease, and Alzheimer’s disease. Its etiological pathways are not well defined, although many contributory mechanisms have been established. This article summarizes such mechanisms into the hypothesis that factors like nutrient overload, physical inactivity, hypoxia, psychological stress, and environmental pollutants induce a network of cellular stresses, stress responses, and stress response dysregulations that jointly inhibit insulin signaling in insulin target cells including endothelial cells, hepatocytes, myocytes, hypothalamic neurons, and adipocytes. The insulin resistance-inducing cellular stresses include oxidative, nitrosative, carbonyl/electrophilic, genotoxic, and endoplasmic reticulum stresses; the stress responses include the ubiquitin-proteasome pathway, the DNA damage response, the unfolded protein response, apoptosis, inflammasome activation, and pyroptosis, while the dysregulated responses include the heat shock response, autophagy, and nuclear factor erythroid-2-related factor 2 signaling. Insulin target cells also produce metabolites that exacerbate cellular stress generation both locally and systemically, partly through recruitment and activation of myeloid cells which sustain a state of chronic inflammation. Thus, insulin resistance may be prevented or attenuated by multiple approaches targeting the different cellular stresses and stress responses.
The hormone insulin plays an important role in maintaining physiological levels of blood glucose, through various effects on insulin target cells. In endothelial cells, it promotes the release of nitric oxide and endothelin, which, respectively, promote vasodilation and vasoconstriction, and the combined vasodilatory and vasoconstrictive effects improve the distribution of blood glucose to target organs such as skeletal muscles . It promotes glycogen synthesis in hepatocytes, skeletal myocytes, and adipocytes [2, 3], downregulates the expression of gluconeogenetic enzymes in hepatocytes, and promotes glucose uptake through the GLUT 4 receptor in skeletal myocytes and adipocytes [2, 3]. In specific types of hypothalamic neurons, it inhibits the expression of orexigenic neuropeptides such as neuropeptide Y (NYP) or agouti-related peptide (AgRP) and thereby contributes to decreased food intake [4–8]. Insulin also inhibits food intake by promoting expression of anorexigenic neuropeptides such as proopiomelanocorticotropin (POMC) and cocaine- and amphetamine-regulated transcript (CaRT) in the arcuate nucleus, which together promote the activity of α-melanocyte-stimulating hormone in neurons in the paraventricular nucleus (4–8). Besides inhibiting AgRP synthesis, insulin-induced hyperpolarization of the AgRP-expressing arcuate neurons reduces the firing rate of these neurons and results in the generation and transmission of signals from the motor nucleus of the vagus nerve to the liver, resulting in increased hepatic interleukin 6 (IL-6) production, IL-6-mediated activation of signal transducer and activator of transcription 3 (STAT-3), and STAT-3-mediated decrease in the expression of gluconeogenic genes such as glucose-6-phosphatase and phosphoenol pyruvate carboxykinase (PEPCK) [9–12].
Insulin resistance refers to a condition in which insulin-responsive cells undergo a less than normal response to insulin, such as a reduced activation of endothelial nitric oxide synthase in endothelial cells . It involves disruption of specific events in the insulin signaling pathways. Insulin signaling begins with insulin binding to the insulin receptor (IR), a receptor tyrosine kinase, which then undergoes autophosphorylation of various intracellular tyrosine residues, resulting in the recruitment and tyrosine phosphorylation of adaptor proteins including insulin receptor substrates (IRS) such as IRS1 and IRS2 (Figure 1).
Signaling downstream of IRS occurs by several pathways (Figure 1). One such pathway sequentially involves activation of phosphatidyl inositol 3-kinase (PI3K); conversion of phosphatidyl inositol 4,5-biphosphate (PIP2) to phosphatidyl inositol 3,4,5-triphosphate (PIP3); recruitment of Akt (protein kinase B (PKB)) to the plasma membrane; phosphorylation of Akt by 3-phosphoinositide-dependent kinase-1 (PDK 1) and mammalian target of rapamycin complex 2 (mTORC 2); and Akt-mediated phosphorylation of a number of downstream protein substrates that induce effects such as activation of glycogen synthase (GS) in adipocytes, skeletal myocytes, and hepatocytes, translocation of glucose transporter 4 (GLUT 4) to the plasma membrane of adipocytes and skeletal myocytes, phosphorylation of the forkhead transcription factor (FOXO 1) to inhibit expression of gluconeogenic enzymes in hepatocytes, or activation of endothelial nitric oxide synthase in endothelial cells [1–3, 13] (Figure 1). Akt also activates mTORC 1 which not only is involved in feedback inhibition of IRS but also inhibits synthesis of orexigenic neuropeptides by hypothalamic neurons (not shown) .
In another pathway which involves orexigenic (AgRP-producing) hypothalamic neurons, PI3K promotes opening of ATP-sensitive K+ channels, resulting in sequential hyperpolarization of these neurons, transmission of signals from the vagus nerve to the liver, increased hepatic IL-6 synthesis, activation of STAT-3, and decreased expression of gluconeogenic enzymes (Figure 1) [9–12]. On the other hand, insulin-mediated upregulation of the production of anorexigenic neuropeptides by hypothalamic neurons proceeds through IRS-mediated activation of the growth factor receptor-bound 2- (Grb2-) son of sevenless (Sos) protein complex (Grb2-Sos) and downstream activation of the Ras-Raf-MEK-ERK pathway . In endothelial cells, ERK promotes the synthesis of endothelin-1 .
Because insulin resistance contributes to the development of noncommunicable diseases such as diabetes, cardiovascular disease, fatty liver disease, Alzheimer’s disease, and impaired lung function [12, 13, 15–18], much effort has been directed toward understanding the mechanisms of its pathogenesis through studies involving cell cultures, animal models, and clinical studies. Cell cultures of hepatocytes, adipocytes, skeletal muscle cells, endothelial cells, or neurons incubated with palmitate or high sugar concentrations develop insulin resistance [19–26]. Some of the cellular events and mechanisms that have been shown to be involved in the development of insulin resistance in these cells both in vitro and in vivo include (i) toll-like receptor 4 (TLR4) and associated inhibitor of kappa B kinase- (IKK-) nuclear factor kappa B (NF-κB) signaling [27–31]; (ii) advanced glycation end products (AGEs) or uric acid-induced receptor for AGE (RAGE) signaling via NF-κB [30, 32–34]; (iii) oxidized low-density lipoprotein- (oxLDL-) mediated RAGE or Lox-1 signaling and the resultant activation of NF-κB and formation of peroxynitrite [30, 35, 36]; (iv) upregulation of NADPH oxidase (Nox) expression and activity [20, 21, 30, 37–39]; (v) increased mitochondrial reactive oxygen species (ROS) generation [30, 40]; (vi) upregulation of inducible nitric oxide synthase (INOS) [30, 41–43]; (vii) increased diacylglycerol synthesis [30, 44]; (viii) increased ceramide synthesis [30, 45, 46]; (ix) activation of protein kinase C (PKC) isoforms [30, 37, 47]; (x) activation of mitogen-activated protein kinases (MAPKs) such as c-Jun N-terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK) [20, 28, 30]; (xi) endoplasmic reticulum stress and the unfolded protein response [30, 43, 48–50]; (xii) dysregulation of the heat shock response [51–53]; (xiii) autophagy dysregulation ; (xiv) apoptosis ; (xv) p53 activation ; and (xvi) inflammasome activation [57, 58]. Thus, insulin resistance is regarded as a complex disorder that defies a single etiological pathway .
This review summarizes the above mechanisms into a unifying hypothesis that the pathogenesis of insulin resistance involves generation of oxidative stress, nitrosative stress, carbonyl stress, endoplasmic reticulum stress, and genotoxic stress through interconnected pathways; induction of various responses to these stresses, such as the unfolded protein response (UPR), the ubiquitin proteasome pathway (UPP), DNA damage response (DDR), the NRLP3 inflammasome, and apoptosis; and the dysregulation of stress responses such as autophagy, heat shock response, and nuclear factor erythroid-2-related factor 2 (Nrf2) signaling in insulin target cells (as exemplified in Figure 2). Each of the stresses, stress responses, and stress response dysregulations contributes to insulin resistance in multiple ways.
2. Pathways to Cellular Stresses in Insulin Target Cells
2.1. Pathways to Oxidative and Nitrosative Stresses in Response to Overnutrition, Physical Inactivity, Hypoxia, Psychological Stress, or Environmental Pollutants
As illustrated in Figure 2, cell surface receptors such as the TLR4, RAGE, Lox-1, and angiotensin receptor type 1 (AT1) are involved in signaling pathways that generate oxidative stress and nitrosative stress.
A high-fat or high-fructose diet promotes the growth of gram-negative bacteria in the colon, resulting in endotoxemia and the release of enteric lipopolysaccharide (LPS) into blood plasma [60, 61]. LPS is a direct ligand for TLR4 and induces TLR4-dependent oxidative stress and inhibition of insulin signaling in both peripheral insulin target cells and hypothalamic neurons [28, 30, 62, 63]. TLR4 signaling via MyD88 and IRAK 4 leads to the activation of IKK [28, 30, 64]. One of the most important targets of IKK activation is NF-κB, which, for example, was found to be essential for palmitate-induced insulin resistance in C2C12 skeletal muscle cells . NF-κB induces expression of protein tyrosine phosphatase B (PTPB), a negative regulator of the insulin receptor  and proinflammatory genes such as tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6) . It also upregulates the expression of Nox and iNOS, which produce superoxide anions (O2−) and nitric oxide (NO), respectively [28–30, 68, 69]. Superoxide anions are rapidly converted to hydrogen peroxide (H2O2) by superoxide dismutase (SOD) . Superoxide anions also rapidly react with NO to form peroxynitrite (OONO−) , which reacts with hydrogen peroxide (H2O2) to form singlet oxygen (1O2) [30, 71], which in turn reacts with biomolecules such as lipids and proteins to form organic hydroperoxides (ROOH) . Excessive production of reactive oxygen species (ROS) such as superoxide anions, hydrogen peroxide, organic hydroperoxides, and singlet oxygen results in oxidative stress when the ROS outweigh the cellular antioxidant capacity . Likewise, excessive formation of peroxynitrite results in nitrosative stress. NF-κB-dependent induction of iNOS and Nox may further contribute to mitochondrial oxidative and nitrosative stresses. This is because, even when H2O2 and NO are generated extramitochondrially, they readily enter the mitochondria and induce electron leakage from the electron transport chain (ETC), thus promoting the generation of mitochondrial superoxide anions, H2O2, peroxynitrite, singlet oxygen, and lipid hydroperoxides [30, 70].
The nonenzymatic reaction of sugars with proteins (Maillard reaction) leads to the formation of hydrogen peroxide, singlet oxygen, and advanced glycation end products (AGEs) such as glyoxal lysine and methylglyoxal lysine [73, 74]. AGEs accumulate in plasma and tissues of animals and humans on diets rich in fructose or preformed AGEs . AGEs signal via the RAGE receptor to induce activation of NF-κB via some components of the TLR4 pathway and thus produce similar effects as LPS, including the induction of oxidative and nitrosative stresses (Figure 2) [30, 32, 76].
Oversupply of fatty acids to insulin target cells occurs because of excessive dietary intake, obesity, or muscle inactivity-associated decrease in beta oxidation of fatty acids [59, 77, 78]. Palmitate and laurate can induce the activation of IKK, NF-κB, and oxidative stress independently of LPS [79–84]. This at least partly involves increased synthesis of diacylglycerol (DAG), a cofactor of protein kinase C (PKC) isoforms which activate Nox isoforms and NF-κB [30, 59, 80, 82–85]. Similarly, exposure of endothelial cells to high glucose levels results in DAG formation and subsequent activation of PKC and Nox . The activation of Nox and NF-κB by PKC isoforms may involve PKC-induced TLR4 signaling as shown in Figure 2 [30, 64, 81]. However, DAG-PKC-induced insulin resistance without TLR4 activation has also been reported .
Palmitate is a substrate of serine palmitoyl transferase (SPT) in the first step of the de novo biosynthesis of the sphingolipid ceramide, an inhibitor of insulin signaling by multiple mechanisms including activation of protein phosphatase 2A (PP2A) and PKC-ζ, which promote dephosphorylation of Akt or serine phosphorylation of IRS, respectively [45, 81, 86, 87]. Long-term ceramide action also promotes serine phosphorylation of IRS via sequential activation of the double-stranded RNA-activated protein kinase (PKR) and JNK . Palmitate-induced TLR4-IKK signaling promotes ceramide biosynthesis by upregulating the synthesis of SPT and ceramide synthases (Figure 2) [81, 86]. Ceramide is an important contributor to oxidative stress. It induces mitochondrial superoxide anion and H2O2 generation by blocking the electron transport system at complex III . Mitochondrial superoxide anions generated in this manner induce opening of the mitochondrial permeability transition pore, allowing mitochondrial ROS to move into the cytoplasm . Some mechanisms by which ceramide induces insulin resistance, such as apoptosis induction, JNK activation, and mitochondrial fission, depend on such ceramide-induced oxidative stress [91–95]. ROS and NO promote mitochondrial fission, which in turn promotes ROS formation through cytochrome c oxidase [96, 97].
In a recent clinical trial, a high-saturated-fat diet increased the serum concentrations of angiotensin-converting enzyme (ACE) independently of weight gain . In the classical renin-angiotensin system (RAS), ACE converts angiotensin I to the active angiotensin II which signals via angiotensin receptors 1 and 2 (AT1 and AT2)  and TLR4 to induce NF-κB activation, mitochondrial fission, and insulin resistance in skeletal muscle cells, vascular smooth muscle cells, and endothelial cells [31, 99–104]. Angiotensin II signaling upregulates xanthine oxidase protein expression and activity in a Nox-dependent manner in endothelial cells . Furthermore, it activates 12-lipoxygenase, whose product, 12-hydroxyeicosatetraenoic acid (12-HETE), induces NF-κB in endothelial cells and aldosterone in adrenal glomerulosa cells [106, 107]. Aldosterone levels increase in humans during obesity, and this hormone correlates with insulin resistance independently of the body mass index [108, 109]. Aldosterone increases superoxide production in endothelial cells though mineralocorticoid receptor- (MR-) mediated activation of Nox and Rac 1 . It also promotes MR-induced de novo ceramide synthesis in these cells . This adrenal hormone readily enters the brain, such that its levels in the brain are directly proportional to its plasma levels in rats . It activates the hypothalamic renin-angiotensin system and associated oxidative stress in hypothalamic neurons [112, 113].
Psychological stress (PS) is another major inducer of oxidative stress and insulin resistance [114–116]. This is partly through increased production of aldosterone , angiotensin II , and glucocorticoids such as corticosterone and cortisol (Figure 3) [118–120]. Glucocorticoids upregulate the expression of SPT and ceramide synthases and thus contribute to ceramide-mediated oxidative stress and insulin resistance [121, 122]. They have a higher affinity for the mineralocorticoid receptor than for the glucocorticoid receptor, and their binding to the former increases Nox expression in adipocytes . PS also contributes to LPS-induced oxidative stress and insulin resistance by promoting colonic barrier permeability and the translocation of bacteria and LPS from the intestinal lumen to the blood . Chronic peripheral administration of corticotropin-releasing factor was demonstrated to cause such colonic barrier dysfunction in rats . This involves glucocorticoid-mediated downregulation of the intestinal epithelial tight junction protein, claudin 1 .
Chronic activation of the sympathetic nervous system and the associated increase in catecholamines such as epinephrine and norepinephrine are another hallmark of PS . These catecholamines contribute to insulin resistance in the heart by activating β-adrenergic receptors (β-AR) . Activation of β-AR induces oxidative stress in cardiomyocytes, adipocytes, and endothelial cells, at least partly by β2-AR-mediated upregulation of Nox [128–132]. The β3-AR activates hormone-sensitive lipase in adipocytes and thus promotes accumulation of free fatty acids and the associated increase in ceramide synthesis and MAPK activation . AR stimulation inhibits adiponectin gene expression in adipocytes via protein kinase A , and this should further promote ceramide accumulation and ceramide-dependent oxidative stress because adiponectin increases ceramidase activity .
Mountain climbing or obstructive sleep apnea (OSA) induces insulin resistance, and this is associated with hypoxia-induced oxidative and nitrosative stresses [136, 137]. OSA worsens during periods of rapid weight gain . Chronic asthma also induces intermittent hypoxia , and an association between asthma and insulin resistance was demonstrated in children and adolescents [18, 140, 141]. Many mechanisms have been reported to be involved in hypoxia-induced oxidative and nitrosative stresses. During the switch from normoxia to hypoxia, a burst of superoxide formation occurs at mitochondrial complex 1 due to deactivation of this complex in cells such as endothelial cells and neurons . Hypoxia also increases superoxide formation at mitochondrial complex III . In human umbilical endothelial cells, hypoxia was found to induce expression of the human circadian locomotor output cycle protein kaput (hCLOCK), which promoted the production of ROS, which in turn promoted Rhoa and NF-κB signaling . Hypoxia upregulates 12/15-lipoxygenase, whose metabolites, namely, 13-hydroperoxyoctadecadienoc acid (13-HPODE), 12-hydroxyeicosatetraenoic acid (12-HETE), and 15-hydroxy-eicosatetraenoic acid (15-HETE), activate NF-κB, iNOS, and mitochondrial oxidative stress in endothelial cells, cardiomyocytes, smooth muscle cells, neurons, and adipocytes [145–151]. Since 13-HPODE, 12-HETE, and 15-HETE activate PKC isoforms [149, 152, 153], the 12/15-lipoxygenase-dependent, hypoxia-induced oxidative and nitrosative stresses may follow the pathway outlined in Figure 4.
As indicated in this figure, 15-S-HETE also activates xanthine oxidase (XO) in endothelial cells . Such increase in XO activity occurs during hypoxia  and leads to increased uric acid (UA) formation in lowlanders at high altitude . Uric acid is a promoter of oxidative stress via the RAGE receptor in endothelial cells . During intermittent hypoxia, XO-derived ROS activate Nox2 . In addition, hypoxia increases catecholamine production  and, like psychological stress, has been reported to induce mucosal barrier failure and endotoxemia in rats and primates [159, 160]. However, a recent study in humans found that hypoxia increased gut inflammation but not gut permeability .
Long-term exposure to traffic-related air pollution was found to be positively associated with insulin resistance in children . Particulate matter, ozone, nitrogen oxides, and transition metals are among the potent oxidants in polluted air that induce endogenous ROS formation and oxidative stress . Cadmium, a heavy metal pollutant from industrial plants, which makes its way into the food chain and induces oxidative stress was recently found to be positively associated with insulin resistance .
2.2. Oxidative Stress Produces Carbonyl Stress and Vice Versa
Decomposition of lipid hydroperoxides produces reactive carbonyl compounds including acrolein, glyoxal, methylglyoxal, malondialdehyde, 4-hydroperoxy-2-nonenal, 4-hydroxy-2-nonenal (HNE), 4-oxo-2-nonenal, 2,4-decadienal, and 9-oxo-nonanic acid . Elevated formation of such products constitutes carbonyl stress. Thus, oxidative stress, through increased production of lipid hydroperoxides, promotes carbonyl stress. As mentioned in the previous section, methylglyoxal- and glyoxal-derived AGEs promote oxidative stress via the RAGE receptor. Likewise, 4-HNE, one of the predominant lipid-derived aldehydes formed in insulin-responsive cells during high-fat or high-glucose diets, promotes the formation of reactive oxygen and nitrogen species . Cholesterol secosterol aldehydes, which are produced via the reaction of cholesterol with singlet oxygen or ozone [30, 167], increase oxidative stress by inactivating catalase and thus promoting the accumulation of hydrogen peroxide and lipid hydroperoxides .
2.3. Oxidative and Carbonyl Stresses Promote Endoplasmic Reticulum Stress and Vice Versa
Noncytoplasmic and nonmembrane proteins synthesized at the rough endoplasmic reticulum (ER) undergo translocation into the ER lumen, where calcium-dependent molecular chaperones assist their folding into the correct tertiary structures . The ER calcium transporter, sarco- (endo-) plasmic reticulum Ca2+ ATPase (SERCA), pumps calcium ions into this organelle and thereby promotes the activity of the molecular chaperones [170, 171]. The reversible S-glutathionylation of SERCA thiols by NO and peroxynitrite increases SERCA activity, but the irreversible sulfonation of these thiols by ROS such as hydrogen peroxide and singlet oxygen causes its inactivation [30, 170–172]. The ensuing accumulation of unfolded or misfolded proteins in the ER constitutes ER stress . Carbonylation by aldehydes such as acrolein, methylglyoxal, glyoxal, and HNE also reduces SERCA activity [174, 175]. ER stress leads to enhanced Nox 4 activity in the ER, resulting in increased hydrogen peroxide formation and oxidative stress . Such increased ER oxidative stress promotes calcium efflux from the ER and calcium influx into the mitochondria, which induces mitochondrial ROS production and oxidative stress [30, 176]. Thus, there is a vicious cycle between ER stress and oxidative stress [30, 177].
2.4. Oxidative, Carbonyl, and Nitrosative Stresses Generate Genotoxic Stress
Oxidative stress, carbonyl stress, and nitrosative stress contribute to genotoxic stress by availing genotoxic reactive oxygen, carbonyl, and nitrogen species that modify DNA. ROS react with the nitrogenous bases in DNA to induce a variety of base modifications. One of the most common of such modifications is the conversion of guanine to 8-oxo-7,8-dihydroguanine (8-oxoG), whose levels in urine have been suggested to be a marker of whole-body oxidative stress [178, 179]. 8-oxoG is most readily formed by singlet oxygen, although the hydroxyl radical also contributes to its formation [180, 181]. Mitochondrial DNA is exposed to singlet oxygen generated through mechanisms such as the reaction of peroxynitrite with hydrogen peroxide or cytochrome c-mediated conversion of cardiolipin hydroperoxide to triplet carbonyls in the mitochondria . DNA-damaging hydroxyl radicals may be generated by the Fenton reaction between DNA-bound Fe2+ and hydrogen peroxide . 8-oxoG undergoes further oxidative modifications, as well as crosslinking with lysine to generate protein-DNA adducts . The reaction of singlet oxygen or hydroxyl radicals with deoxyribose in DNA generates single-strand breaks, but double-strand breaks can be generated when the single-strand breaks occur in close proximity [178, 184]. Peroxynitrite induces single-strand breaks in DNA through deoxyribose oxidation or via the formation of 8-nitroguanine . Reactive carbonyl compounds derived from the decomposition of lipid hydroperoxides react with DNA bases to form exocyclic propano- and etheno-DNA adducts, as recently reviewed . The glycoxidation of histone proteins by glyoxal and methylglyoxal promotes the oxidative generation of DNA strand breaks . The formation of hydrogen peroxide and singlet oxygen during protein glycoxidation  may explain this phenomenon. Genotoxic stress in turn promotes oxidative stress (Section 3.4).
3. Mechanisms of the Inhibition of Insulin Signaling by Cellular Stresses
3.1. Oxidative Stress
The oxidative modifications of biomolecules including lipids, nucleic acids, and proteins contribute to insulin resistance. Some common types of oxidative protein modifications include hydroperoxidation, glutathionylation, and sulfonation. As shown in Figure 5, proteins (Pr) react with singlet oxygen to form protein hydroperoxides (Pr-OOH). The latter is relatively long lived and inactivates enzymes even when singlet oxygen is no longer in the system [188, 189]. Pr-OOHs react with thiol (-SH) groups in other proteins to form hydroxy proteins (Pr-OH) and protein sulfenic acids (Pr-S-OH), and the latter readily reacts with glutathione (GSH) to form glutathionylated proteins (Pr-S-SG) [190–192]. Hydrogen peroxide also induces protein glutathionylation, analogously to protein hydroperoxides, but the latter is more reactive . Sulfenic acids (Pr-SOH) react further with H2O2 to form sulfinic acids (Pr-SO2H), which react with H2O2 to form sulfonic acids (Pr-SO3H) . The reaction of superoxide radicals with thiols may also lead to the conversion of the latter to sulfonates via persulphenyl derivatives . Ozone or ozone-like oxidants have been suggested to be formed in biological systems [74, 167]. Ozone largely converts thiolate ions to sulfonates  and was postulated to be an important contributor to the conversion of methionine sulfoxide to methionine sulfonate .
At low levels, ROS including H2O2 and singlet oxygen stimulate insulin signaling by the PI3K-Akt pathway through inhibition of protein tyrosine phosphatase 1B (PTP1B) which dephosphorylates the insulin receptor [196, 197]. On the other hand, a high concentration of H2O2 was found to induce insulin resistance in hepatocytes, and systemic removal of hydrogen peroxide improved insulin resistance in obese mice [196, 198]. ROS activate stress-sensitive kinases which reduce insulin signaling , and it was proposed that at high H2O2 concentrations, JNK activation outweighs PTP1B inactivation .
Activation of JNK and p38 by ROS occurs through the modification of their regulatory proteins. For example, MAPK phosphatase 1 deactivates JNK and p38 MAPK by dephosphorylation, but glutathionylation targets this phosphatase for proteosomal degradation .
Protein-protein interaction between glutathione S-transferase P (GSTP) and JNK keeps the latter in an inactive state, but oxidative modification of the former breaks this interaction and activates JNK [200, 201]. Another protein whose oxidative modification promotes insulin resistance is thioredoxin which, in the native state, binds to and inactivates apoptotic signaling kinase 1 (ASK1), an upstream activator of both JNK and p38 pathways [202, 203]. While the release of thioredoxin from ASK would also allow the former to act as a thiol-reducing antioxidant, oxidative stress promotes the p38 MAPK- and FOXO-dependent expression of thioredoxin-interacting protein (TXNIP)  and transfer of the latter from the nucleus to the cytoplasm and mitochondria, where it binds to thioredoxin 1 and thioredoxin 2, respectively, and this aggravates oxidative stress [204, 205]. Increased oxidative stress also favors the activatory binding of TXNIP to the NLRP3 inflammasome , a key contributor to insulin resistance as described in Section 4.5.
Several studies have reported that the inhibition of glycolysis in muscle cells induces insulin resistance [206–208], for example, through a compensatory increase in lipid uptake . Protein peroxides generated by singlet oxygen inhibit the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GPD) . Besides reduced glycolysis, GPD inhibition enhances the conversion of dihydroxyacetone phosphate to methylglyoxal , which is one of the major reactive carbonyls contributing to insulin resistance (Section 3.3).
Reactive oxygen species such as H2O2 promote Ser637 dephosphorylation of the GTPase, dynamin-related protein 1 (Drp1), resulting in translocation of the latter to the mitochondria, where its polymerization into a ring-like structure induces mitochondrial fission , an important contributor to insulin resistance and oxidative stress [94, 95].
Perhaps one of the greatest contributions of oxidative stress to insulin resistance is that it generates metabolites that create positive feedback loops for potentiation of TLR4, RAGE, and other signaling pathways associated with activation of NF-κB and insulin signal-inhibiting serine kinases such as PKC, IKK, JNK, and p38 MAPK. For example, oxidative stress leads to the oxidation of low-density lipoproteins (LDL), and oxidized LDL (oxLDL) signals via Lox-1, RAGE, and Fas receptors to activate NF-κB and MAPKs as recently reviewed , and the plasma concentration of oxLDL is an independent risk factor for insulin resistance .
p38 MAPK promotes the expression of aldose reductase (ALDR) , which is subsequently activated by oxidative modification , and makes a major contribution to insulin resistance . ALDR reduces HNE-glutathione adduct (GS-HNE) to glutathionyl-1,4-dihydroxynonene (GS-HN), which activates phospholipase C, leading to DAG formation and the activation of PKC, MAPKs, and NF-κB (Figure 2) [166, 216]. DAG oxidation also contributes to PKC-dependent signaling, since DAG hydroperoxide is a more potent activator of PKC than unoxidized DAG . In the presence of excess glucose, ALDR catalyses the first reaction of the polyol pathway, which leads to the production of both DAG and AGES, thus contributing to signaling via both TLR4 and RAGE . The role of ALDR in potentiating LPS-TLR4 signaling via PKC is evidenced by findings that its inhibition alleviates endotoxin-induced inflammatory diseases [216, 219, 220].
Mammalian xanthine dehydrogenase (XDH) is reversibly converted to xanthine oxidase (XO) by oxidative modification of specific cysteine residues . As already mentioned, lipoxygenase-mediated 15-HETE formation during hypoxia activates XO. Fructose metabolism in hepatocytes is associated with increased XO-mediated conversion of AMP to uric acid [85, 222–224], which promotes insulin resistance through RAGE, TLR4, NF-κB, Nox, mitochondrial oxidative stress, ER stress, and skeletal muscle atrophy [30, 34, 223–227].
Oxidative stress promotes ceramide synthesis even independently of SPT and ceramide synthases. Singlet oxygen converts sphingomyelin to ceramide, even in protein-free liposomes . In glioma cells, superoxide promotes ceramide formation through activation of neutral sphingomyelinase . Sphingomyelinase inhibition reduces intramyocellular ceramide and protects muscle cells from insulin resistance [230, 231].
H2O2 downregulates the expression of carnitine palmitoyl transferase 1 (CPT1), acyl COA oxidase (ACOX), and peroxisome proliferator-activated receptor-alpha (PPAR-α) in hepatocytes  and PPAR-γ in endothelial cells . CPT1 and ACOX are involved in fatty acid oxidation and reduction of DAG and ceramide levels [232, 234, 235]. PPAR-α reduces oxidative stress by upregulating superoxide dismutase and catalase expression and inhibiting NF-κB activity [232, 236, 237]. PPAR-γ inhibits NF-κB and upregulates the expression of adiponectin, an adipokine that improves insulin sensitivity [238–240].
3.2. Nitrosative Stress
The importance of nitrosative stress in insulin resistance is evidenced by reports that inhibition of iNOS or peroxynitrite in various cell types prevents insulin resistance [41–43]. Peroxynitrite decomposes into radicals that cause inhibitory tyrosine nitration of proteins in the insulin signaling pathway . The reaction of peroxynitrite with proteins generates thyl radicals and sulfenates, leading to protein glutathionylation . Nitrosoglutathione causes glutathionylation and inhibition of GADPH . Peroxynitrite contributes to palmitate-induced DNA damage and inflammasome activation [23, 242]. It also induces ceramide formation in endothelial cells . Nevertheless, the effects of peroxynitrite are mediated to some extent by ROS since peroxynitrite-derived radicals can initiate free radical lipid peroxidation , and the reaction of peroxynitrite with hydrogen peroxide generates singlet oxygen [30, 71]. Thus, iNOS and NO donor-induced IRS-1 degradation in skeletal muscle cells was accentuated by concomitant oxidative stress .
3.3. Carbonyl/Electrophilic Stress
Reactive carbonyl species contribute to insulin resistance in various ways. Methylglyoxal, HNE, and cholesterol secosterol aldehydes participate in the generation of oxidative stress and associated NF-κB and MAPK activation (Sections 2.1, 2.2, and 3.1). In addition, methylglyoxal adducts insulin and inhibits the latter’s proper interaction with the insulin receptor . Protein-HNE adducts correlate with intramyocellular lipid content and the severity of insulin resistance in humans . HNE forms Michael adducts with His196 and Cys311 of Akt2 and thus inhibits downstream phosphorylation of Akt substrates such as glycogen synthase kinase 3β (GSK3β) and MDM2, resulting in the activation of the former and inhibition of the latter . GSK3β inhibits glycogen synthase and IRS and thus prevents both glycogen synthesis and glucose transport [248–250]. It also promotes hepatic gluconeogenesis by an unknown mechanism  and contributes to the dysregulation of the Nrf2 antioxidant response . MDM2 is a negative regulator of the p53 protein, which promotes insulin resistance as discussed in Section 3.4.
Human adipocytes and white adipose tissue express the full enzymatic machinery required for the synthesis and metabolism of asymmetric NGNGdimethylarginine (ADMA) which uncouples NOS and thus promotes ROS formation, increases TLR4 expression, decreases IRS-1 and GLUT-4 expression, and inhibits IRS-1 tyrosine phosphorylation and GLUT-4 translocation [253–256]. Plasma levels of ADMA increase during oxidative stress, mainly due to decreased expression and activity of the ADMA-degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH) [255–259]. HNE downregulates DDAH-1 expression through an miR-21-dependent mechanism .
3.4. Genotoxic Stress
Increased oxidative DNA damage determined as serum 8-hydroxy-2-deoxy-guanosine (8-OHdG) was found in lean normoglycemic offspring of type 2 diabetics, who are more predisposed to insulin resistance . Similarly, serum level of 8-OHdG was found to be increased in prediabetes . Mice deficient in 8-oxoguanine DNA glycosylase (the enzyme that performs base excision repair of DNA by cleaving 8-oxoG and other modified bases) were found to be prone to insulin resistance upon high-fat feeding . Mitochondrial DNA damage promotes palmitate-induced insulin resistance mainly by increasing mitochondrial oxidative stress, ER stress, JNK activation, and apoptosis, since overexpression of DNA glycosylase/apurinic/apyrimidinic lyase (hOGG1) in the mitochondria of skeletal muscle cells abrogated these effects [263, 264]. Interestingly, prevention of mitochondrial DNA damage in cardiomyocytes exposed to angiotensin II prevented mitochondrial superoxide production in these cells . In the latter study, mtDNA damage was found to cause impairments in mitochondrial protein expression, cellular respiration, and complex 1 activity prior to enhanced mitochondrial superoxide production. In addition, oxidized mitochondrial DNA released into the cytoplasm during apoptotic signaling activates the NLRP3 inflammasome .
3.5. Endoplasmic Reticulum Stress
Endoplasmic reticulum stress contributes to insulin resistance by promoting oxidative stress, especially mitochondrial oxidative stress and the resultant carbonyl and genotoxic stresses (Section 2.3) and ceramide synthesis , as well as by triggering the unfolded protein response , inflammasome activation , and apoptosis (Section 4.4).
4. Inhibition of Insulin Signaling by Cellular Stress Responses
4.1. The Ubiquitin-Proteosome Pathway
The ubiquitin-proteosome pathway (UPP) is the major cytosolic mechanism for the selective degradation of damaged proteins, such as oxidatively modified proteins, whereby the damaged proteins are conjugated to multiple ubiquitin molecules and then degraded by the 26S proteasome . This system is upregulated by mild and moderate oxidative stress and is required for cells to cope with oxidative stress . On the other hand, UPP-mediated degradation of the NF-κB inhibitor, iKB, causes activation of NF-κB . NF-κB promotes oxidative stress and induces expression of proinflammatory cytokines including TNF-α and IL-6 which, via the JAK-STAT pathway, upregulate expression of suppressors of cytokine signaling (SOCS) proteins such as SOCS1 and SOCS3 [271–273]. Association of the SOCS proteins with IRS targets the latter for degradation by the ubiquitin-proteosome pathway in multiple cell types [271–273]. Accordingly, palmitate-induced insulin resistance in L6 myotubes was found to be dependent on constitutive phosphorylation of STAT 3 and the associated increase in protein expression of SOCS 3 , and the ubiquitination and proteosomal degradation of IRS-1 and Akt was demonstrated to contribute to palmitate or NO donor-induced insulin resistance in HepG2 cells and skeletal muscle cells, respectively [245, 275]. Moreover, increased SOCS1/SOCS3 expression during uveitis induces insulin resistance in neuroretina , and SOCS3 overexpression is responsible for the induction of insulin resistance in mice infected with hepatitis C virus .
Several factors contribute to increased UPP during the pathogenesis of insulin resistance. For example, the 15-lipoxygenase product, 15-HETE, induces the expression of key enzymes of the UPP pathway . Inhibition of the adipose tissue ERK1/2 pathway during a high-fat diet was reported to enhance the UPP-mediated degradation of adiponectin , although contradictory results that ERK activity increases in hypertrophic adipocytes have also been obtained . Increased HNE activity during a high-fat diet enhances the ubiquitin-proteosome-mediated degradation of adiponectin . This is detrimental since adiponectin improves insulin sensitivity by (i) upregulating ceramidase activity to decrease ceramide levels ; (ii) increasing the levels of tetrahydrobiopterin (BH4), which lowers hepatocyte gluconeogenesis by activating AMP-activated kinase (AMPK) in an eNOS-dependent process ; and (iii) upregulating the silent information regulator 1 (SIRT1), a nicotinamide adenine dinucleotide-dependent histone deacetylase .
SIRT1 plays a role in the reduction of oxidative stress through increased expression of superoxide dismutase and catalase subsequently to FOXO4 deacetylation . It also activates AMP-activated kinase (AMPK), which promotes insulin sensitivity by inhibiting PKC isoforms and the associated NF-κB activation, oxidative stress, ER stress, and apoptosis [284–291]. AMPK also induces mitochondrial biogenesis, which limits endothelial cell dysfunction, for example, in response to angiotensin II signaling . Phosphorylation of SIRT1 by JNK1 primes SIRT1 for ubiquitination and degradation, and persistent JNK1 activation in obesity causes severe hepatic SIRT1 degradation . SIRT1 reduction is detrimental to insulin signaling in various tissues including liver, skeletal muscle, and adipose tissues [294–296]. AMPK1 is also diminished in insulin-resistant individuals, and pharmacological agents that activate it, such as metformin, improve insulin signaling .
Increased mitochondrial DNA methylation in NADH dehydrogenase 6 (ND6) and displacement loop (D-loop) regions significantly correlates with insulin resistance, and SIRT1 deregulation was suggested to be involved in such epigenetic changes . Since AMPK-mediated phosphorylation results in inhibition of DNA methyl transferase 1 (DNMT1) , UPP-mediated SIRT1 downregulation may induce such epigenetic changes through AMPK inhibition. Inflammasome activation might also contribute to this process by promoting DNMT1 expression (see Section 4.5). On the other hand, one study recently found that oxidative stress downregulated DNMT1 isoform 3, the isoform that is responsible for mitochondrial DNA methylation . Further studies are necessary to resolve this apparent contradiction.
The UPP may especially be relevant in skeletal muscle insulin resistance by contributing to skeletal muscle atrophy, which occurs in two steps, namely, (i) the release of myofilaments from the sarcomere by cysteine proteases such as calpain and caspases and (ii) UPP-mediated degradation of the myofilament fragments [300, 301]. Calpain activation may in turn rely on the release of calcium from the ER during ER stress. Calpain activation in the skeletal muscle results in inhibited Akt activity, which in turn results in the activation of Foxo transcription factors that activate expression of components of the ubiquitin-proteosome system involved in muscle protein degradation . Muscle atrophy per se has been associated with insulin resistance due to a decline in muscle oxidative capacity . Exposure of C2C12 myotubes to 25 μM H2O2 induced calpain-dependent atrophy without cell death . Exposure of C2 myotubes to peroxynitrite induced degradation of the myosin heavy chain muscle through activation of p38 MAPK and upregulation of the muscle-specific E3 ubiquitin ligases atrogin-1 and MuRF1 . Increased expression of the transforming growth factor-β (TGF-β) and myostatin, via NF-κB, induces proteosomal degradation of cellular proteins [304, 305], and muscle myostatin mRNA correlates with HOMA2-IR in nondiabetic individuals .
While mild or moderate oxidative stress upregulates the ubiquitin-proteosome pathway, severe or sustained oxidative stress inactivates this system, especially the 26S proteasome [269, 307]. This also contributes to insulin resistance since proteosomal dysfunction, characterized by increased levels of carbonylated and ubiquitinated proteins, aggravates oxidative stress and ER stress .
4.2. The Unfolded Protein Response
ER stress triggers a transcriptional and translational response referred to as the unfolded protein response (UPR), aimed at reducing the translation of global proteins, enhancing the degradation of unfolded proteins, and increasing the transcription of genes that enhance the protein folding capacity of the ER . The double-stranded RNA-dependent protein kinase- (PKR-) like ER kinase (PERK), the inositol requiring kinase 1 (IRE 1), and activating transcription factor 6 (ATF 6) are ER transmembrane proteins that are key components of three different UPR signaling pathways . Details of the signaling events that occur after activation of PERK, IRE1, and ATF 6 have been described elsewhere [267, 309].
All three UPR pathways promote NF-κB activity and oxidative stress [310, 311]. Besides, IRE-1 stimulates ASK-1 and thus activates JNK and p38 MAPK . PERK promotes insulin resistance by (i) activating JNK and p38 MAPK [49, 313]; (ii) phosphorylating FOXO on S298, a site which is not phosphorylated by Akt and whose phosphorylation counteracts the effects of Akt ; (iii) downregulating expression of the serine protease prostatin (PRSS8), which regulatorily degrades TLR4 ; (iv) inducing the pseudokinase tribble 3 (TRB3), which is increased in the liver of obese mice and humans and contributes to hepatic insulin resistance [49, 315]. TRB3 binds to Akt and prevents insulin-mediated Akt phosphorylation [49, 173, 315].
Low-grade hypothalamic inflammation induced by TNF-α was found to reduce oxygen consumption and the expression of thermogenic proteins in adipose tissue and skeletal muscles, and this was associated with insulin resistance in a rat model . PERK, to a lesser extent, ATF, and IRE upregulate the C/EBP homologous protein (CHOP) , which downregulates cAMP-induced upregulation of uncoupling protein 1 in adipocytes and thus prevents adaptive thermogenesis .
4.3. The DNA Damage Response
The DNA damage response is a complex mechanism to detect DNA damage, including strand breaks or base modifications, promote their repair, and in case of excessive damage to activate cell death pathways . Sensing of double-strand breaks by the Mre11-Rad50-Nbs1 (MRN) complex leads to the activation of ataxia telangiectasia mutated (ATM) and subsequent activation of DNA damage checkpoints . ATM activates NF-κB following DNA damage . Checkpoints induce changes in telomeric chromatin, recruit DNA repair proteins to sites of DNA damage, and induce cell death by apoptosis . One of the checkpoints, Chk2, promotes transcription of genes involved in DNA repair and phosphorylates tumor suppressor p53, thereby reversing inhibition of the latter by MDM2 . Chk2 also phosphorylates MDM4 and thereby reduces p53 degradation . Such activation of the p53 pathway is upregulated in adipose, endothelial, hepatic, and skeletal muscle tissues of obese rodents and humans [322–326]. Although this protein exhibits antioxidant activity at low levels of oxidative stress, it becomes prooxidant at higher oxidative stress levels, through activation of NF-κB  and promotion of ceramide synthesis by upregulating ceramide synthases . p53 promotes cellular senescence in adipose tissue, and this is associated with increased production of proinflammatory cytokines, which promote adipose tissue infiltration by neutrophils and macrophages, and systemic insulin resistance [322–326]. Many other metabolic effects of p53 are opposed to insulin signaling, as has been exhaustively reviewed [322, 327], including but not limited to JNK activation; apoptosis; repressed expression of the insulin receptor and glucose transporters 1, 3, and 4; enhanced transcription of phosphatase and tensin homologue (PTEN) which reduces phosphorylation of P13K and Akt; Akt degradation; glycolysis inhibition; and downregulated expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in the skeletal muscle, leading to the reduction in mitochondrial biogenesis and energy consumption. Reduced mitochondrial biogenesis leads to a lower capacity for fatty acid metabolism in skeletal muscle cells and accumulation of intramyocellular lipids including DAG which is a major contributor to skeletal muscle insulin resistance [329, 330].
Apoptosis is a type of programmed cell death in response to cellular damage or other physiological cues, characterized by controlled autodigestion of the cell by caspases [331, 332]. It is regarded as extrinsic when it involves death receptors such as CD95 (Fas) or intrinsic if it occurs independently of such receptors, and both forms of apoptosis were found to be involved in insulin resistance in a mouse model . Caspase-8 and caspase-9, respectively, act as initiator caspases for extrinsic and intrinsic apoptosis, and each initiator caspase starts off a cascade for the activation of executer caspases, which degrade key cellular proteins .
Oxidative stress promotes Fas ligand expression in various cell types and thus promotes extrinsic apoptosis . Activation of the Fas receptor by metabolites such as IL-1β, oxLDL, singlet oxygen, HNE, or JNK leads to its intracellular recruitment of the adaptor protein FADD to form a death-inducing complex (DISC) which activates initiator caspase-8, while the autocatalytic activation of procaspase-9, the initiator of intrinsic apoptosis, requires the assembly of a multiprotein complex, the apoptosome, which comprises seven copies of heterodimers between apoptotic protease-activating factor 1 (Apaf-1) and cytochrome c [331–335]. Thus, the release of the latter from the mitochondrial membrane into the cytoplasm is a key event in intrinsic apoptosis.
During unresolved ER stress, ER calcium efflux promotes lysosomal membrane permeabilization (LMP) and the release of lysosomal cathepsins, which promote mitochondrial outer membrane permeabilization (MOMP) and the release of cytochrome c from the mitochondrial intermembrane space [331, 332]. Localization of p53 protein on the lysosomal membrane upon sustained DNA damage also contributes to LMP . Activated JNK contributes to apoptosis in various ways including (i) inducing the expression of proapoptotic genes through transactivation of c-jun or p53, (ii) phosphorylating the BH3-only family of Bcl2 proteins which antagonize the antiapoptotic activity of Bcl2 or Bcl Xl, and (iii) activating Bim, a BH3-domain-only protein which activates Bax, which in turn promotes MOMP and cytochrome c release .
In humans, the progression of nonalcoholic fatty liver disease is associated with increasing apoptosis and insulin resistance in the muscle, liver, and adipose tissue . The link between hepatocyte apoptosis and insulin resistance was demonstrated in a mouse model . Adipocytes of obese mice were found to display a proapoptotic phenotype, and genetic inactivation of the key proapoptotic protein Bid protected against adipose tissue macrophage infiltration and systemic insulin resistance . Prevention of apoptosis prevents palmitate-induced insulin resistance in hypothalamic neurons . Palmitate induces apoptosis and insulin resistance in skeletal muscle myotubes, and cell-permeable effector caspase inhibitors reverse the insulin resistance, indicating that cellular remodeling associated with apoptotic signaling induces insulin resistance . In these cells, caspases inhibit glycolysis, in particular the glycolysis-limiting enzymes phosphofructokinase and pyruvate kinase [340, 341]. In adipocytes, the proapoptotic caspase-3 and caspase-6, which participate in both intrinsic and extrinsic apoptosis, cleave peroxisome proliferator-activated receptor-γ (PPAR-γ), which results in the nuclear export and cytoplasmic degradation of this transcription factor . Inactivation of PPAR-γ in adipocytes leads to downregulation of some genes that are important for insulin sensitivity not only in adipose tissue but also in other tissues such as those of the skeletal muscle. For example, PPAR-γ inactivation results in decreased expression of GLUT 4 and decreased secretion of adiponectin [343, 344]. Extensive apoptosis of adipocytes, hepatocytes, and skeletal muscle cells is also expected to contribute to systemic hyperglycemia and hyperglycemia-induced stresses that lead to insulin resistance.
4.5. NRLP3 Inflammasome Activation
Interleukin-1β (IL-1β) is an inflammatory cytokine which activates both myeloid and nonmyeloid cells to produce other inflammatory cytokines and chemokines [345, 346]. Processing of the inactive pro-IL-1β into the active IL-1β requires the formation and activation of a cytoplasmic multiprotein complex called the inflammasome [58, 345]. One of the most intensively studied inflammasomes is the NLRP3 inflammasome which is expressed by myeloid cells and some nonmyeloid cells such as adipocytes, hepatocytes, endothelial cells, skeletal muscle cells, and aortic smooth muscle cells [345, 347–350]. Components of the NLRP3 inflammasome include the NLRP3 sensor, ASC adaptor, and caspase-1 . Signaling pathways through NF-κB, p38, and ERK1 are involved in the expression of both NLRP3 and pro-IL-1β [345, 351–353]. Assembly of the NLRP3 components into the active inflammasome complex occurs in response to “danger signals” including increased intracellular ceramide; RAGE- or IREα-dependent increased expression of thioredoxin-binding protein (TXNIP); oxidation of thioredoxin and its dissociation from TXNIP, allowing the latter to bind to the inflammasome; release of lysosomal cathepsin B as a result of LMP; IRE1-α- and PERK-dependent activation of CHOP; and release of oxidized mitochondrial DNA as a result of MOMP [58, 204, 205, 265, 267, 353–359].
IL-1β is a ligand for the IL-1 receptor which, like TLR4, signals via MyD88, IL-1 receptor-activated kinases (IRAK1 to 4), IKK, and NF-κB (Figure 2) [57, 58, 360] and should thus potentiate the whole model for insulin resistance in insulin target cells (Figure 2). It downregulates IRS-1 expression and reduces tyrosine phosphorylation of IRS-1 in adipocytes [58, 361]. Preadipocytes release IL-1β, which both controls adipocyte differentiation and promotes adipocyte insulin resistance even in the absence of macrophages . IL-1β also induces epigenetic changes that promote insulin resistance. For example, it stimulates the expression of DNA methyl transferase 1, which hypermethylates the adiponectin promoter and thereby suppresses the expression of this proinsulin signaling adipokine .
While inflammasome assembly, caspase-1 activation, and IL-1β processing occur and promote insulin resistance in hepatocytes and mature adipocytes, secretion of IL-1β by these cells is controversial [58, 268, 363]. Nevertheless, caspase-1 induces the highly inflammatory pyroptotic death of these cells, and this could contribute to the recruitment and activation of inflammatory myeloid cells such as macrophages that secrete IL-1β [268, 363]. In the skeletal muscle, activation of the inflammasome contributes to muscle atrophy through activation of atrogenic genes such as MuRF1 and atrogin 1 .
NLRP inflammasome activation in endothelial cells leads to increased IL-1β in serum and C-reactive protein (CRP) production by endothelial cells . IL-1β stimulates endothelial cell production of chemokines such as monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) which promote leukocyte-endothelium interactions [349, 364], and this may contribute to the transient migration of neutrophils into adipose tissue that occurs at an early stage of high-fat feeding . This process may be further facilitated by the chemotactic effects of H2O2 and IL-8 produced by adipocytes [30, 366]. Once in adipose tissue, neutrophils may produce large quantities of chemokines and cytokines including IL-1β and IL8, resulting in the recruitment of other immune system cells such as macrophages which sustain chronic inflammation [367, 368].
5. Inhibition of Insulin Signaling through the Dysregulation of Cellular Stress Responses
5.1. Dysregulation of the Heat Shock Response
The heat shock response, which relies on heat shock proteins such as HSP70, is important for physiological resolution of inflammation . Cellular HSP70, HSP72, and HSP25 protect against insulin resistance in humans by mechanisms involving prevention of JNK phosphorylation and apoptosis [51–53]. Obese, insulin-resistant individuals have reduced expression of HSP72 . In adipocytes, downregulation of HSP expression follows sustained NLRP3 inflammasome activation and the associated caspase-1-mediated cleavage of HuR, an mRNA-binding protein that enhances the expression of SIRT1 . This results in reduced SIRT1-dependent upregulation of the transcription and activity of heat shock factor 1 (HSF1), the transcription factor of heat shock proteins .
5.2. Autophagy Dysregulation
(Macro)autophagy is a homoeostatic process for the bulk degradation of cytoplasmic components including damaged organelles, misfolded proteins, and oxidized lipids, whereby such components are enclosed into double-membraned vesicles called autophagosomes that subsequently fuse with lysosomes [54, 370–372]. Autophagy-related proteins (Atg) are involved in autophagosome formation, and these are functionally categorized into several units, namely, the Atg1/ULK complex (mammals express Ulk 1/2), the class III phosphatidyl inositol 3-kinase (PI3K) complex, the Atg2-Atg18/WIPI complex, the Atg12 conjugation system, the Atg8/LC3 conjugation system, and Atg9 vesicles .
Low levels of ROS induce autophagy [373–375], but higher ROS levels inhibit this response . Obesity, which is associated with oxidative stress, is characterized by inhibited autophagy , even in adipose tissue that has elevated expression of autophagy genes . Autophagy inhibition occurs partly due to (i) degradation of autophagy proteins by cell death proteases including calpain 1 and caspases such as caspase-3, caspase-6, and caspase-8 , (ii) LMP and the release of cathepsins [379, 380], (iii) SIRT downregulation [381, 382], (vi) inhibition of PPAR-α , and (vii) increased expression of GSK3β .
Severe hepatic downregulation of the autophagy gene Atg7 was found to occur in genetic and dietary models of obesity, and this caused insulin resistance through enhanced ER stress . Paradoxically, muscle- or liver-specific knockout of the Atg7 gene protected mice from obesity and insulin resistance by upregulating the expression of fibroblast growth factor (FGF21) . FGF21 improves insulin sensitivity by inhibiting mTORC 1 [385, 386], activating NRf2 antioxidant signaling, suppressing the NF-κB pathway, enhancing adiponectin production, and promoting thermogenesis [387–391]. The apparently contradictory effects of obesity-associated downregulation of Atg7 and genetic knockout of Atg7 on hepatocyte insulin resistance [54, 385] may be better understood by considering that Atg7 knockout prevents obesity . In obesity, but not in the lean state, there is resistance to FGF21, because of downregulation of its receptor machinery, including β-klotho protein levels [392–394]. Although klotho is critical for FGF21 function , it was recently reported that factors beyond β-klotho downregulation are important contributors to adipose tissue FGF21 resistance .
5.3. Dysregulation of the Nrf2 Antioxidant Response
The nuclear factor erythroid-2-related factor-2 (Nrf2) is the master regulator of antioxidant responses, attenuating both oxidative and electrophilic stresses [397, 398]. Under basal conditions, Nrf2 localizes on the cytoskeleton, where its activity is limited through interaction with Kelch-like ECH-associated protein 1 (Keap1), which targets it for ubiquitination and proteosomal degradation . Modification of cysteine residues in Keap1 by ROS, RNS, or RCCs frees Nrf2 to translocate to the nucleus and induce transcription of antioxidant genes having the antioxidant response element in the promoter region [397, 400]. Nevertheless, Nrf2 levels were found to be lower in prediabetic and diabetic patients than in healthy subjects , and short-term treatment of high-fat diet-fed mice with curcumin was found to improve insulin sensitivity through attenuating Nrf2 signaling defect .
Suppression of Nrf2 activity may be partly due to the direct interaction of p53 with ARE-containing promoters . ERK activation was reported to induce Nrf2 suppression and insulin resistance in cardiomyocytes exposed to hydrogen peroxide , but an opposite effect of ERK activation was reported in HepG2 cells exposed to methylglyoxal . In neuronal cells exposed to H2O2, GSK3β activation was shown to be responsible for the cytoplasmic accumulation of Nrf2 . This may involve H2O2-mediated activatory phosphorylation of tyrosine 216 of GSK3β, and the latter phosphorylates the tyrosine kinase Fyn, which then translocates to the nucleus, and phosphorylates tyrosine 568 of Nrf2, leading to Nrf2 export from the nucleus .
Nrf2 antioxidant response is also downregulated by cortisol , whose production is increased during psychological stress . Obesity is associated with higher adipose tissue expression of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), an enzyme that converts cortisone to active cortisol [408, 409]. Cortisol is a ligand for the mineralocorticoid receptor, whose expression increases in obesity .
Notably, Nrf2 is Janus-faced, and its overexpression was found to worsen insulin resistance in mice . Nrf2-knockout mice on a long-term high-fat diet had increased FGF21 expression and better insulin sensitivity than wild-type mice on the same diet, and overexpression of Nrf2 in ST-2 cells was found to decrease insulin sensitivity associated with decreased FGF21 mRNA levels and activity . Nrf2 overexpression may occur during autophagy blockade, which is associated with an increase in the cellular levels of p62 [412, 413]. p62 normally participates in autophagosome formation and undergoes lysosomal degradation with the contents of the autophagosome [412, 413]. However, during autophagy blockade, it sequesters Keap1 into autophagosomes, leading to stabilization and overactivation of Nrf2 by the so called noncanonical pathway . Thus, for beneficial effects, the level of Nrf2 activation needs tight regulation.
There is substantial literature in support of the hypothesis that insulin resistance develops from a coordinated interplay between various cellular stresses and stress responses that develop upon the exposure of insulin-responsive cells to hypoxia, excess sugars or certain types of fatty acids, environmental pollutants, or hormones released during psychological stress and obesity. This knowledge will help in the design of better strategies for the prevention and management of insulin resistance.
Conflicts of Interest
The author declares that there are no conflicts of interests regarding the publication of this paper.
- C. M. Kolka and R. N. Bergman, “The endothelium in diabetes: its role in insulin access and diabetic complications,” Reviews in Endocrine and Metabolic Disorders, vol. 14, no. 1, pp. 13–19, 2013.
- K. Siddle, “Signalling by insulin and IGF receptors: supporting acts and new players,” Journal of Molecular Endocrinology, vol. 47, no. 1, pp. R1–R10, 2011.
- G. Dimitriadis, P. Mitrou, V. Lambadiari, E. Maratou, and S. A. Raptis, “Insulin effects in muscle and adipose tissue,” Diabetes Research and Clinical Practice, vol. 93, Supplement 1, pp. S52–S59, 2011.
- L. J. Fick and D. D. Belsham, “Nutrient sensing and insulin signaling in neuropeptide-expressing immortalized, hypothalamic neurons: a cellular model of insulin resistance,” Cell Cycle, vol. 9, no. 16, pp. 3186–3193, 2010.
- L. Plum, B. F. Belgardt, and J. C. Bruning, “Central insulin action in energy and glucose homeostasis,” Journal of Clinical Investigation, vol. 116, no. 7, pp. 1761–1766, 2006.
- A. Kleinridders, H. A. Ferris, W. Cai, and C. R. Kahn, “Insulin action in brain regulates systemic metabolism and brain function,” Diabetes, vol. 63, no. 7, pp. 2232–2243, 2014.
- K. A. Posey, D. J. Clegg, R. L. Printz et al., “Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet,” American Journal of Physiology-Endocrinology and Metabolism, vol. 296, no. 5, pp. E1003–E1012, 2009.
- D. J. Clegg, K. Gotoh, C. Kemp et al., “Consumption of a high-fat diet induces central insulin resistance independent of adiposity,” Physiology & Behavior, vol. 103, no. 1, pp. 10–16, 2011.
- A. C. Könner, R. Janoschek, L. Plum et al., “Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production,” Cell Metabolism, vol. 5, no. 6, pp. 438–449, 2007.
- S. Obici, B. B. Zhang, G. Karkanias, and L. Rossetti, “Hypothalamic insulin signaling is required for inhibition of glucose production,” Nature Medicine, vol. 8, no. 12, pp. 1376–1382, 2002.
- A. Pocai, T. K. T. Lam, R. Gutierrez-Juarez et al., “Hypothalamic KATP channels control hepatic glucose production,” Nature, vol. 434, no. 7036, pp. 1026–1031, 2005.
- E. Blázquez, E. Velázquez, V. Hurtado-Carneiro, and J. M. Ruiz-Albusac, “Insulin in the brain: its pathophysiological implications for states related with central insulin resistance, type 2 diabetes and Alzheimer’s disease,” Frontiers in Endocrinology, vol. 5, p. 161, 2014.
- M. H. Shanik, Y. Xu, J. Skrha, R. Dankner, Y. Zick, and J. Roth, “Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse?” Diabetes Care, vol. 31, Supplement 2, pp. S262–S268, 2008.
- K. R. Watterson, D. Bestow, J. Gallagher et al., “Anorexigenic and orexigenic hormone modulation of mammalian target of rapamycin complex 1 activity and the regulation of hypothalamic agouti-related protein mRNA expression,” Neurosignals, vol. 21, no. 1-2, pp. 28–41, 2013.
- M. Milanski, A. P. Arruda, A. Coope et al., “Inhibition of hypothalamic inflammation reverses diet-induced insulin resistance in the liver,” Diabetes, vol. 61, no. 6, pp. 1455–1462, 2012.
- C.-L. Lin and C.-N. Huang, “The neuroprotective effects of the anti-diabetic drug linagliptin against Aß-induced neurotoxicity,” Neural Regeneration Research, vol. 11, no. 2, pp. 236-237, 2016.
- S. M. de la Monte, “Insulin resistance and neurodegeneration: progress towards the development of new therapeutics for Alzheimer’s disease,” Drugs, vol. 77, no. 1, pp. 47–65, 2017.
- E. Forno, Y.-Y. Han, R. H. Muzumdar, and J. C. Celedón, “Insulin resistance, metabolic syndrome, and lung function in US adolescents with and without asthma,” Journal of Allergy and Clinical Immunology, vol. 136, no. 2, pp. 304–311.e8, 2015.
- Q. Wang, X. L. Cheng, D. Y. Zhang et al., “Tectorigenin attenuates palmitate-induced endothelial insulin resistance via targeting ROS-associated inflammation and IRS-1 pathway,” PLoS One, vol. 8, no. 6, article e66417, 2013.
- D. Gao, S. Nong, X. Huang et al., “The effects of palmitate on hepatic insulin resistance are mediated by NADPH oxidase 3-derived reactive oxygen species through JNK and p38MAPK pathways,” Journal of Biological Chemistry, vol. 285, no. 39, pp. 29965–29973, 2010.
- A. S. P. de Figueiredo, A. B. Salmon, F. Bruno et al., “Nox2 mediates skeletal muscle insulin resistance induced by a high fat diet,” Journal of Biological Chemistry, vol. 290, no. 21, pp. 13427–13439, 2015.
- L. Yuzefovych, G. Wilson, and L. Rachek, “Different effects of oleate vs. palmitate on mitochondrial function, apoptosis, and insulin signaling in L6 skeletal muscle cells: role of oxidative stress,” American Journal of Physiology-Endocrinology and Metabolism, vol. 299, no. 6, pp. E1096–E1105, 2010.
- L. I. Rachek, S. I. Musiyenko, S. P. LeDoux, and G. L. Wilson, “Palmitate induced mitochondrial deoxyribonucleic acid damage and apoptosis in l6 rat skeletal muscle cells,” Endocrinology, vol. 148, no. 1, pp. 293–299, 2007.
- F. Renström, J. Burén, M. Svensson, and J. W. Eriksson, “Insulin resistance induced by high glucose and high insulin precedes insulin receptor substrate 1 protein depletion in human adipocytes,” Metabolism, vol. 56, no. 2, pp. 190–198, 2007.
- N. Jaiswal, C. K. Maurya, J. Pandey, A. K. Rai, and A. K. Tamrakar, “Fructose-induced ROS generation impairs glucose utilization in L6 skeletal muscle cells,” Free Radical Research, vol. 49, no. 9, pp. 1055–1068, 2015.
- B. Kwon and H. W. Querfurth, “Opposite effects of saturated and unsaturated free fatty acids on intracellular signaling and metabolism in neuronal cells,” Inflammation and Cell Signaling, vol. 1, no. 2, 2014.
- J. C. Moraes, A. Coope, J. Morari et al., “High-fat diet induces apoptosis of hypothalamic neurons,” PLoS One, vol. 4, no. 4, article e5045, 2009.
- J. J. Kim and D. D. Sears, “TLR4 and insulin resistance,” Gastroenterology Research and Practice, vol. 2010, Article ID 212563, 11 pages, 2010.
- L. A. Velloso, F. Folli, and M. J. Saad, “TLR4 at the crossroads of nutrients, gut microbiota, and metabolic inflammation,” Endocrine Reviews, vol. 36, no. 3, pp. 245–271, 2015.
- A. N. Onyango, “The contribution of singlet oxygen to insulin resistance,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 8765972, 14 pages, 2017.
- T. Nakashima, S. Umemoto, K. Yoshimura et al., “TLR4 is a critical regulator of angiotensin II-induced vascular remodeling: the roles of extracellular SOD and NADPH oxidase,” Hypertension Research, vol. 38, no. 10, pp. 649–655, 2015.
- M. Sakaguchi, H. Murata, K. Yamamoto et al., “TIRAP, an adaptor protein for TLR2/4, transduces a signal from RAGE phosphorylated upon ligand binding,” PLoS One, vol. 6, no. 8, article e23132, 2011.
- K. H. J. Gaens, G. H. Goossens, P. M. Niessen et al., “Nε-(carboxymethyl)lysine-receptor for advanced glycation end product axis is a key modulator of obesity-induced dysregulation of adipokine expression and insulin resistance,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 34, no. 6, pp. 1199–1208, 2014.
- W. Cai, X.-M. Duan, Y. Liu et al., “Uric acid induces endothelial dysfunction by activating the HMGB1/RAGE signaling pathway,” BioMed Research International, vol. 2017, Article ID 4391920, 11 pages, 2017.
- B. Scazzocchio, R. Varì, M. D'Archivio et al., “Oxidized LDL impair adipocyte response to insulin by activating serine/threonine kinases,” Journal of Lipid Research, vol. 50, no. 5, pp. 832–845, 2009.
- N. Clavreul, M. M. Bachschmid, X. Hou et al., “S-Glutathiolation of p21ras by peroxynitrite mediates endothelial insulin resistance caused by oxidized low-density lipoprotein,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 26, no. 11, pp. 2454–2461, 2006.
- S. Pereira, E. Park, Y. Mori et al., “FFA-induced hepatic insulin resistance in vivo is mediated by PKCδ, NADPH oxidase, and oxidative stress,” American Journal of Physiology-Endocrinology and Metabolism, vol. 307, no. 1, pp. E34–E46, 2014.
- P. Sukumar, H. Viswambharan, H. Imrie et al., “Nox2 NADPH oxidase has a critical role in insulin resistance–related endothelial cell dysfunction,” Diabetes, vol. 62, no. 6, pp. 2130–2134, 2013.
- L. J. den Hartigh, M. Omer, L. Goodspeed et al., “Adipocyte-specific deficiency of NADPH oxidase 4 delays the onset of insulin resistance and attenuates adipose tissue inflammation in obesity,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 37, no. 3, pp. 466–475, 2017.
- E. J. Anderson, M. E. Lustig, K. E. Boyle et al., “Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans,” The Journal of Clinical Investigation, vol. 119, no. 3, pp. 573–581, 2009.
- H.-N. Cha, S. E. Song, Y.-W. Kim, J.-Y. Kim, K.-C. Won, and S.-Y. Park, “Lack of inducible nitric oxide synthase prevents lipid-induced skeletal muscle insulin resistance without attenuating cytokine level,” Journal of Pharmacological Sciences, vol. 117, no. 2, pp. 77–86, 2011.
- A. Charbonneau and A. Marette, “Inducible nitric oxide synthase induction underlies lipid-induced hepatic insulin resistance in mice: potential role of tyrosine nitration of insulin signaling proteins,” Diabetes, vol. 59, no. 4, pp. 861–871, 2010.
- T. M. Zanotto, P. G. F. Quaresma, D. Guadagnini et al., “Blocking iNOS and endoplasmic reticulum stress synergistically improves insulin resistance in mice,” Molecular Metabolism, vol. 6, no. 2, pp. 206–218, 2017.
- D. M. Erion and G. I. Shulman, “Diacylglycerol-mediated insulin resistance,” Nature Medicine, vol. 16, no. 4, pp. 400–402, 2010.
- M. Campana, L. Bellini, C. Rouch et al., “Inhibition of central de novo ceramide synthesis restores insulin signaling in hypothalamus and enhances β-cell function of obese Zucker rats,” Molecular Metabolism, vol. 8, pp. 23–36, 2018.
- J. A. Chavez and S. A. Summers, “A ceramide-centric view of insulin resistance,” Cell Metabolism, vol. 15, no. 5, pp. 585–594, 2012.
- S. Turban and E. Hajduch, “Protein kinase C isoforms: mediators of reactive lipid metabolites in the development of insulin resistance,” FEBS Letters, vol. 585, no. 2, pp. 269–274, 2011.
- E. Panzhinskiy, J. Ren, and S. Nair, “Protein tyrosine phosphatase 1B and insulin resistance: role of endoplasmic reticulum stress/reactive oxygen species/nuclear factor kappa B axis,” PLoS One, vol. 8, no. 10, article e77228, 2013.
- W. Zhang, V. Hietakangas, S. Wee, S. C. Lim, J. Gunaratne, and S. M. Cohen, “ER stress potentiates insulin resistance through PERK-mediated FOXO phosphorylation,” Genes & Development, vol. 27, no. 4, pp. 441–449, 2013.
- B. Diaz, L. Fuentes-Mera, A. Tovar et al., “Saturated lipids decrease mitofusin 2 leading to endoplasmic reticulum stress activation and insulin resistance in hypothalamic cells,” Brain Research, vol. 1627, pp. 80–89, 2015.
- J. Chung, A. K. Nguyen, D. C. Henstridge et al., “HSP72 protects against obesity-induced insulin resistance,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 5, pp. 1739–1744, 2008.
- P. C. Geiger and A. A. Gupte, “Heat shock proteins are important mediators of skeletal muscle insulin sensitivity,” Exercise and Sport Sciences Reviews, vol. 39, no. 1, pp. 34–42, 2011.
- L. Chichester, A. T. Wylie, S. Craft, and K. Kavanagh, “Muscle heat shock protein 70 predicts insulin resistance with aging,” The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, vol. 70, no. 2, pp. 155–162, 2015.
- L. Yang, P. Li, S. Fu, E. S. Calay, and G. S. Hotamisligil, “Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance,” Cell Metabolism, vol. 11, no. 6, pp. 467–478, 2010.
- N. Alkhouri, A. Gornicka, M. P. Berk et al., “Adipocyte apoptosis, a link between obesity, insulin resistance, and hepatic steatosis,” Journal of Biological Chemistry, vol. 285, no. 5, pp. 3428–3438, 2010.
- Z. Derdak, C. H. Lang, K. A. Villegas et al., “Activation of p53 enhances apoptosis and insulin resistance in a rat model of alcoholic liver disease,” Journal of Hepatology, vol. 54, no. 1, pp. 164–172, 2011.
- O. Nov, A. Kohl, E. C. Lewis et al., “Interleukin-1β may mediate insulin resistance in liver-derived cells in response to adipocyte inflammation,” Endocrinology, vol. 151, no. 9, pp. 4247–4256, 2010.
- R. Stienstra, C. J. Tack, T.-D. Kanneganti, L. A. B. Joosten, and M. G. Netea, “The inflammasome puts obesity in the danger zone,” Cell Metabolism, vol. 15, no. 1, pp. 10–18, 2012.
- V. T. Samuel and G. I. Shulman, “Mechanisms for insulin resistance: common threads and missing links,” Cell, vol. 148, no. 5, pp. 852–871, 2012.
- S. Pendyala, J. M. Walker, and P. R. Holt, “A high-fat diet is associated with endotoxemia that originates from the gut,” Gastroenterology, vol. 142, no. 5, pp. 1100–1101.e2, 2012.
- B. di Luccia, R. Crescenzo, A. Mazzoli et al., “Rescue of fructose-induced metabolic syndrome by antibiotics or faecal transplantation in a rat model of obesity,” PLoS One, vol. 10, no. 8, article e0134893, 2015.
- L. Jia, C. R. Vianna, M. Fukuda et al., “Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance,” Nature Communications, vol. 5, p. 3778, 2014.
- R. Rorato, B. d. C. Borges, E. T. Uchoa, J. Antunes-Rodrigues, C. F. Elias, and L. L. K. Elias, “LPS-induced low-grade inflammation increases hypothalamic JNK expression and causes central insulin resistance irrespective of body weight changes,” International Journal of Molecular Sciences, vol. 18, no. 12, p. 1431, 2017.
- D. J. Loegering and M. R. Lennartz, “Protein kinase C and toll-like receptor signaling,” Enzyme Research, vol. 2011, Article ID 537821, 7 pages, 2011.
- J. Zhang, W. Wu, D. Li, Y. Guo, and H. Ding, “Overactivation of NF-κB impairs insulin sensitivity and mediates palmitate-induced insulin resistance in C2C12 skeletal muscle cells,” Endocrine, vol. 37, no. 1, pp. 157–166, 2010.
- I.-C. Yu, H.-Y. Lin, N.-C. Liu et al., “Neuronal androgen receptor regulates insulin sensitivity via suppression of hypothalamic NF-κB–mediated PTP1B expression,” Diabetes, vol. 62, no. 2, pp. 411–423, 2013.
- L. Chen, R. Chen, H. Wang, and F. Liang, “Mechanisms linking inflammation to insulin resistance,” International Journal of Endocrinology, vol. 2015, Article ID 508409, 9 pages, 2015.
- T. Kawasaki and T. Kawai, “Toll-like receptor signaling pathways,” Frontiers in Immunology, vol. 5, p. 461, 2014.
- M. J. Morgan and Z. Liu, “Crosstalk of reactive oxygen species and NF-κB signaling,” Cell Research, vol. 21, no. 1, pp. 103–115, 2011.
- R. Radi, “Protein tyrosine nitration: biochemical mechanisms and structural basis of functional effects,” Accounts of Chemical Research, vol. 46, no. 2, pp. 550–559, 2013.
- P. di Mascio, E. J. H. Bechara, M. H. G. Medeiros, K. Briviba, and H. Sies, “Singlet molecular oxygen production in the reaction of peroxynitrite with hydrogen peroxide,” FEBS Letters, vol. 355, no. 3, pp. 287–289, 1994.
- J. Lugrin, N. Rosenblatt-Velin, R. Parapanov, and L. Liaudet, “The role of oxidative stress during inflammatory processes,” Biological Chemistry, vol. 395, no. 2, pp. 203–230, 2014.
- A. Elgawish, M. Glomb, M. Friedlander, and V. M. Monnier, “Involvement of hydrogen peroxide in collagen cross-linking by high glucose in vitro and in vivo,” Journal of Biological Chemistry, vol. 271, no. 22, pp. 12964–12971, 1996.
- A. N. Onyango, “Endogenous generation of singlet oxygen and ozone in human and animal tissues: mechanisms, biological significance, and influence of dietary components,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 2398573, 22 pages, 2016.
- M. Aragno and R. Mastrocola, “Dietary sugars and endogenous formation of advanced glycation endproducts: emerging mechanisms of disease,” Nutrients, vol. 9, no. 12, p. 385, 2017.
- C. O. Silva, O. A. da Silva, G. P. Duarte, B. Descomps, and S. La, “Apocynin decreases AGEs-induced stimulation of NF-κB protein expression in vascular smooth muscle cells from GK rats,” Pharmaceutical Biology, vol. 53, no. 4, pp. 488–493, 2015.
- J. W. Eriksson, “Metabolic stress in insulin’s target cells leads to ROS accumulation – a hypothetical common pathway causing insulin resistance,” FEBS Letters, vol. 581, no. 19, pp. 3734–3742, 2007.
- E. Salaun, L. Lefeuvre-Orfila, T. Cavey et al., “Myriocin prevents muscle ceramide accumulation but not muscle fiber atrophy during short-term mechanical unloading,” Journal of Applied Physiology, vol. 120, no. 2, pp. 178–187, 2016.
- C. Y. Han, A. Y. Kargi, M. Omer et al., “Differential effect of saturated and unsaturated free fatty acids on the generation of monocyte adhesion and chemotactic factors by adipocytes: dissociation of adipocyte hypertrophy from inflammation,” Diabetes, vol. 59, no. 2, pp. 386–396, 2010.
- T. Inoguchi, P. Li, F. Umeda et al., “High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD(P)H oxidase in cultured vascular cells,” Diabetes, vol. 49, no. 11, pp. 1939–1945, 2000.
- W. L. Holland, B. T. Bikman, L.-P. Wang et al., “Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid–induced ceramide biosynthesis in mice,” The Journal of Clinical Investigation, vol. 121, no. 5, pp. 1858–1870, 2011.
- P. Barma, S. Bhattacharya, A. Bhattacharya et al., “Lipid induced overexpression of NF-κB in skeletal muscle cells is linked to insulin resistance,” Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, vol. 1792, no. 3, pp. 190–200, 2009.
- L. C. Joseph, E. Barca, P. Subramanyam et al., “Inhibition of NAPDH oxidase 2 (NOX2) prevents oxidative stress and mitochondrial abnormalities caused by saturated fat in cardiomyocytes,” PLoS One, vol. 11, no. 1, article e0145750, 2016.
- T. Galbo, R. J. Perry, M. J. Jurczak et al., “Saturated and unsaturated fat induce hepatic insulin resistance independently of TLR-4 signaling and ceramide synthesis in vivo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 31, pp. 12780–12785, 2013.
- D. Cosentino-Gomes, N. Rocco-Machado, and J. R. Meyer-Fernandes, “Cell signaling through protein kinase C oxidation and activation,” International Journal of Molecular Sciences, vol. 13, no. 12, pp. 10697–10721, 2012.
- M. Maceyka and S. Spiegel, “Sphingolipid metabolites in inflammatory disease,” Nature, vol. 510, no. 7503, pp. 58–67, 2014.
- D. J. Powell, S. Turban, A. Gray, E. Hajduch, and H. S. Hundal, “Intracellular ceramide synthesis and protein kinase Cζ activation play an essential role in palmitate-induced insulin resistance in rat L6 skeletal muscle cells,” Biochemical Journal, vol. 382, no. 2, pp. 619–629, 2004.
- R. Hage Hassan, A. C. Pacheco de Sousa, R. Mahfouz et al., “Sustained action of ceramide on the insulin signaling pathway in muscle cells: implication of the double-stranded RNA-activated protein kinase,” Journal of Biological Chemistry, vol. 291, no. 6, pp. 3019–3029, 2016.
- C. García-Ruiz, A. Colell, M. Marí, A. Morales, and J. C. Fernández-Checa, “Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species,” Journal of Biological Chemistry, vol. 272, no. 17, pp. 11369–11377, 1997.
- E. P. Taddeo, R. C. Laker, D. S. Breen et al., “Opening of the mitochondrial permeability transition pore links mitochondrial dysfunction to insulin resistance in skeletal muscle,” Molecular Metabolism, vol. 3, no. 2, pp. 124–134, 2014.
- T. Matsunaga, S. Kotamraju, S. V. Kalivendi, A. Dhanasekaran, J. Joseph, and B. Kalyanaraman, “Ceramide-induced intracellular oxidant formation, iron signaling, and apoptosis in endothelial cells: protective role of endogenous nitric oxide,” Journal of Biological Chemistry, vol. 279, no. 27, pp. 28614–28624, 2004.
- J. D. Symons and E. D. Abel, “Lipotoxicity contributes to endothelial dysfunction: a focus on the contribution from ceramide,” Reviews in Endocrine and Metabolic Disorders, vol. 14, no. 1, pp. 59–68, 2013.
- S. P. Didion and F. M. Faraci, “Ceramide-induced impairment of endothelial function is prevented by CuZn superoxide dismutase overexpression,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, pp. 90–95, 2004.
- M. E. Smith, T. S. Tippetts, E. S. Brassfield et al., “Mitochondrial fission mediates ceramide-induced metabolic disruption in skeletal muscle,” Biochemical Journal, vol. 456, no. 3, pp. 427–439, 2013.
- H. F. Jheng, P. J. Tsai, S. M. Guo et al., “Mitochondrial fission contributes to mitochondrial dysfunction and insulin resistance in skeletal muscle,” Molecular and Cellular Biology, vol. 32, no. 2, pp. 309–319, 2012.
- H. Yuan, A. A. Gerencser, G. Liot et al., “Mitochondrial fission is an upstream and required event for bax foci formation in response to nitric oxide in cortical neurons,” Cell Death & Differentiation, vol. 14, no. 3, pp. 462–471, 2007.
- G. Zhao, K. Cao, C. Xu et al., “Crosstalk between mitochondrial fission and oxidative stress in paraquat-induced apoptosis in mouse alveolar type II cells,” International Journal of Biological Sciences, vol. 13, no. 7, pp. 888–900, 2017.
- R. Schüler, M. A. Osterhoff, T. Frahnow et al., “High‐saturated‐fat diet increases circulating angiotensin‐converting enzyme, which is enhanced by the rs4343 polymorphism defining persons at risk of nutrient‐dependent increases of blood pressure,” Journal of the American Heart Association, vol. 6, no. 1, article e004465, 2017.
- C. Cabello-Verrugio, M. G. Morales, J. C. Rivera, D. Cabrera, and F. Simon, “Renin-angiotensin system: an old player with novel functions in skeletal muscle,” Medicinal Research Reviews, vol. 35, no. 3, pp. 437–463, 2015.
- M. Ruiz-Ortega, O. Lorenzo, M. Ruperez, S. Konig, B. Wittig, and J. Egido, “Angiotensin II activates nuclear transcription factor κB through AT1 and AT2 in vascular smooth muscle cells: molecular mechanisms,” Circulation Research, vol. 86, no. 12, pp. 1266–1272, 2000.
- Y. Ji, J. Liu, Z. Wang, and N. Liu, “Angiotensin II induces inflammatory response partly via toll-like receptor 4-dependent signaling pathway in vascular smooth muscle cells,” Cellular Physiology and Biochemistry, vol. 23, no. 4-6, pp. 265–276, 2009.
- M.-S. Zhou, C. Liu, R. Tian, A. Nishiyama, and L. Raij, “Skeletal muscle insulin resistance in salt-sensitive hypertension: role of angiotensin II activation of NFκB,” Cardiovascular Diabetology, vol. 14, no. 1, p. 45, 2015.
- M. Mitsuishi, K. Miyashita, A. Muraki, and H. Itoh, “Angiotensin II reduces mitochondrial content in skeletal muscle and affects glycemic control,” Diabetes, vol. 58, no. 3, pp. 710–717, 2009.
- Y. Chen, J.-R. Lin, and P.-J. Gao, “Mitochondrial division inhibitor Mdivi-1 ameliorates angiotensin II-induced endothelial dysfunction,” Acta Physiologica Sinica, vol. 68, no. 5, pp. 669–676, 2016.
- U. Landmesser, S. Spiekermann, C. Preuss et al., “Angiotensin II induces endothelial xanthine oxidase activation: role for endothelial dysfunction in patients with coronary disease,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 27, no. 4, pp. 943–948, 2007.
- C. Vonach, K. Viola, B. Giessrigl et al., “NF-κB mediates the 12(S)-HETE-induced endothelial to mesenchymal transition of lymphendothelial cells during the intravasation of breast carcinoma cells,” British Journal of Cancer, vol. 105, no. 2, pp. 263–271, 2011.
- J. L. Nadler, R. Natarajan, and N. Stern, “Specific action of the lipoxygenase pathway in mediating angiotensin II-induced aldosterone synthesis in isolated adrenal glomerulosa cells,” The Journal of Clinical Investigation, vol. 80, no. 6, pp. 1763–1769, 1987.
- T. Bruder-Nascimento, M. A. B. da Silva, and R. C. Tostes, “The involvement of aldosterone on vascular insulin resistance: implications in obesity and type 2 diabetes,” Diabetology & Metabolic Syndrome, vol. 6, no. 1, p. 90, 2014.
- L. D. Kubzansky and G. K. Adler, “Aldosterone: a forgotten mediator of the relationship between psychological stress and heart disease,” Neuroscience & Biobehavioral Reviews, vol. 34, no. 1, pp. 80–86, 2010.
- F. Iwashima, T. Yoshimoto, I. Minami, M. Sakurada, Y. Hirono, and Y. Hirata, “Aldosterone induces superoxide generation via Rac1 activation in endothelial cells,” Endocrinology, vol. 149, no. 3, pp. 1009–1014, 2008.
- Y. Zhang, Y. Pan, Z. Bian et al., “Ceramide production mediates aldosterone-induced human umbilical vein endothelial cell (HUVEC) damages,” PLoS One, vol. 11, no. 1, article e0146944, 2016.
- Z.-H. Zhang, Y. Yu, Y.-M. Kang, S.-G. Wei, and R. B. Felder, “Aldosterone acts centrally to increase brain renin-angiotensin system activity and oxidative stress in normal rats,” American Journal of Physiology-Heart and Circulatory Physiology, vol. 294, no. 2, pp. H1067–H1074, 2008.
- B. S. Huang, H. Zheng, J. Tan, K. P. Patel, and F. H. H. Leenen, “Regulation of hypothalamic renin-angiotensin system and oxidative stress by aldosterone,” Experimental Physiology, vol. 96, no. 10, pp. 1028–1038, 2011.
- L. Wang, G. Muxin, H. Nishida, C. Shirakawa, S. Sato, and T. Konishi, “Psychological stress-induced oxidative stress as a model of sub-healthy condition and the effect of TCM,” Evidence-Based Complementary and Alternative Medicine, vol. 4, no. 2, 202 pages, 2007.
- L. Li, X. Li, W. Zhou, and J. L. Messina, “Acute psychological stress results in the rapid development of insulin resistance,” Journal of Endocrinology, vol. 217, no. 2, pp. 175–184, 2013.
- K. Aschbacher, A. O’Donovan, O. M. Wolkowitz, F. S. Dhabhar, Y. Su, and E. Epel, “Good stress, bad stress and oxidative stress: insights from anticipatory cortisol reactivity,” Psychoneuroendocrinology, vol. 38, no. 9, pp. 1698–1708, 2013.
- M. Hayashi, K. Takeshita, Y. Uchida et al., “Angiotensin II receptor blocker ameliorates stress-induced adipose tissue inflammation and insulin resistance,” PLoS One, vol. 9, no. 12, article e116163, 2014.
- K. M. M. Hasan, M. S. Rahman, K. M. T. Arif, and M. E. Sobhani, “Psychological stress and aging: role of glucocorticoids (GCs),” Age, vol. 34, no. 6, pp. 1421–1433, 2012.
- A. Zafir and N. Banu, “Modulation of in vivo oxidative status by exogenous corticosterone and restraint stress in rats,” Stress, vol. 12, no. 2, pp. 167–177, 2009.
- A. Joergensen, K. Broedbaek, A. Weimann et al., “Association between urinary excretion of cortisol and markers of oxidatively damaged DNA and RNA in humans,” PLoS One, vol. 6, no. 6, article e20795, 2011.
- W. L. Holland, J. T. Brozinick, L.-P. Wang et al., “Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance,” Cell Metabolism, vol. 5, no. 3, pp. 167–179, 2007.
- T.-C. Chen, D. I. Benjamin, T. Kuo et al., “The glucocorticoid-Angptl4-ceramide axis induces insulin resistance through PP2A and PKCζ,” Science Signaling, vol. 10, no. 489, article eaai7905, 2017.
- A. Hirata, N. Maeda, H. Nakatsuji et al., “Contribution of glucocorticoid–mineralocorticoid receptor pathway on the obesity-related adipocyte dysfunction,” Biochemical and Biophysical Research Communications, vol. 419, no. 2, pp. 182–187, 2012.
- K. de Punder and L. Pruimboom, “Stress induces endotoxemia and low-grade inflammation by increasing barrier permeability,” Frontiers in Immunology, vol. 6, p. 223, 2015.
- A. A. Teitelbaum, M. G. Gareau, J. Jury, P. C. Yang, and M. H. Perdue, “Chronic peripheral administration of corticotropin-releasing factor causes colonic barrier dysfunction similar to psychological stress,” American Journal of Physiology-Gastrointestinal and Liver Physiology, vol. 295, no. 3, pp. G452–G459, 2008.
- G. Zheng, G. Victor Fon, W. Meixner et al., “Chronic stress and intestinal barrier dysfunction: glucocorticoid receptor and transcription repressor HES1 regulate tight junction protein claudin-1 promoter,” Scientific Reports, vol. 7, no. 1, p. 4502, 2017.
- S. Ranabir and K. Reetu, “Stress and hormones,” Indian Journal of Endocrinology and Metabolism, vol. 15, no. 1, pp. 18–22, 2011.
- S. Mangmool, T. Denkaew, W. Parichatikanond, and H. Kurose, “β-Adrenergic receptor and insulin resistance in the heart,” Biomolecules & Therapeutics, vol. 25, no. 1, pp. 44–56, 2017.
- Y.-C. Fu, S.-C. Yin, C.-S. Chi, B. Hwang, and S.-L. Hsu, “Norepinephrine induces apoptosis in neonatal rat endothelial cells via a ROS-dependent JNK activation pathway,” Apoptosis, vol. 11, no. 11, pp. 2053–2063, 2006.
- T. Theccanat, J. L. Philip, A. M. Razzaque et al., “Regulation of cellular oxidative stress and apoptosis by G protein-coupled receptor kinase-2; the role of NADPH oxidase 4,” Cellular Signalling, vol. 28, no. 3, pp. 190–203, 2016.
- D. C. Andersson, J. Fauconnier, T. Yamada et al., “Mitochondrial production of reactive oxygen species contributes to the β-adrenergic stimulation of mouse cardiomycytes,” The Journal of Physiology, vol. 589, no. 7, pp. 1791–1801, 2011.
- Q. Xu, A. Dalic, L. Fang et al., “Myocardial oxidative stress contributes to transgenic β2-adrenoceptor activation-induced cardiomyopathy and heart failure,” British Journal of Pharmacology, vol. 162, no. 5, pp. 1012–1028, 2011.
- E. P. Mottillo, X. J. Shen, and J. G. Granneman, “β3-adrenergic receptor induction of adipocyte inflammation requires lipolytic activation of stress kinases p38 and JNK,” Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, vol. 1801, no. 9, pp. 1048–1055, 2010.
- M. Fasshauer, J. Klein, S. Neumann, M. Eszlinger, and R. Paschke, “Adiponectin gene expression is inhibited by β-adrenergic stimulation via protein kinase A in 3T3-L1 adipocytes,” FEBS Letters, vol. 507, no. 2, pp. 142–146, 2001.
- W. L. Holland, J. Y. Xia, J. A. Johnson et al., “Inducible overexpression of adiponectin receptors highlight the roles of adiponectin-induced ceramidase signaling in lipid and glucose homeostasis,” Molecular Metabolism, vol. 6, no. 3, pp. 267–275, 2017.
- M. Siervo, H. L. Riley, B. O. Fernandez et al., “Effects of prolonged exposure to hypobaric hypoxia on oxidative stress, inflammation and gluco-insular regulation: the not-so-sweet price for good regulation,” PLoS One, vol. 9, no. 4, article e94915, 2014.
- L. Lavie, “Oxidative stress—a unifying paradigm in obstructive sleep apnea and comorbidities,” Progress in Cardiovascular Diseases, vol. 51, no. 4, pp. 303–312, 2009.
- G. S. Hamilton and S. A. Joosten, “Obstructive sleep apnoea and obesity,” Australian Family Physician, vol. 46, no. 7, pp. 460–463, 2017.
- R.-B. Guo, P. L. Sun, A. P. Zhao et al., “Chronic asthma results in cognitive dysfunction in immature mice,” Experimental Neurology, vol. 247, pp. 209–217, 2013.
- M. Arshi, J. Cardinal, R. J. Hill, P. S. W. Davies, and C. Wainwright, “Asthma and insulin resistance in children,” Respirology, vol. 15, no. 5, pp. 779–784, 2010.
- L. Cottrell, W. A. Neal, C. Ice, M. K. Perez, and G. Piedimonte, “Metabolic abnormalities in children with asthma,” American Journal of Respiratory and Critical Care Medicine, vol. 183, no. 4, pp. 441–448, 2011.
- P. Hernansanz-Agustín, E. Ramos, E. Navarro et al., “Mitochondrial complex I deactivation is related to superoxide production in acute hypoxia,” Redox Biology, vol. 12, pp. 1040–1051, 2017.
- N. S. Chandel, D. S. McClintock, C. E. Feliciano et al., “Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1α during hypoxia,” Journal of Biological Chemistry, vol. 275, no. 33, pp. 25130–25138, 2000.
- X. Tang, D. Guo, C. Lin et al., “hCLOCK causes Rho-kinase-mediated endothelial dysfunction and NF-κB-mediated inflammatory responses,” Oxidative Medicine and Cellular Longevity, vol. 2015, Article ID 671839, 9 pages, 2015.
- L. Song, H. Yang, H. X. Wang et al., “Inhibition of 12/15 lipoxygenase by baicalein reduces myocardial ischemia/reperfusion injury via modulation of multiple signaling pathways,” Apoptosis, vol. 19, no. 4, pp. 567–580, 2014.
- R. Choudhary, U. Malairaman, and A. Katyal, “Inhibition of 12/15 LOX ameliorates cognitive and cholinergic dysfunction in mouse model of hypobaric hypoxia via. attenuation of oxidative/nitrosative stress,” Neuroscience, vol. 359, pp. 308–324, 2017.
- S. Pallast, K. Arai, X. Wang, E. H. Lo, and K. van Leyen, “12/15-Lipoxygenase targets neuronal mitochondria under oxidative stress,” Journal of Neurochemistry, vol. 111, no. 3, pp. 882–889, 2009.
- D. D. Sears, P. D. Miles, J. Chapman et al., “12/15-Lipoxygenase is required for the early onset of high fat diet-induced adipose tissue inflammation and insulin resistance in mice,” PLoS One, vol. 4, no. 9, article e7250, 2009.
- R. Natarajan, M. A. Reddy, K. U. Malik, S. Fatima, and B. V. Khan, “Signaling mechanisms of nuclear factor-κB-mediated activation of inflammatory genes by 13-hydroperoxyoctadecadienoic acid in cultured vascular smooth muscle cells,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 21, no. 9, pp. 1408–1413, 2001.
- A. S. Whitehouse, J. Khal, and M. J. Tisdale, “Induction of protein catabolism in myotubes by 15(S)-hydroxyeicosatetraenoic acid through increased expression of the ubiquitin–proteasome pathway,” British Journal of Cancer, vol. 89, no. 4, pp. 737–745, 2003.
- J. Li, J. Rao, Y. Liu et al., “15-Lipoxygenase promotes chronic hypoxia–induced pulmonary artery inflammation via positive interaction with nuclear factor-κB,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 33, no. 5, pp. 971–979, 2013.
- L. Guo, X. Tang, X. Chu et al., “Role of protein kinase C in 15-HETE-induced hypoxic pulmonary vasoconstriction,” Prostaglandins, Leukotrienes and Essential Fatty Acids, vol. 80, no. 2-3, pp. 115–123, 2009.
- D. G. Tang, C. A. Diglio, and K. V. Honn, “12(S)-HETE-induced microvascular endothelial cell retraction results from PKC-dependent rearrangement of cytoskeletal elements and αVβ3 integrins,” Prostaglandins, vol. 45, no. 3, pp. 249–267, 1993.
- R. Chattopadhyay, A. Tinnikov, E. Dyukova et al., “12/15-Lipoxygenase-dependent ROS production is required for diet-induced endothelial barrier dysfunction,” Journal of Lipid Research, vol. 56, no. 3, pp. 562–577, 2015.
- L. S. Terada, D. M. Guidot, J. A. Leff et al., “Hypoxia injures endothelial cells by increasing endogenous xanthine oxidase activity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 8, pp. 3362–3366, 1992.
- S. Sinha, S. N. Singh, and U. S. Ray, “Total antioxidant status at high altitude in lowlanders and native highlanders: role of uric acid,” High Altitude Medicine & Biology, vol. 10, no. 3, pp. 269–274, 2009.
- J. Nanduri, D. R. Vaddi, S. A. Khan et al., “HIF-1α activation by intermittent hypoxia requires NADPH oxidase stimulation by xanthine oxidase,” PLoS One, vol. 10, no. 3, article e0119762, 2015.
- G. K. Kumar, V. Rai, S. D. Sharma et al., “Chronic intermittent hypoxia induces hypoxia-evoked catecholamine efflux in adult rat adrenal medulla via oxidative stress,” Journal of Physiology, vol. 575, no. 1, pp. 229–239, 2006.
- F. Zhang, W. Wu, Z. Deng et al., “High altitude increases the expression of hypoxia-inducible factor 1α and inducible nitric oxide synthase with intest-inal mucosal barrier failure in rats,” Interantional Journal of Clinical and Experimental Pathology, vol. 8, pp. 5189–5195, 2015.
- S. L. Gaffin, J. Brock-Utne, A. Zanotti, and M. T. Wells, “Hypoxia-induced endotoxemia in primates: role of reticuloendothelial system function and anti-lipopolysaccharide plasma,” Aviation, Space, and Environmental Medicine, vol. 57, pp. 1044–1049, 1986.
- R. Šket, N. Treichel, T. Debevec et al., “Hypoxia and inactivity related physiological changes (constipation, inflammation) are not reflected at the level of gut metabolites and butyrate producing microbial community: the PlanHab study,” Frontiers in Physiology, vol. 8, p. 250, 2017.
- E. Thiering, J. Cyrys, J. Kratzsch et al., “Long-term exposure to traffic-related air pollution and insulin resistance in children: results from the GINIplus and LISAplus birth cohorts,” Diabetologia, vol. 56, no. 8, pp. 1696–1704, 2013.
- M. Lodovici and E. Bigagli, “Oxidative stress and air pollution exposure,” Journal of Toxicology, vol. 2011, Article ID 487074, 9 pages, 2011.
- G. Pizzino, N. Irrera, A. Bitto et al., “Cadmium-induced oxidative stress impairs glycemic control in adolescents,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 6341671, 6 pages, 2017.
- A. N. Onyango, “Small reactive carbonyl compounds as tissue lipid oxidation products; and the mechanisms of their formation thereby,” Chemistry and Physics of Lipids, vol. 165, no. 7, pp. 777–786, 2012.
- K. V. Ramana, A. Bhatnagar, S. Srivastava et al., “Mitogenic responses of vascular smooth muscle cells to lipid peroxidation-derived aldehyde 4-hydroxy-trans-2-nonenal (HNE): role of aldose reductase-catalyzed reduction of the HNE-glutathione conjugates in regulating cell growth,” Journal of Biological Chemistry, vol. 281, no. 26, pp. 17652–17660, 2006.
- P. Wentworth Jr., J. Nieva, C. Takeuchi et al., “Evidence for ozone formation in human atherosclerotic arteries,” Science, vol. 302, no. 5647, pp. 1053–1056, 2003.
- L. Laynes, A. C. Raghavamenon, O. D’Auvergne, V. Achuthan, and R. M. Uppu, “MAPK signaling in H9c2 cardiomyoblasts exposed to cholesterol secoaldehyde – role of hydrogen peroxide,” Biochemical and Biophysical Research Communications, vol. 404, no. 1, pp. 90–95, 2011.
- I. Braakman and D. N. Hebert, “Protein folding in the endoplasmic reticulum,” Cold Spring Harbor Perspectives in Biology, vol. 5, no. 5, article a013201, 2013.
- T. Adachi, R. M. Weisbrod, D. R. Pimentel et al., “S-Glutathiolation by peroxynitrite activates SERCA during arterial relaxation by nitric oxide,” Nature Medicine, vol. 10, no. 11, pp. 1200–1207, 2004.
- A. Pastore and F. Piemonte, “Protein glutathionylation in cardiovascular diseases,” International Journal of Molecular Sciences, vol. 14, no. 12, pp. 20845–20876, 2013.
- F. Qin, D. A. Siwik, S. Lancel et al., “Hydrogen peroxide–mediated SERCA cysteine 674 oxidation contributes to impaired cardiac myocyte relaxation in senescent mouse heart,” Journal of the American Heart Association, vol. 2, no. 4, article e000184, 2013.
- U. Ozcan, Q. Cao, E. Yilmaz et al., “Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes,” Science, vol. 306, no. 5695, pp. 457–461, 2004.
- P. Haberzettl, E. Vladykovskaya, S. Srivastava, and A. Bhatnagar, “Role of endoplasmic reticulum stress in acrolein-induced endothelial activation,” Toxicology and Applied Pharmacology, vol. 234, no. 1, pp. 14–24, 2009.
- C. H. Shao, H. L. Capek, K. P. Patel et al., “Carbonylation contributes to SERCA2a activity loss and diastolic dysfunction in a rat model of type 1 diabetes,” Diabetes, vol. 60, no. 3, pp. 947–959, 2011.
- H. Zeeshan, G. Lee, H.-R. Kim, and H.-J. Chae, “Endoplasmic reticulum stress and associated ROS,” International Journal of Molecular Sciences, vol. 17, no. 12, p. 327, 2016.
- R. Chaube and G. H. Werstuck, “Mitochondrial ROS versus ER ROS: which comes first in myocardial calcium dysregulation?” Frontiers in Cardiovascular Medicine, vol. 3, p. 36, 2016.
- A. N. Osipov, N. M. Smetanina, M. V. Pustovalova, E. Arkhangelskaya, and D. Klokov, “The formation of DNA single-strand breaks and alkali-labile sites in human blood lymphocytes exposed to 365-nm UVA radiation,” Free Radical Biology & Medicine, vol. 73, pp. 34–40, 2014.
- A. Valavanidis, T. Vlachogianni, and C. Fiotakis, “8-hydroxy-2-deoxyguanosine (8-OHdG): a critical biomarker of oxidative stress and carcinogenesis,” Journal of Environmental Science and Health, Part C, vol. 27, no. 2, pp. 120–139, 2009.
- J. Cadet and J. R. Wagner, “DNA base damage by reactive oxygen species, oxidizing agents, and UV radiation,” Cold Spring Harbor Perspectives in Biology, vol. 5, article a012559, 2013.
- S. Frelon, T. Douki, A. Favier, and J. Cadet, “Hydroxyl radical is not the main reactive species involved in the degradation of DNA bases by copper in the presence of hydrogen peroxide,” Chemical Research in Toxicology, vol. 16, no. 2, pp. 191–197, 2003.
- E. S. Henle, Z. Han, N. Tang, P. Rai, Y. Luo, and S. Linn, “Sequence-specific DNA cleavage by Fe2+-mediated Fenton reactions has possible biological implications,” Journal of Biological Chemistry, vol. 274, no. 2, pp. 962–971, 1999.
- B. Thapa, B. H. Munk, C. J. Burrows, and H. B. Schlegel, “Computational study of oxidation of guanine by singlet oxygen (1Δg) and formation of guanine:lysine cross-links,” Chemistry - A European Journal, vol. 23, no. 24, pp. 5804–5813, 2017.
- L. Woodbine, H. Brunton, A. A. Goodarzi, A. Shibata, and P. A. Jeggo, “Endogenously induced DNA double strand breaks arise in heterochromatic DNA regions and require ataxia telangiectasia mutated and Artemis for their repair,” Nucleic Acids Research, vol. 39, no. 16, pp. 6986–6997, 2011.
- B. ul Islam, S. Habib, P. Ahmad, S. Allarakha, Moinuddin, and A. Ali, “Pathophysiological role of peroxynitrite induced DNA damage in human diseases: a special focus on poly(ADP-ribose) polymerase (PARP),” Indian Journal of Clinical Biochemistry, vol. 30, no. 4, pp. 368–385, 2015.
- F. Gentile, A. Arcaro, S. Pizzimenti et al., “DNA damage by lipid peroxidation products: implications in cancer, inflammation and autoimmunity,” AIMS Genetics, vol. 4, no. 2, pp. 103–137, 2017.
- M. J. Roberts, G. T. Wondrak, D. C. Laurean, M. K. Jacobson, and E. L. Jacobson, “DNA damage by carbonyl stress in human skin cells,” Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, vol. 522, no. 1-2, pp. 45–56, 2003.
- M. Gracanin and M. J. Davies, “Inhibition of protein tyrosine phosphatases by amino acid, peptide, and protein hydroperoxides: potential modulation of cell signaling by protein oxidation products,” Free Radical Biology & Medicine, vol. 42, no. 10, pp. 1543–1551, 2007.
- A. S. Rahmanto, P. E. Morgan, C. L. Hawkins, and M. J. Davies, “Cellular effects of photogenerated oxidants and long-lived, reactive, hydroperoxide photoproducts,” Free Radical Biology & Medicine, vol. 49, no. 10, pp. 1505–1515, 2010.
- V. Gupta and K. S. Carroll, “Sulfenic acid chemistry, detection and cellular lifetime,” Biochimica et Biophysica Acta (BBA) - General Subjects, vol. 1840, no. 2, pp. 847–875, 2014.
- I. Dalle-Donne, R. Rossi, D. Giustarini, R. Colombo, and A. Milzani, “S-Glutathionylation in protein redox regulation,” Free Radical Biology & Medicine, vol. 43, no. 6, pp. 883–898, 2007.
- C. L. Grek, J. Zhang, Y. Manevich, D. M. Townsend, and K. D. Tew, “Causes and consequences of cysteine S-glutathionylation,” The Journal of Biological Chemistry, vol. 288, no. 37, pp. 26497–26504, 2013.
- H. Wefers and H. Sies, “Oxidation of glutathione by the superoxide radical to the disulfide and the sulfonate yielding singlet oxygen,” European Journal of Biochemistry, vol. 137, no. 1-2, pp. 29–36, 1983.
- S. Enami, M. R. Hoffmann, and A. J. Colussi, “Ozone oxidizes glutathione to a sulfonic acid,” Chemical Research in Toxicology, vol. 22, no. 1, pp. 35–40, 2009.
- A. N. Onyango, “Alternatives to the ‘water oxidation pathway’ of biological ozone formation,” Journal of Chemical Biology, vol. 9, no. 1, pp. 1–8, 2016.
- S. Iwakami, H. Misu, T. Takeda et al., “Concentration-dependent dual effects of hydrogen peroxide on insulin signal transduction in H4IIEC hepatocytes,” PLoS One, vol. 6, no. 11, article e27401, 2011.
- S. Zhuang and I. E. Kochevar, “Singlet oxygen–induced activation of Akt/protein kinase B is independent of growth factor receptors,” Photochemistry and Photobiology, vol. 78, no. 4, pp. 361–371, 2003.
- M. Ikemura, M. Nishikawa, K. Hyoudou, Y. Kobayashi, F. Yamashita, and M. Hashida, “Improvement of insulin resistance by removal of systemic hydrogen peroxide by PEGylated catalase in obese mice,” Molecular Pharmaceutics, vol. 7, no. 6, pp. 2069–2076, 2010.
- Y. Son, Y.-K. Cheong, N.-H. Kim, H.-T. Chung, D. G. Kang, and H.-O. Pae, “Mitogen-activated protein kinases and reactive oxygen species: how can ROS activate MAPK pathways?” Journal of Signal Transduction, vol. 2011, Article ID 792639, 6 pages, 2011.
- M. Castro-Caldas, A. N. Carvalho, E. Rodrigues, C. Henderson, C. R. Wolf, and M. J. Gama, “Glutathione S-transferase pi mediates MPTP-induced c-Jun N-terminal kinase activation in the nigrostriatal pathway,” Molecular Neurobiology, vol. 45, no. 3, pp. 466–477, 2012.
- K. D. Tew, Y. Manevich, C. Grek, Y. Xiong, J. Uys, and D. M. Townsend, “The role of glutathione S-transferase P in signaling pathways and S-glutathionylation in cancer,” Free Radical Biology & Medicine, vol. 51, no. 2, pp. 299–313, 2011.
- L.-O. Klotz, K.-D. Kröncke, and H. Sies, “Singlet oxygen-induced signaling effects in mammalian cells,” Photochemical & Photobiological Sciences, vol. 2, no. 2, pp. 88–94, 2003.
- J. Matsukawa, A. Matsuzawa, K. Takeda, and H. Ichijo, “The ASK1-MAP kinase cascades in mammalian stress response,” Journal of Biochemistry, vol. 136, no. 3, pp. 261–265, 2004.
- X. Li, Y. Rong, M. Zhang et al., “Up-regulation of thioredoxin interacting protein (Txnip) by p38 MAPK and FOXO1 contributes to the impaired thioredoxin activity and increased ROS in glucose-treated endothelial cells,” Biochemical and Biophysical Research Communications, vol. 381, no. 4, pp. 660–665, 2009.
- T. Lane, B. Flam, R. Lockey, and N. Kolliputi, “TXNIP shuttling: missing link between oxidative stress and inflammasome activation,” Frontiers in Physiology, vol. 4, no. 50, 2013.
- C. S. Choi, Y.-B. Kim, F. N. Lee, J. M. Zabolotny, B. B. Kahn, and J. H. Youn, “Lactate induces insulin resistance in skeletal muscle by suppressing glycolysis and impairing insulin signaling,” American Journal of Physiology-Endocrinology and Metabolism, vol. 283, no. 2, pp. E233–E240, 2002.
- M. Kleinert, L. Sylow, D. J. Fazakerley et al., “Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo,” Molecular Metabolism, vol. 3, no. 6, pp. 630–641, 2014.
- L. C. Chao, K. Wroblewski, Z. Zhang et al., “Insulin resistance and altered systemic glucose metabolism in mice lacking nur77,” Diabetes, vol. 58, no. 12, pp. 2788–2796, 2009.
- P. E. Morgan, R. T. Dean, and M. J. Davies, “Inhibition of glyceraldehyde-3-phosphate dehydrogenase by peptide and protein peroxides generated by singlet oxygen attack,” European Journal of Biochemistry, vol. 269, no. 7, pp. 1916–1925, 2002.
- P. J. Beisswenger, S. K. Howell, K. Smith, and B. S. Szwergold, “Glyceraldehyde-3-phosphate dehydrogenase activity as an independent modifier of methylglyoxal levels in diabetes,” Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, vol. 1637, no. 1, pp. 98–106, 2003.
- S. Iqbal and D. A. Hood, “Oxidative stress-induced mitochondrial fragmentation and movement in skeletal muscle myoblasts,” American Journal of Physiology-Cell Physiology, vol. 306, no. 12, pp. C1176–C1183, 2014.
- K. Park, M. Gross, D.-H. Lee et al., “Oxidative stress and insulin resistance: the coronary artery risk development in young adults study,” Diabetes Care, vol. 32, no. 7, pp. 1302–1307, 2009.
- Z. Huang, Q. Hong, X. Zhang et al., “Aldose reductase mediates endothelial cell dysfunction induced by high uric acid concentrations,” Cell Communication and Signaling, vol. 15, no. 1, p. 3, 2017.
- K. V. Ramana, B. Friedrich, R. Tammali, M. B. West, A. Bhatnagar, and S. K. Srivastava, “Requirement of aldose reductase for the hyperglycemic activation of protein kinase C and formation of diacylglycerol in vascular smooth muscle cells,” Diabetes, vol. 54, no. 3, pp. 818–829, 2005.
- M. A. Lanaspa, T. Ishimoto, N. Li et al., “Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome,” Nature Communications, vol. 4, p. 2434, 2013.
- K.-W. Zeng, J. Li, X. Dong et al., “Anti-neuroinflammatory efficacy of the aldose reductase inhibitor FMHM via phospholipase C/protein kinase C-dependent NF-κB and MAPK pathways,” Toxicology and Applied Pharmacology, vol. 273, no. 1, pp. 159–171, 2013.
- K. Toriumi, Y. Horikoshi, R. Yoshiyuki Osamura, Y. Yamamoto, N. Nakamura, and S. Takekoshi, “Carbon tetrachloride-induced hepatic injury through formation of oxidized diacylglycerol and activation of the PKC/NF-κB pathway,” Laboratory Investigation, vol. 93, no. 2, pp. 218–229, 2013.
- S. K. Srivastava, U. C. S. Yadav, A. B. M. Reddy et al., “Aldose reductase inhibition suppresses oxidative stress-induced inflammatory disorders,” Chemico-Biological Interactions, vol. 191, no. 1-3, pp. 330–338, 2011.
- S. Pandey, S. K. Srivastava, and K. V. Ramana, “A potential therapeutic role for aldose reductase inhibitors in the treatment of endotoxin-related inflammatory diseases,” Expert Opinion on Investigational Drugs, vol. 21, no. 3, pp. 329–339, 2012.
- X.-M. Song, Q. Yu, X. Dong et al., “Aldose reductase inhibitors attenuate β-amyloid-induced TNF-α production in microlgia via ROS-PKC-mediated NF-κB and MAPK pathways,” International Immunopharmacology, vol. 50, pp. 30–37, 2017.
- T. Nishino, K. Okamoto, B. T. Eger, E. F. Pai, and T. Nishino, “Mammalian xanthine oxidoreductase – mechanism of transition from xanthine dehydrogenase to xanthine oxidase,” FEBS Journal, vol. 275, no. 13, pp. 3278–3289, 2008.
- M. F. Abdelmalek, M. Lazo, A. Horska et al., “Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes,” Hepatology, vol. 56, no. 3, pp. 952–960, 2012.
- M. A. Lanaspa, L. G. Sanchez-Lozada, Y. J. Choi et al., “Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver,” Journal of Biological Chemistry, vol. 287, no. 48, pp. 40732–40744, 2012.
- R. Spiga, M. A. Marini, E. Mancuso et al., “Uric acid is associated with inflammatory biomarkers and induces inflammation via activating the NF-κB signaling pathway in HepG2 cells,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 37, no. 6, pp. 1241–1249, 2017.
- Y. J. Choi, H. S. Shin, H. S. Choi et al., “Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes,” Laboratory Investigation, vol. 94, no. 10, pp. 1114–1125, 2014.
- M. Kanbay, T. Jensen, Y. Solak et al., “Uric acid in metabolic syndrome: from an innocent bystander to a central player,” European Journal of Internal Medicine, vol. 29, pp. 3–8, 2016.
- F. Derbre, B. Ferrando, M. C. Gomez-Cabrera et al., “Inhibition of xanthine oxidase by allopurinol prevents skeletal muscle atrophy: role of p38 MAPkinase and E3 ubiquitin ligases,” PLoS One, vol. 7, no. 10, article e46668, 2012.
- S. Grether-Beck, G. Bonizzi, H. Schmitt-Brenden et al., “Non-enzymatic triggering of the ceramide signalling cascade by solar UVA radiation,” The EMBO Journal, vol. 19, no. 21, pp. 5793–5800, 2000.
- M. Sawada, S. Nakashima, T. Kiyono et al., “p53 regulates ceramide formation by neutral sphingomyelinase through reactive oxygen species in human glioma cells,” Oncogene, vol. 20, no. 11, pp. 1368–1378, 2001.
- J. R. Ussher, T. R. Koves, V. J. J. Cadete et al., “Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption,” Diabetes, vol. 59, no. 10, pp. 2453–2464, 2010.
- M. Verma, A. Yateesh, K. Neelima et al., “Inhibition of neutral sphingomyelinases in skeletal muscle attenuates fatty-acid induced defects in metabolism and stress,” SpringerPlus, vol. 3, no. 1, p. 255, 2014.
- J.-L. Li, Q.-Y. Wang, H.-Y. Luan, Z.-C. Kang, and C.-B. Wang, “Effects of L-carnitine against oxidative stress in human hepatocytes: involvement of peroxisome proliferator-activated receptor alpha,” Journal of Biomedical Science, vol. 19, no. 1, p. 32, 2012.
- C. Blanquicett, B.-Y. Kang, J. D. Ritzenthaler, D. P. Jones, and C. M. Hart, “Oxidative stress modulates PPARγ in vascular endothelial cells,” Free Radical Biology & Medicine, vol. 48, no. 12, pp. 1618–1625, 2010.
- M. B. Paumen, Y. Ishida, M. Muramatsu, M. Yamamoto, and T. Honjo, “Inhibition of carnitine palmitoyltransferase I augments sphingolipid synthesis and palmitate-induced apoptosis,” Journal of Biological Chemistry, vol. 272, no. 6, pp. 3324–3329, 1997.
- S. M. H. Chan, R.-Q. Sun, X.-Y. Zeng et al., “Activation of PPARα ameliorates hepatic insulin resistance and steatosis in high fructose–fed mice despite increased endoplasmic reticulum stress,” Diabetes, vol. 62, no. 6, pp. 2095–2105, 2013.
- N. Zhang, E. S. H. Chu, J. Zhang et al., “Peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating NF-κB signaling pathway,” Oncotarget, vol. 5, no. 18, pp. 8330–8340, 2014.
- M. Pawlak, P. Lefebvre, and B. Staels, “Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease,” Journal of Hepatology, vol. 62, no. 3, pp. 720–733, 2015.
- X. Liu, Z. Yu, X. Huang et al., “Peroxisome proliferator-activated receptor γ (PPARγ) mediates the protective effect of quercetin against myocardial ischemia-reperfusion injury via suppressing the NF-κB pathway,” American Journal of Translational Research, vol. 8, no. 12, pp. 5169–5186, 2016.
- Y. Zhang, R.-X. Zhan, J.-Q. Chen et al., “Pharmacological activation of PPAR gamma ameliorates vascular endothelial insulin resistance via a non-canonical PPAR gamma-dependent nuclear factor-kappa B trans-repression pathway,” European Journal of Pharmacology, vol. 754, pp. 41–51, 2015.
- M. Bouskila, U. B. Pajvani, and P. E. Scherer, “Adiponectin: a relevant player in PPARγ-agonist-mediated improvements in hepatic insulin sensitivity?” International Journal of Obesity, vol. 29, no. S1, pp. S17–S23, 2005.
- S. Mohr, H. Hallak, A. de Boitte, E. G. Lapetina, and B. Brüne, “Nitric oxide-induced S-glutathionylation and inactivation of glyceraldehyde-3-phosphate dehydrogenase,” Journal of Biological Chemistry, vol. 274, no. 14, pp. 9427–9430, 1999.
- I. Bellezza, S. Grottelli, E. Costanzi et al., “Peroxynitrite activates the NLRP3 inflammasome cascade in SOD1(G93A) mouse model of amyotrophic lateral sclerosis,” Molecular Neurobiology, 2017.
- A. Pautz, R. Franzen, S. Dorsch et al., “Cross-talk between nitric oxide and superoxide determines ceramide formation and apoptosis in glomerular cells,” Kidney International, vol. 61, no. 3, pp. 790–796, 2002.
- M. Morita, Y. Naito, T. Yoshikawa, and E. Niki, “Plasma lipid oxidation induced by peroxynitrite, hypochlorite, lipoxygenase and peroxyl radicals and its inhibition by antioxidants as assessed by diphenyl-1-pyrenylphosphine,” Redox Biology, vol. 8, pp. 127–135, 2016.
- H. Sugita, M. Fujimoto, T. Yasukawa et al., “Inducible nitric-oxide synthase and NO donor induce insulin receptor substrate-1 degradation in skeletal muscle cells,” Journal of Biological Chemistry, vol. 280, no. 14, pp. 14203–14211, 2005.
- C. Nigro, G. A. Raciti, A. Leone et al., “Methylglyoxal impairs endothelial insulin sensitivity both in vitro and in vivo,” Diabetologia, vol. 57, no. 7, pp. 1485–1494, 2014.
- K. H. Ingram, H. Hill, D. R. Moellering et al., “Skeletal muscle lipid peroxidation and insulin resistance in humans,” The Journal of Clinical Endocrinology & Metabolism, vol. 97, no. 7, pp. E1182–E1186, 2012.
- C. T. Shearn, K. S. Fritz, P. Reigan, and D. R. Petersen, “Modification of Akt2 by 4-hydroxynonenal inhibits insulin-dependent Akt signaling in HepG2 cells,” Biochemistry, vol. 50, no. 19, pp. 3984–3996, 2011.
- S. J. Orena, A. J. Torchia, and R. S. Garofalo, “Inhibition of glycogen-synthase kinase 3 stimulates glycogen synthase and glucose transport by distinct mechanisms in 3T3-L1 adipocytes,” Journal of Biological Chemistry, vol. 275, no. 21, pp. 15765–15772, 2000.
- K. MacAulay and J. R. Woodgett, “Targeting glycogen synthase kinase-3 (GSK-3) in the treatment of type 2 diabetes,” Expert Opinion on Therapeutic Targets, vol. 12, no. 10, pp. 1265–1274, 2008.
- C. Sutherland, “What are the bona fide GSK3 substrates?” International Journal of Alzheimer's Disease, vol. 2011, Article ID 505607, 23 pages, 2011.
- A. I. Rojo, M. R. . Sagarra, and A. Cuadrado, “GSK-3β down-regulates the transcription factor Nrf2 after oxidant damage: relevance to exposure of neuronal cells to oxidative stress,” Journal of Neurochemistry, vol. 105, no. 1, pp. 192–202, 2008.
- B. Spoto, R. M. Parlongo, G. Parlongo, E. Sgro', and C. Zoccali, “The enzymatic machinery for ADMA synthesis and degradation is fully expressed in human adipocytes,” Journal of Nephrology, vol. 20, no. 5, pp. 554–559, 2007.
- H. Iwasaki, “Activities of asymmetric dimethylarginine-related enzymes in white adipose tissue are associated with circulating lipid biomarkers,” Diabetology & Metabolic Syndrome, vol. 4, no. 1, p. 17, 2012.
- Z.-C. Yang, K. S. Wang, Y. Wu et al., “Asymmetric dimethylarginine impairs glucose utilization via ROS/TLR4 pathway in adipocytes: an effect prevented by vitamin E,” Cellular Physiology and Biochemistry, vol. 24, no. 1-2, pp. 115–124, 2009.
- J. Zheng, K. Wang, P. Jin et al., “The association of adipose-derived dimethylarginine dimethylaminohydrolase-2 with insulin sensitivity in experimental type 2 diabetes mellitus,” Acta Biochimica et Biophysica Sinica, vol. 45, no. 8, pp. 641–648, 2013.
- M. Trocha, A. Merwid-Lad, A. Szuba, T. Sozanski, J. Magdalan, and A. Szelag, “Asymmetric dimethylarginine synthesis and degradation under physiological and pathological conditions,” Advanced Clinical and Experimental Medicine, vol. 19, pp. 233–243, 2010.
- P. Chen, K. Xia, Z. Zhao, X. Deng, and T. Yang, “Atorvastatin modulates the DDAH1/ADMA system in high-fat diet-induced insulin-resistant rats with endothelial dysfunction,” Vascular Medicine, vol. 17, no. 6, pp. 416–423, 2012.
- L. Chen, J.-P. Zhou, D.-B. Kuang, J. Tang, Y.-J. Li, and X.-P. Chen, “4-HNE increases intracellular ADMA levels in cultured HUVECs: evidence for miR-21-dependent mechanisms,” PLoS One, vol. 8, no. 5, article e64148, 2013.
- A. Zengi, G. Ercan, O. Caglayan et al., “Increased oxidative DNA damage in lean normoglycemic offspring of type 2 diabetic patients,” Experimental and Clinical Endocrinology & Diabetes, vol. 119, no. 8, pp. 467–471, 2011.
- H. A. Al-Aubaidy and H. F. Jelinek, “8-Hydroxy-2-deoxy-guanosine identifies oxidative DNA damage in a rural prediabetes cohort,” Redox Report, vol. 15, no. 4, pp. 155–160, 2010.
- H. Sampath, V. Vartanian, M. R. Rollins, K. Sakumi, Y. Nakabeppu, and R. S. Lloyd, “8-Oxoguanine DNA glycosylase (OGG1) deficiency increases susceptibility to obesity and metabolic dysfunction,” PLoS One, vol. 7, no. 12, article e51697, 2012.
- L. V. Yuzefovych, V. A. Solodushko, G. L. Wilson, and L. I. Rachek, “Protection from palmitate-induced mitochondrial DNA damage prevents from mitochondrial oxidative stress, mitochondrial dysfunction, apoptosis, and impaired insulin signaling in rat L6 skeletal muscle cells,” Endocrinology, vol. 153, no. 1, pp. 92–100, 2012.
- L. V. Yuzefovych, S. P. LeDoux, G. L. Wilson, and L. I. Rachek, “Mitochondrial DNA damage via augmented oxidative stress regulates endoplasmic reticulum stress and autophagy: crosstalk, links and signaling,” PLoS One, vol. 8, no. 12, article e83349, 2013.
- C. Ricci, V. Pastukh, J. Leonard et al., “Mitochondrial DNA damage triggers mitochondrial-superoxide generation and apoptosis,” American Journal of Physiology-Cell Physiology, vol. 294, no. 2, pp. C413–C422, 2008.
- K. Shimada, T. R. Crother, J. Karlin et al., “Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis,” Immunity, vol. 36, no. 3, pp. 401–414, 2012.
- I. Kim, W. Xu, and J. C. Reed, “Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities,” Nature Reviews Drug Discovery, vol. 7, no. 12, pp. 1013–1030, 2008.
- C. Lebeaupin, E. Proics, C. H. D. de Bieville et al., “ER stress induces NLRP3 inflammasome activation and hepatocyte death,” Cell Death & Disease, vol. 6, no. 9, article e1879, 2015.
- F. Shang and A. Taylor, “Ubiquitin–proteasome pathway and cellular responses to oxidative stress,” Free Radical Biology & Medicine, vol. 51, no. 1, pp. 5–16, 2011.
- Z. J. Chen, “Ubiquitin signalling in the NF-κB pathway,” Nature Cell Biology, vol. 7, no. 8, pp. 758–765, 2005.
- B. Emanuelli, P. Peraldi, C. Filloux et al., “SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-α in the adipose tissue of obese mice,” Journal of Biological Chemistry, vol. 276, no. 51, pp. 47944–47949, 2001.
- L. Rui, M. Yuan, D. Frantz, S. Shoelson, and M. F. White, “SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2,” Journal of Biological Chemistry, vol. 277, no. 44, pp. 42394–42398, 2002.
- J. J. Senn, P. J. Klover, I. A. Nowak et al., “Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes,” Journal of Biological Chemistry, vol. 278, no. 16, pp. 13740–13746, 2003.
- F. Mashili, A. V. Chibalin, A. Krook, and J. R. Zierath, “Constitutive STAT3 phosphorylation contributes to skeletal muscle insulin resistance in type 2 diabetes,” Diabetes, vol. 62, no. 2, pp. 457–465, 2013.
- M. Ishii, A. Maeda, S. Tani, and M. Akagawa, “Palmitate induces insulin resistance in human HepG2 hepatocytes by enhancing ubiquitination and proteasomal degradation of key insulin signaling molecules,” Archives of Biochemistry and Biophysics, vol. 566, pp. 26–35, 2015.
- X. Liu, M. G. Mameza, Y. S. Lee et al., “Suppressors of cytokine-signaling proteins induce insulin resistance in the retina and promote survival of retinal cells,” Diabetes, vol. 57, no. 6, pp. 1651–1658, 2008.
- H. Lerat, M. R. Imache, J. Polyte et al., “Hepatitis C virus induces a prediabetic state by directly impairing hepatic glucose metabolism in mice,” Journal of Biological Chemistry, vol. 292, no. 31, pp. 12860–12873, 2017.
- D. Gu, Z. Wang, X. Dou et al., “Inhibition of ERK1/2 pathway suppresses adiponectin secretion via accelerating protein degradation by ubiquitin–proteasome system: relevance to obesity-related adiponectin decline,” Metabolism, vol. 62, no. 8, pp. 1137–1148, 2013.
- K.-I. Ozaki, M. Awazu, M. Tamiya et al., “Targeting the ERK signaling pathway as a potential treatment for insulin resistance and type 2 diabetes,” American Journal of Physiology-Endocrinology and Metabolism, vol. 310, no. 8, pp. E643–E651, 2016.
- Z. Wang, X. Dou, D. Gu et al., “4-Hydroxynonenal differentially regulates adiponectin gene expression and secretion via activating PPARγ and accelerating ubiquitin–proteasome degradation,” Molecular and Cellular Endocrinology, vol. 349, no. 2, pp. 222–231, 2012.
- A. Abudukadier, Y. Fujita, A. Obara et al., “Tetrahydrobiopterin has a glucose-lowering effect by suppressing hepatic gluconeogenesis in an endothelial nitric oxide synthase–dependent manner in diabetic mice,” Diabetes, vol. 62, no. 9, pp. 3033–3043, 2013.
- Z. Shen, X. Liang, C. Q. Rogers, D. Rideout, and M. You, “Involvement of adiponectin-SIRT1-AMPK signaling in the protective action of rosiglitazone against alcoholic fatty liver in mice,” American Journal of Physiology-Gastrointestinal and Liver Physiology, vol. 298, no. 3, pp. G364–G374, 2010.
- Y. Cheng, H. Takeuchi, Y. Sonobe et al., “Sirtuin 1 attenuates oxidative stress via upregulation of superoxide dismutase 2 and catalase in astrocytes,” Journal of Neuroimmunology, vol. 269, no. 1-2, pp. 38–43, 2014.
- G. Ceolotto, A. Gallo, I. Papparella et al., “Rosiglitazone reduces glucose-induced oxidative stress mediated by NAD(P)H oxidase via AMPK-dependent mechanism,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 27, no. 12, pp. 2627–2633, 2007.
- M. Balteau, A. van Steenbergen, A. D. Timmermans et al., “AMPK activation by glucagon-like peptide-1 prevents NADPH oxidase activation induced by hyperglycemia in adult cardiomyocytes,” American Journal of Physiology-Heart and Circulatory Physiology, vol. 307, no. 8, pp. H1120–H1133, 2014.
- J. M. Cacicedo, N. Yagihashi, J. F. Keaney Jr, N. B. Ruderman, and Y. Ido, “AMPK inhibits fatty acid-induced increases in NF-κB transactivation in cultured human umbilical vein endothelial cells,” Biochemical and Biophysical Research Communications, vol. 324, no. 4, pp. 1204–1209, 2004.
- A. Salminen, J. M. T. Hyttinen, and K. Kaarniranta, “AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan,” Journal of Molecular Medicine, vol. 89, no. 7, pp. 667–676, 2011.
- W. M. Yang and W. Lee, “CTRP5 ameliorates palmitate-induced apoptosis and insulin resistance through activation of AMPK and fatty acid oxidation,” Biochemical and Biophysical Research Communications, vol. 452, no. 3, pp. 715–721, 2014.
- K.-L. Tsai, L.-H. Chen, S.-H. Chiou et al., “Coenzyme Q10 suppresses oxLDL-induced endothelial oxidative injuries by the modulation of LOX-1-mediated ROS generation via the AMPK/PKC/NADPH oxidase signaling pathway,” Molecular Nutrition & Food Research, vol. 55, no. S2, pp. S227–S240, 2011.
- N. B. Ruderman, D. Carling, M. Prentki, and J. M. Cacicedo, “AMPK, insulin resistance, and the metabolic syndrome,” Journal of Clinical Investigation, vol. 123, no. 7, pp. 2764–2772, 2013.
- W. S. Cheang, X. Y. Tian, W. T. Wong et al., “Metformin protects endothelial function in diet-induced obese mice by inhibition of endoplasmic reticulum stress through 5 adenosine monophosphate–activated protein kinase–peroxisome proliferator–activated receptor δ pathway,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 34, no. 4, pp. 830–836, 2014.
- C. Li, M. M. Reif, S. M. Craige, S. Kant, and J. F. Keaney Jr, “Endothelial AMPK activation induces mitochondrial biogenesis and stress adaptation via eNOS-dependent mTORC1 signaling,” Nitric Oxide, vol. 55-56, pp. 45–53, 2016.
- Z. Gao, J. Zhang, I. Kheterpal, N. Kennedy, R. J. Davis, and J. Ye, “Sirtuin 1 (SIRT1) protein degradation in response to persistent c-Jun N-terminal kinase 1 (JNK1) activation contributes to hepatic steatosis in obesity,” Journal of Biological Chemistry, vol. 286, no. 25, pp. 22227–22234, 2011.
- Y. Cao, X. Jiang, H. Ma, Y. Wang, P. Xue, and Y. Liu, “SIRT1 and insulin resistance,” Journal of Diabetes and Its Complications, vol. 30, no. 1, pp. 178–183, 2016.
- A. Salminen, K. Kaarniranta, and A. Kauppinen, “Crosstalk between oxidative stress and SIRT1: impact on the aging process,” International Journal of Molecular Sciences, vol. 14, no. 2, pp. 3834–3859, 2013.
- H.-H. Zhang, X.-J. Ma, L.-N. Wu et al., “SIRT1 attenuates high glucose-induced insulin resistance via reducing mitochondrial dysfunction in skeletal muscle cells,” Experimental Biology and Medicine, vol. 240, no. 5, pp. 557–565, 2015.
- L. D. Zheng, L. E. Linarelli, J. Brooke et al., “Mitochondrial epigenetic changes link to increased diabetes risk and early-stage prediabetes indicator,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 5290638, 10 pages, 2016.
- T. L. Marin, B. Gongol, F. Zhang et al., “AMPK promotes mitochondrial biogenesis and function by phosphorylating the epigenetic factors DNMT1, RBBP7, and HAT1,” Science Signaling, vol. 10, no. 464, article eaaf7478, 2017.
- S. K. Saini, K. C. Mangalhara, G. Prakasam, and R. N. K. Bamezai, “DNA methyltransferase1 (DNMT1) isoform3 methylates mitochondrial genome and modulates its biology,” Scientific Reports, vol. 7, no. 1, p. 1525, 2017.
- J. M. McClung, A. R. Judge, E. E. Talbert, and S. K. Powers, “Calpain-1 is required for hydrogen peroxide-induced myotube atrophy,” American Journal of Physiology-Cell Physiology, vol. 296, no. 2, pp. C363–C371, 2009.
- I. J. Smith, S. H. Lecker, and P.-O. Hasselgren, “Calpain activity and muscle wasting in sepsis,” American Journal of Physiology-Endocrinology and Metabolism, vol. 295, no. 4, pp. E762–E771, 2008.
- M. L. Dirks, B. T. Wall, B. van de Valk et al., “One week of bed rest leads to substantial muscle atrophy and induces whole-body insulin resistance in the absence of skeletal muscle lipid accumulation,” Diabetes, vol. 65, no. 10, pp. 2862–2875, 2016.
- O. Rom, S. Kaisari, A. Z. Reznick, and D. Aizenbud, “Peroxynitrite induces degradation of myosin heavy chain via p38 MAPK and muscle-specific E3 ubiquitin ligases in C2 skeletal myotubes,” Advances in Experimental Medicine and Biology, vol. 832, pp. 1–8, 2014.
- G. Carnac, B. Vernus, and A. Bonnieu, “Myostatin in the pathophysiology of skeletal muscle,” Current Genomics, vol. 8, no. 7, pp. 415–422, 2007.
- S. Sriram, S. Subramanian, D. Sathiakumar et al., “Modulation of reactive oxygen species in skeletal muscle by myostatin is mediated through NF-κB,” Aging Cell, vol. 10, no. 6, pp. 931–948, 2011.
- C. Brandt, A. R. Nielsen, C. P. Fischer, J. Hansen, B. K. Pedersen, and P. Plomgaard, “Plasma and muscle myostatin in relation to type 2 diabetes,” PLoS One, vol. 7, no. 5, article e37236, 2012.
- B. Catalgol, I. Ziaja, N. Breusing et al., “The proteasome is an integral part of solar ultraviolet a radiation-induced gene expression,” Journal of Biological Chemistry, vol. 284, no. 44, pp. 30076–30086, 2009.
- A. Díaz-Ruiz, R. Guzmán-Ruiz, N. R. Moreno et al., “Proteasome dysfunction associated to oxidative stress and proteotoxicity in adipocytes compromises insulin sensitivity in human obesity,” Antioxidants & Redox Signaling, vol. 23, no. 7, pp. 597–612, 2015.
- Y. Mei, M. D. Thompson, R. A. Cohen, and X. Y. Tong, “Endoplasmic reticulum stress and related pathological processes,” Journal of Pharmacological & Biomedical Analysis, vol. 1, no. 2, 2013.
- A. B. Tam, E. L. Mercado, A. Hoffmann, and M. Niwa, “ER stress activates NF-κB by integrating functions of basal IKK activity, IRE1 and PERK,” PLoS One, vol. 7, no. 10, article e45078, 2012.
- J. A. Willy, S. K. Young, J. L. Stevens, H. C. Masuoka, and R. C. Wek, “CHOP links endoplasmic reticulum stress to NF-κB activation in the pathogenesis of nonalcoholic steatohepatitis,” Molecular Biology of the Cell, vol. 26, no. 12, pp. 2190–2204, 2015.
- R. Sano and J. C. Reed, “ER stress-induced cell death mechanisms,” Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, vol. 1833, no. 12, pp. 3460–3470, 2013.
- S. S. Cao, K. L. Luo, and L. Shi, “Endoplasmic reticulum stress interacts with inflammation in human diseases,” Journal of Cellular Physiology, vol. 231, no. 2, pp. 288–294, 2016.
- K. Uchimura, M. Hayata, T. Mizumoto et al., “The serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signalling,” Nature Communications, vol. 5, p. 3428, 2014.
- K. Du, S. Herzig, R. N. Kulkarni, and M. Montminy, “TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver,” Science, vol. 300, no. 5625, pp. 1574–1577, 2003.
- A. P. Arruda, M. Milanski, A. Coope et al., “Low-grade hypothalamic inflammation leads to defective thermogenesis, insulin resistance, and impaired insulin secretion,” Endocrinology, vol. 152, no. 4, pp. 1314–1326, 2011.
- Y. Li, Y. Guo, J. Tang, J. Jiang, and Z. Chen, “New insights into the roles of CHOP-induced apoptosis in ER stress,” Acta Biochimica et Biophysica Sinica, vol. 46, no. 8, pp. 629–640, 2014.
- M. Okla, W. Wang, I. Kang, A. Pashaj, T. Carr, and S. Chung, “Activation of Toll-like receptor 4 (TLR4) attenuates adaptive thermogenesis via endoplasmic reticulum stress,” Journal of Biological Chemistry, vol. 290, no. 44, pp. 26476–26490, 2015.
- S. Nowsheen and E. S. Yang, “The intersection between DNA damage response and cell death pathways,” Experimental Oncology, vol. 34, no. 3, pp. 243–254, 2013.
- B. Piret, S. Schoonbroodt, and J. Piette, “The ATM protein is required for sustained activation of NF-κB following DNA damage,” Oncogene, vol. 18, no. 13, pp. 2261–2271, 1999.
- B. B. S. Zhou and S. J. Elledge, “The DNA damage response: putting checkpoints in perspective,” Nature, vol. 408, no. 6811, pp. 433–439, 2000.
- J. Strycharz, J. Drzewoski, J. Szemraj, and A. Sliwinska, “Is p53 involved in tissue-specific insulin resistance formation?” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 9270549, 23 pages, 2017.
- I. Shimizu, Y. Yoshida, M. Suda, and T. Minamino, “DNA damage response and metabolic disease,” Cell Metabolism, vol. 20, no. 6, pp. 967–977, 2014.
- T. Minamino, M. Orimo, I. Shimizu et al., “A crucial role for adipose tissue p53 in the regulation of insulin resistance,” Nature Medicine, vol. 15, no. 9, pp. 1082–1087, 2009.
- I. Shimizu, Y. Yoshida, T. Katsuno et al., “p53-induced adipose tissue inflammation is critically involved in the development of insulin resistance in heart failure,” Cell Metabolism, vol. 15, no. 1, pp. 51–64, 2012.
- B. Vergoni, P. J. Cornejo, J. Gilleron et al., “DNA damage and the activation of the p53 pathway mediate alterations in metabolic and secretory functions of adipocytes,” Diabetes, vol. 65, no. 10, pp. 3062–3074, 2016.
- V. Picco and G. Pagès, “Linking JNK activity to the DNA damage response,” Genes & Cancer, vol. 4, no. 9-10, pp. 360–368, 2013.
- L. A. Heffernan-Stroud and L. M. Obeid, “p53 and regulation of bioactive sphingolipids,” Advances in Enzyme Regulation, vol. 51, no. 1, pp. 219–228, 2011.
- K. F. Petersen, S. Dufour, D. Befroy, R. Garcia, and G. I. Shulman, “Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes,” New England Journal of Medicine, vol. 350, no. 7, pp. 664–671, 2004.
- J. Szendroedi, T. Yoshimura, E. Phielix et al., “Role of diacylglycerol activation of PKCθ in lipid-induced muscle insulin resistance in humans,” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 26, pp. 9597–9602, 2014.
- J. M. Matés, J. A. Segura, F. J. Alonso, and J. Márquez, “Oxidative stress in apoptosis and cancer: an update,” Archives of Toxicology, vol. 86, no. 11, pp. 1649–1665, 2012.
- M. Zhou, Y. Li, Q. Hu et al., “Atomic structure of the apoptosome: mechanism of cytochrome c- and dATP-mediated activation of Apaf-1,” Genes & Development, vol. 29, no. 22, pp. 2349–2361, 2015.
- S. P. Cullen and S. J. Martin, “Caspase activation pathways: some recent progress,” Cell Death & Differentiation, vol. 16, no. 7, pp. 935–938, 2009.
- M. Suzuki, K. Aoshiba, and A. Nagai, “Oxidative stress increases Fas ligand expression in endothelial cells,” Journal of Inflammation, vol. 3, no. 1, p. 11, 2006.
- A. Sommerfeld, R. Reinehr, and D. Häussinger, “Free fatty acids shift insulin-induced hepatocyte proliferation towards CD95-dependent apoptosis,” Journal of Biological Chemistry, vol. 290, no. 7, pp. 4398–4409, 2015.
- A.-C. Johansson, H. Appelqvist, C. Nilsson, K. Kågedal, K. Roberg, and K. Öllinger, “Regulation of apoptosis-associated lysosomal membrane permeabilization,” Apoptosis, vol. 15, no. 5, pp. 527–540, 2010.
- H. Malhi, S. F. Bronk, N. W. Werneburg, and G. J. Gores, “Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis,” Journal of Biological Chemistry, vol. 281, no. 17, pp. 12093–12101, 2006.
- D. M. S. Ferreira, R. E. Castro, M. V. Machado et al., “Apoptosis and insulin resistance in liver and peripheral tissues of morbidly obese patients is associated with different stages of non-alcoholic fatty liver disease,” Diabetologia, vol. 54, no. 7, pp. 1788–1798, 2011.
- C. M. Mayer and D. D. Belsham, “Palmitate attenuates insulin signaling and induces endoplasmic reticulum stress and apoptosis in hypothalamic neurons: rescue of resistance and apoptosis through adenosine 5 monophosphate-activated protein kinase activation,” Endocrinology, vol. 151, no. 2, pp. 576–585, 2010.
- S. M. Turpin, G. I. Lancaster, I. Darby, M. A. Febbraio, and M. J. Watt, “Apoptosis in skeletal muscle myotubes is induced by ceramides and is positively related to insulin resistance,” American Journal of Physiology-Endocrinology and Metabolism, vol. 291, no. 6, pp. E1341–E1350, 2006.
- L. A. Pradelli, E. Villa, B. Zunino, S. Marchetti, and J.-E. Ricci, “Glucose metabolism is inhibited by caspases upon the induction of apoptosis,” Cell Death & Disease, vol. 5, no. 9, article e1406, 2014.
- A. Guilherme, G. J. Tesz, K. V. P. Guntur, and M. P. Czech, “Tumor necrosis factor-α induces caspase-mediated cleavage of peroxisome proliferator-activated receptor γ in adipocytes,” Journal of Biological Chemistry, vol. 284, no. 25, pp. 17082–17091, 2009.
- M. Keuper, I. Wernstedt Asterholm, P. E. Scherer et al., “TRAIL (TNF-related apoptosis-inducing ligand) regulates adipocyte metabolism by caspase-mediated cleavage of PPARgamma,” Cell Death & Disease, vol. 4, no. 1, article e474, 2013.
- S. El Akoum, “PPAR gamma at the crossroads of health and disease: a masterchef in metabolic homeostasis,” Endocrinology & Metabolic Syndrome, vol. 3, no. 1, p. 126, 2014.
- J. Tőzsér and S. Benkő, “Natural compounds as regulators of NLRP3 inflammasome-mediated IL-1β production,” Mediators of Inflammation, vol. 2016, Article ID 5460302, 16 pages, 2016.
- G. Meng, F. Zhang, I. Fuss, A. Kitani, and W. Strober, “A mutation in the Nlrp3 gene causing inflammasome hyperactivation potentiates Th17 cell-dominant immune responses,” Immunity, vol. 30, no. 6, pp. 860–874, 2009.
- P. Libby, J. M. Ordovas, K. R. Auger, A. H. Robbins, L. K. Birinyi, and C. A. Dinarello, “Endotoxin and tumor necrosis factor induce interleukin-1 gene expression in adult human vascular endothelial cells,” The American Journal of Pathology, vol. 124, no. 2, pp. 179–185, 1986.
- T. N. Tangi, A. A. Elmabsout, T. Bengtsson, A. Sirsjö, and K. Fransén, “Role of NLRP3 and CARD8 in the regulation of TNF-α induced IL-1β release in vascular smooth muscle cells,” International Journal of Molecular Medicine, vol. 30, no. 3, pp. 697–702, 2012.
- Y. Li, P. Wang, X. Yang et al., “SIRT1 inhibits inflammatory response partly through regulation of NLRP3 inflammasome in vascular endothelial cells,” Molecular Immunology, vol. 77, pp. 148–156, 2016.
- N. Huang, M. Kny, F. Riediger et al., “Deletion of Nlrp3 protects from inflammation-induced skeletal muscle atrophy,” Intensive Care Medicine Experimental, vol. 5, no. 1, p. 3, 2017.
- F. G. Bauernfeind, G. Horvath, A. Stutz et al., “Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression,” Journal of Immunology, vol. 183, no. 2, pp. 787–791, 2009.
- M. G. Ghonime, O. R. Shamaa, S. Das et al., “Inflammasome priming by lipopolysaccharide is dependent upon ERK signaling and proteasome function,” Journal of Immunology, vol. 192, no. 8, pp. 3881–3888, 2014.
- Q. He, H. You, X.-M. Li, T.-H. Liu, P. Wang, and B.-E. Wang, “HMGB1 promotes the synthesis of pro-IL-1β and pro-IL-18 by activation of p38 MAPK and NF-κB through receptors for advanced glycation end-products in macrophages,” Asian Pacific Journal of Cancer Prevention, vol. 13, no. 4, pp. 1365–1370, 2012.
- B. Vandanmagsar, Y.-H. Youm, A. Ravussin et al., “The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance,” Nature Medicine, vol. 17, no. 2, pp. 179–188, 2011.
- H. Scheiblich, A. Schlütter, D. T. Golenbock, E. Latz, P. Martinez-Martinez, and M. T. Heneka, “Activation of the NLRP3 inflammasome in microglia: the role of ceramide,” Journal of Neurochemistry, vol. 143, no. 5, pp. 534–550, 2017.
- O. Gross, C. J. Thomas, G. Guarda, and J. Tschopp, “The inflammasome: an integrated view,” Immunological Reviews, vol. 243, no. 1, pp. 136–151, 2011.
- R. Zhou, A. S. Yazdi, P. Menu, and J. Tschopp, “A role for mitochondria in NLRP3 inflammasome activation,” Nature, vol. 469, no. 7329, pp. 221–225, 2011.
- A. G. Lerner, J. P. Upton, P. V. K. Praveen et al., “IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress,” Cell Metabolism, vol. 16, no. 2, pp. 250–264, 2012.
- M. R. de Zoete, N. W. Palm, S. Zhu, and R. A. Flavell, “Inflammasomes,” Cold Spring Harbor Perspectives in Biology, vol. 6, no. 12, 2014.
- C. Li, J. Zienkiewicz, and J. Hawiger, “Interactive sites in the MyD88 toll/interleukin (IL) 1 receptor domain responsible for coupling to the IL1β signaling pathway,” Journal of Biological Chemistry, vol. 280, no. 28, pp. 26152–26159, 2005.
- J. Jager, T. Grémeaux, M. Cormont, Y. Le Marchand-Brustel, and J. F. Tanti, “Interleukin-1β-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression,” Endocrinology, vol. 148, no. 1, pp. 241–251, 2007.
- A. Y. Kim, Y. J. Park, X. Pan et al., “Obesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance,” Nature Communications, vol. 6, no. 1, p. 7585, 2015.
- A. Wree, A. Eguchi, M. D. McGeough et al., “NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice,” Hepatology, vol. 59, no. 3, pp. 898–910, 2014.
- H. Xiao, M. Lu, T. Y. Lin et al., “Sterol regulatory element binding p1rotein 2 activation of NLRP3 inflammasome in endothelium mediates hemodynamic-induced atherosclerosis susceptibility,” Circulation, vol. 128, no. 6, pp. 632–642, 2013.
- V. Elgazar-Carmon, A. Rudich, N. Hadad, and R. Levy, “Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding,” Journal of Lipid Research, vol. 49, no. 9, pp. 1894–1903, 2008.
- K. Makki, P. Froguel, and I. Wolowczuk, “Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines,” ISRN Inflammation, vol. 2013, Article ID 139239, 12 pages, 2013.
- A. Mantovani, M. A. Cassatella, C. Costantini, and S. Jaillon, “Neutrophils in the activation and regulation of innate and adaptive immunity,” Nature Reviews Immunology, vol. 11, no. 8, pp. 519–531, 2011.
- M. Mraz and M. Haluzik, “The role of adipose tissue immune cells in obesity and low-grade inflammation,” The Journal of Endocrinology, vol. 222, no. 3, pp. R113–R127, 2014.
- P. Newsholme and P. I. H. de Bittencourt Jr., “The fat cell senescence hypothesis: a mechanism responsible for abrogating the resolution of inflammation in chronic disease,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 17, no. 4, pp. 295–305, 2014.
- P. Codogno and A. J. Meijer, “Autophagy: a potential link between obesity and insulin resistance,” Cell Metabolism, vol. 11, no. 6, pp. 449–451, 2010.
- G. S. Hotamisligil, “Endoplasmic reticulum stress and the inflammatory basis of metabolic disease,” Cell, vol. 140, no. 6, pp. 900–917, 2010.
- Y. Zhao, C.-F. Zhang, H. Rossiter et al., “Autophagy is induced by UVA and promotes removal of oxidized phospholipids and protein aggregates in epidermal keratinocytes,” Journal of Investigative Dermatology, vol. 133, no. 6, pp. 1629–1637, 2013.
- S. T. Shibutani and T. Yoshimori, “A current perspective of autophagosome biogenesis,” Cell Research, vol. 24, no. 1, pp. 58–68, 2014.
- M. Rahman, M. Mofarrahi, A. S. Kristof, B. Nkengfac, S. Harel, and S. N. A. Hussain, “Reactive oxygen species regulation of autophagy in skeletal muscles,” Antioxidants & Redox Signaling, vol. 20, no. 3, pp. 443–459, 2014.
- A. Sasnauskiene, J. Kadziauskas, N. Vezelyte, V. Jonusiene, and V. Kirveliene, “Damage targeted to the mitochondrial interior induces autophagy, cell cycle arrest and, only at high doses, apoptosis,” Autophagy, vol. 5, no. 5, pp. 743-744, 2009.
- C. Luo, Y. Li, H. Wang et al., “Mitochondrial accumulation under oxidative stress is due to defects in autophagy,” Journal of Cellular Biochemistry, vol. 114, no. 1, pp. 212–219, 2013.
- M. Portovedo, L. M. Ignacio-Souza, B. Bombassaro et al., “Saturated fatty acids modulate autophagy’s proteins in the hypothalamus,” PLoS One, vol. 10, no. 3, article e0119850, 2015.
- H. Soussi, K. Clément, and I. Dugail, “Adipose tissue autophagy status in obesity: expression and flux—two faces of the picture,” Autophagy, vol. 12, no. 3, pp. 588-589, 2016.
- J. M. Norman, G. M. Cohen, and E. T. W. Bampton, “The in vitro cleavage of the hAtg proteins by cell death proteases,” Autophagy, vol. 6, no. 8, pp. 1042–1056, 2010.
- N. Rodríguez-Muela, A. M. Hernández-Pinto, A. Serrano-Puebla et al., “Lysosomal membrane permeabilization and autophagy blockade contribute to photoreceptor cell death in a mouse model of retinitis pigmentosa,” Cell Death & Differentiation, vol. 22, no. 3, pp. 476–487, 2015.
- M. S. Goligorsky, “SIRTing out the link between autophagy and ageing,” Nephrology Dialysis Transplantation, vol. 25, no. 8, pp. 2434–2436, 2010.
- J.-H. Cho, G.-Y. Kim, C.-J. Pan et al., “Downregulation of SIRT1 signaling underlies hepatic autophagy impairment in glycogen storage disease type Ia,” PLoS Genetics, vol. 13, no. 5, article e1006819, 2017.
- M. Jiao, F. Ren, L. Zhou et al., “Peroxisome proliferator-activated receptor α activation attenuates the inflammatory response to protect the liver from acute failure by promoting the autophagy pathway,” Cell Death & Disease, vol. 5, no. 8, article e1397, 2014.
- F. Ren, L. Zhang, X. Zhang et al., “Inhibition of glycogen synthase kinase 3β promotes autophagy to protect mice from acute liver failure mediated by peroxisome proliferator-activated receptor α,” Cell Death & Disease, vol. 7, no. 3, article e2151, 2016.
- K. H. Kim, Y. T. Jeong, H. Oh et al., “Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine,” Nature Medicine, vol. 19, no. 1, pp. 83–92, 2013.
- Q. Gong, Z. Hu, F. Zhang et al., “Fibroblast growth factor 21 improves hepatic insulin sensitivity by inhibiting mammalian target of rapamycin complex 1 in mice,” Hepatology, vol. 64, no. 2, pp. 425–438, 2016.
- Y. Yu, J. He, S. Li et al., “Fibroblast growth factor 21 (FGF21) inhibits macrophage-mediated inflammation by activating Nrf2 and suppressing the NF-κB signaling pathway,” International Immunopharmacology, vol. 38, pp. 144–152, 2016.
- Z. Lin, H. Tian, K. S. L. Lam et al., “Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice,” Cell Metabolism, vol. 17, no. 5, pp. 779–789, 2013.
- W. L. Holland, A. C. Adams, J. T. Brozinick et al., “An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice,” Cell Metabolism, vol. 17, no. 5, pp. 790–797, 2013.
- P. Xu, Y. Zhang, W. Wang et al., “Long-term administration of fibroblast growth factor 21 prevents chemically-induced hepatocarcinogenesis in mice,” Digestive Diseases and Sciences, vol. 60, no. 10, pp. 3032–3043, 2015.
- J. Zhang and Y. Li, “Fibroblast growth factor 21 analogs for treating metabolic disorders,” Frontiers in Endocrinology, vol. 6, p. 168, 2015.
- F. M. Fisher, P. C. Chui, P. J. Antonellis et al., “Obesity is a fibroblast growth factor 21 (FGF21)-resistant state,” Diabetes, vol. 59, no. 11, pp. 2781–2789, 2010.
- J. Y. Jeon, S.-E. Choi, E. S. Ha et al., “Association between insulin resistance and impairment of FGF21 signal transduction in skeletal muscles,” Endocrine, vol. 53, no. 1, pp. 97–106, 2016.
- J. M. Gallego-Escuredo, J. Gomez-Ambrosi, V. Catalan et al., “Opposite alterations in FGF21 and FGF19 levels and disturbed expression of the receptor machinery for endocrine FGFs in obese patients,” International Journal of Obesity, vol. 39, no. 1, pp. 121–129, 2015.
- A. C. Adams, C. C. Cheng, T. Coskun, and A. Kharitonenkov, “FGF21 requires βklotho to act in vivo,” PLoS One, vol. 7, no. 11, article e49977, 2012.
- K. R. Markan, M. C. Naber, S. M. Small, L. Peltekian, R. L. Kessler, and M. J. Potthoff, “FGF21 resistance is not mediated by downregulation of beta-klotho expression in white adipose tissue,” Molecular Metabolism, vol. 6, no. 6, pp. 602–610, 2017.
- S. Kim, H.-G. Lee, S.-A. Park et al., “Keap1 cysteine 288 as a potential target for diallyl trisulfide-induced Nrf2 activation,” PLoS One, vol. 9, no. 1, article e85984, 2014.
- J. A. David, W. J. Rifkin, P. S. Rabbani, and D. J. Ceradini, “The Nrf2/Keap1/ARE pathway and oxidative stress as a therapeutic target in type II diabetes mellitus,” Journal of Diabetes Research, vol. 2017, Article ID 4826724, 15 pages, 2017.
- B. Chen, Y. Lu, Y. Chen, and J. Cheng, “The role of Nrf2 in oxidative stress-induced endothelial injuries,” Journal of Endocrinology, vol. 225, no. 3, pp. R83–R99, 2015.
- S. Fourquet, R. Guerois, D. Biard, and M. B. Toledano, “Activation of NRF2 by nitrosative agents and H2O2 involves KEAP1 disulfide formation,” Journal of Biological Chemistry, vol. 285, no. 11, pp. 8463–8471, 2010.
- A. Jiménez-Osorio, A. Picazo, S. González-Reyes, D. Barrera-Oviedo, M. Rodríguez-Arellano, and J. Pedraza-Chaverri, “Nrf2 and redox status in prediabetic and diabetic patients,” International Journal of Molecular Sciences, vol. 15, no. 12, pp. 20290–20305, 2014.
- H.-J. He, G.-Y. Wang, Y. Gao, W.-H. Ling, Z.-W. Yu, and T.-R. Jin, “Curcumin attenuates Nrf2 signaling defect, oxidative stress in muscle and glucose intolerance in high fat diet-fed mice,” World Journal of Diabetes, vol. 3, no. 5, pp. 94–104, 2012.
- R. Faraonio, P. Vergara, D. di Marzo et al., “p53 suppresses the Nrf2-dependent transcription of antioxidant response genes,” Journal of Biological Chemistry, vol. 281, no. 52, pp. 39776–39784, 2006.
- Y. Tan, T. Ichikawa, J. Li et al., “Diabetic downregulation of Nrf2 activity via ERK contributes to oxidative stress–induced insulin resistance in cardiac cells in vitro and in vivo,” Diabetes, vol. 60, no. 2, pp. 625–633, 2011.
- A.-S. Cheng, Y.-H. Cheng, C.-H. Chiou, and T.-L. Chang, “Resveratrol upregulates Nrf2 expression to attenuate methylglyoxal-induced insulin resistance in Hep G2 cells,” Journal of Agricultural and Food Chemistry, vol. 60, no. 36, pp. 9180–9187, 2012.
- A. K. Jain and A. K. Jaiswal, “GSK-3β acts upstream of Fyn kinase in regulation of nuclear export and degradation of NF-E2 related factor 2,” Journal of Biological Chemistry, vol. 282, no. 22, pp. 16502–16510, 2007.
- D. V. Kratschmar, D. Calabrese, J. Walsh et al., “Suppression of the Nrf2-dependent antioxidant response by glucocorticoids and 11β-HSD1-mediated glucocorticoid activation in hepatic cells,” PLoS One, vol. 7, no. 5, article e36774, 2012.
- M. Matsuda and I. Shimomura, “Roles of oxidative stress, adiponectin, and nuclear hormone receptors in obesity-associated insulin resistance and cardiovascular risk,” Hormone Molecular Biology and Clinical Investigation, vol. 19, no. 2, pp. 75–88, 2014.
- D. J. Wake, E. Rask, D. E. W. Livingstone, S. Söderberg, T. Olsson, and B. R. Walker, “Local and systemic impact of transcriptional up-regulation of 11β-hydroxysteroid dehydrogenase type 1 in adipose tissue in human obesity,” The Journal of Clinical Endocrinology & Metabolism, vol. 88, no. 8, pp. 3983–3988, 2003.
- J. Xu, S. R. Kulkarni, A. C. Donepudi, V. R. More, and A. L. Slitt, “Enhanced Nrf2 activity worsens insulin resistance, impairs lipid accumulation in adipose tissue, and increases hepatic steatosis in leptin-deficient mice,” Diabetes, vol. 61, no. 12, pp. 3208–3218, 2012.
- D. V. Chartoumpekis, P. G. Ziros, A. I. Psyrogiannis et al., “Nrf2 represses FGF21 during long-term high-fat diet–induced obesity in mice,” Diabetes, vol. 60, no. 10, pp. 2465–2473, 2011.
- A. Lau, X. J. Wang, F. Zhao et al., “A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62,” Molecular and Cellular Biology, vol. 30, no. 13, pp. 3275–3285, 2010.
- A. Lau, Y. Zheng, S. Tao et al., “Arsenic inhibits autophagic flux, activating the Nrf2-Keap1 pathway in a p62-dependent manner,” Molecular and Cellular Biology, vol. 33, no. 12, pp. 2436–2446, 2013.
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