Mediators of Inflammation

Mediators of Inflammation / 2013 / Article
Special Issue

Inflammation in the Disease: Mechanism and Therapies

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Review Article | Open Access

Volume 2013 |Article ID 135698 |

Anna Hernández-Aguilera, Anna Rull, Esther Rodríguez-Gallego, Marta Riera-Borrull, Fedra Luciano-Mateo, Jordi Camps, Javier A. Menéndez, Jorge Joven, "Mitochondrial Dysfunction: A Basic Mechanism in Inflammation-Related Non-Communicable Diseases and Therapeutic Opportunities", Mediators of Inflammation, vol. 2013, Article ID 135698, 13 pages, 2013.

Mitochondrial Dysfunction: A Basic Mechanism in Inflammation-Related Non-Communicable Diseases and Therapeutic Opportunities

Academic Editor: Fábio Santos Lira
Received05 Dec 2012
Revised01 Feb 2013
Accepted01 Feb 2013
Published28 Feb 2013


Obesity is not necessarily a predisposing factor for disease. It is the handling of fat and/or excessive energy intake that encompasses the linkage of inflammation, oxidation, and metabolism to the deleterious effects associated with the continuous excess of food ingestion. The roles of cytokines and insulin resistance in excessive energy intake have been studied extensively. Tobacco use and obesity accompanied by an unhealthy diet and physical inactivity are the main factors that underlie noncommunicable diseases. The implication is that the management of energy or food intake, which is the main role of mitochondria, is involved in the most common diseases. In this study, we highlight the importance of mitochondrial dysfunction in the mutual relationships between causative conditions. Mitochondria are highly dynamic organelles that fuse and divide in response to environmental stimuli, developmental status, and energy requirements. These organelles act to supply the cell with ATP and to synthesise key molecules in the processes of inflammation, oxidation, and metabolism. Therefore, energy sensors and management effectors are determinants in the course and development of diseases. Regulating mitochondrial function may require a multifaceted approach that includes drugs and plant-derived phenolic compounds with antioxidant and anti-inflammatory activities that improve mitochondrial biogenesis and act to modulate the AMPK/mTOR pathway.

1. Background

The burden of noncommunicable diseases is increasing as such diseases are now responsible for more than three in five deaths worldwide. Atherosclerosis and cancer, in which tobacco use and excessive energy intake are determining factors, are the most frequently occurring of these diseases and are potentially preventable [1, 2]. Obesity and associated metabolic disturbances, which have been increasing worldwide in recent years, are the main factors that underlie noncommunicable diseases and are the consequences of unhealthy diets and physical inactivity [3]. Approximately 10–20% of patients with severe obesity, defined as a body mass index (BMI) > 40, present with no other metabolic complications. These patients are referred to by the oxymoronic designation of “metabolically healthy” obese [47]. Such a designation implies that most obese patients are not “metabolically healthy. ” Hence, risk factors for the appearance of noncommunicable diseases have emerged. The reasons for these two phenotypes are unknown; the phenotypes might represent different transitions on a disease timeline, and different levels of either chronic inflammation or insulin resistance are likely contributors. Other contributors include gradual differences in glucose tolerance, inflammatory responses, adipose tissue distribution, patterns of adipokine secretion, and age.

Emerging obesogenic factors are likely to present with significant differences in the elderly, and consequently the prevalence of obesity is expected to increase with increasing age. Therefore, it is likely not coincidental that most co-morbidity associated with obesity and hence with noncommunicable diseases correlates with aging; the processes may share basic mechanisms, particularly mitochondrial age within an individual [7]. Of note, the prevalence of obesity is lower in people over 70 years of age, an effect attributed to the selective mortality of middle-aged people [8].

Current recommendations to decrease food intake and increase physical exercise do result in metabolic improvements, but such lifestyle changes are rarely sustained, despite strong motivation. However, several communities have undertaken initiatives to prevent noncommunicable diseases, and the lessons learned from the implementation of such initiatives should be examined further [9]. The active manipulation of energy sensors and effectors might be a possible alternative therapeutic procedure. Our aim is to provide a succinct review of the scarce and disseminated data that link mitochondrial dysfunction to the pathogenesis of energy-related complications and to discuss a possible multifaceted therapeutic approach.

Mitochondrial defects, systemic inflammation, and oxidative stress are at the root of most noncommunicable diseases such as cancer, atherosclerosis, Parkinson’s disease, Alzheimer’s disease, other neurodegenerative diseases, heart and lung disturbances, diabetes, obesity, and autoimmune diseases [1016]. Obesity and obesity-related complications as well as impairment of mitochondrial function, which is required for normal metabolism and health (Figure 1), are universally associated with these conditions. The exact mechanisms that associate mitochondrial dysfunction, obesity, and aging with metabolic syndrome remain a topic of debate [1722].

Body weight is controlled by molecular messengers that regulate energy status in a limited number of susceptible tissues, including the liver, adipose tissue, skeletal muscles, pancreas, and the hypothalamus [7, 23]. Mouse models of diet-induced obesity have revealed important morphological and molecular differences with respect to humans, particularly those related to the development of fatty liver (NAFLD: nonalcoholic fatty liver disease) or nonalcoholic steatohepatitis (NASH) [2430] (Figure 2). High expectations for a human therapy after the generation of leptin-deficient animals (Ob/Ob) were countered by the determination that leptin is not a therapeutic option in humans [28].

Endoplasmic reticulum (ER) and mitochondrial stress, with the consequent oxidative stress, are immediate consequences of attempts to store excess food energy [23, 29]. Under normal weight conditions, adipose tissue-derived adipokines maintain the homeostasis of glucose and lipid metabolism; however, in obese conditions, the dysregulated production of adipokines favours the development of metabolic syndrome and related complications, particularly the accumulation of triglycerides in nonadipose organs that are not designed to store energy [19]. Other adipokines may cause inflammation and oxidative stress [31], but unknown factors are involved because interventions to ameliorate insulin resistance do not lead uniformly to clinical improvement [32]. It is of paramount importance to understand the mechanisms that disrupt ER homeostasis and lead to the activation of the unfolded protein response and mitochondrial defects in metabolic diseases in order to correctly manage noncommunicable diseases [33].

Incidentally, the role of genetics in low-energy expenditure and chronic food intake, although potentially significant, remains poorly understood [29, 30]. The genetic-selection hypothesis, which attempts to explain the high prevalence of obesity and diabetes in humans, remains controversial, since the recent abandonment of the “thrifty” gene hypothesis [3438]. As a result, the roles of oxidative stress, inflammation, mitochondrial dysfunction, nutritional status, and metabolism might be reinforced in hypotheses regarding the pathogenesis of noncommunicable diseases (Figures 3 and 4).

Inflammation plays a vital role in host defence. Tissue damage, fibrosis, and losses of function occur under chronic inflammatory conditions. Growing evidence links a low-grade, chronic inflammatory state to obesity and its coexisting conditions as well as to noncommunicable diseases [1016]. This low-grade inflammatory state is aggravated by the recruitment of inflammatory cells, mainly macrophages, to adipose tissue. Inflammatory cell recruitment is likely due to the combined effects of the complex regulatory network of cells and mediators that are designed to resolve inflammatory responses [7]. Anti-inflammatory drugs have shown to reverse insulin resistance and other related conditions that result from circulating cytokines that cause and maintain insulin resistance [19, 23, 3942]. Therefore, it is likely that inflammation per se is a causal factor for noncommunicable diseases rather than an associated risk factor.

It is also important to highlight that adipose tissue is comprised of multiple types of cells that have intrinsic and important endocrine functions, particularly those mediated by leptin and adiponectin. Recruited and resident macrophages secrete the majority of inflammatory adipokines, specifically tumour necrosis factor (TNF ), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1), among others. The major roles of TNF and other inflammatory cytokines in the progression of metabolic complications are likely related to oxidative stress [43, 44]. In adipose tissue macrophages, increased concentrations of saturated free fatty acids (FFAs) stimulate the synthesis of TNF directly through the Toll-like receptor 4 (TLR4) or indirectly through cellular accumulation. Both macrophages and adipocytes possess TLR4 receptors that, upon lipid-dependent activation, induce NF-KB translocation to the nucleus and the subsequent synthesis of TNF and IL-6 [7, 43, 44]. However, recruited macrophages have unique inflammatory properties that are not observed in resident tissue macrophages, and the recruitment of these cells is mainly modulated by MCP-1, the most important molecule of the CC chemokine family [7]. In this setting, the roles and polarisation of adipose tissue macrophages (ATMs) seem established [45]. M1 or “classically activated” ATMs are increased, and M2 or “alternatively activated” ATMs are decreased in the adipose tissues of both obese mice and obese humans, as discussed below [46, 47].

It is frequently assumed that, in contrast to hormones, chemokines influence cellular activities in an autocrine or paracrine fashion. However, chemokines may be relevant effectors in chronic systemic inflammation as the confinement of these molecules to well-defined environments is unlikely. Specifically, alterations in plasma MCP-1 concentrations in metabolic disease states, the presence of circulating chemokine reservoirs, recent evidence of novel mechanisms of action, and certain unexplained responses associated with metabolic disturbances suggest that MCP-1 might have a systemic role in metabolic regulation [4850]. How and when obesity might initiate an inflammatory response remains controversial, but the underlying mechanism likely depends on the activation of the c-Jun N-terminal kinase (JNK) in insulin-sensitive tissues, as JNK is likely the principal mechanism through which inflammatory signals interfere with insulin activity [7].

ER stress responses and mitochondrial defects are also linked to the mTOR pathway, discussed below, which is essential for the regulation of numerous processes, including the cell cycle, energy metabolism, the immune response, and autophagy. Therefore, the specific cellular changes associated with metabolic alterations, particularly mitochondrial dysfunction, require further attention.

3. Mitochondria: Bioenergy Couples Metabolism, Oxidation, and Inflammation

Mitochondria are essential organelles that, among other functions, supply the cell with ATP through oxidative phosphorylation, synthesise key molecules, and buffer calcium gradients; however, they are also a source of free radicals (Figures 1, 3, and 4). It is not surprising that mitochondrial health is tightly regulated and associated with the homeostasis and aging of the organism. Within these processes, the antagonistic and balanced activities of the fusion and fission machineries constantly provide adequate responses to events caused by inflammation (Figure 5) [23, 5054]. A shift towards fusion favours the generation of interconnected mitochondria, which contribute to the dissipation and rapid provision of energy. A shift towards fission results in numerous mitochondrial fragments. Apparently, the mixing of the matrix and the inner membrane allows the respiratory machinery components to cooperate most efficiently. Furthermore, fusion maximises ATP synthesis. In quiescent cells, mitochondria are frequently present as numerous morphologically and functionally distinct small spheres or short rods [51, 55, 56]. Upon the exposure of cells to stress, fusion optimises mitochondrial function and plays a beneficial role in the maintenance of long-term bioenergetics capacities. In contrast, the mitochondrial fission machinery contributes to the elimination of irreversibly damaged mitochondria through autophagy [5558]. This process, also called mitophagy, is extremely important under both physiological and pathological conditions (Figure 6). A detailed discussion of the importance of mitophagy is beyond the scope of this review; however, as an example of its importance, recall that amino acids are not stored in the body but are instead mobilised by proteolysis under conditions such as starvation, reduced physical activity, and disease [59]. Furthermore, intense exercise may modulate hepatic metabolism through similar mechanisms [60]. More recently, the mitochondrial E3 ubiquitin protein ligase 1 (Mul 1) was identified as a key protein that promotes mitophagy and skeletal muscle loss [61]. Mitochondrial fission per se triggers organelle dysfunction and muscle loss. The opposite is observed when mitochondrial fission is inhibited. The same authors [61] also demonstrated that the overexpression of Forkhead box O3 (FoxO3) induces mitochondrial disruption via mitophagy.

Therefore, it is not surprising that mitochondrial diseases often have an associated metabolic component, and consequently mitochondrial defects are expected in inflammation, aging, and other energy-dependent disturbances [58, 62]. In such disturbances, cellular oxidative damage caused by the generation of reactive oxygen species (ROS) that exceed the natural antioxidant activity is likely an initiating factor in inflammation and aging [63, 64]. Several potential therapeutic approaches are currently available to slow down age-related functional declines [65], including antioxidant treatments [66]; however, the effectiveness of existing antioxidants is likely suboptimal because these antioxidants are not selective for mitochondria [67]. However, recent experiments with a mitochondria-targeted antioxidant have been successful in animal models [67]. Similar assumptions can be made for endothelial cells, in which oxidation and the accompanying inflammation are recognised factors for atherosclerosis. Oxidative stress, which is mainly derived from mitochondrial dysfunction, decreases NO synthesis, contributes to hypertension, upregulates the secretion of adhesion molecules and inflammatory cytokines, and is responsible for the oxidation of low-density lipoproteins [68, 69].

Defective mitochondrial function in muscle tissues leads to reduced fatty acid oxidation and the inhibition of glucose transport, indicating that insulin-stimulated glucose transport is reduced. This is a hallmark of insulin resistance and type 2 diabetes. The chronic production of excess ROS and inflammation result in mitochondrial dysfunction potentially inducing lipid accumulation in these tissues and the endless vicious cycle of insulin resistance [7074]. Mitochondrial ROS have also been related to the increased activity of uncoupling proteins (UCP), which uncouple ATP synthesis from electron transport. UCP activity leads to heat generation without ATP production, and long-term reductions in ATP levels affect cellular insulin signalling. The roles of the UCPs and the metabolically relevant differences between brown and white adipose tissues were reviewed recently [7577].

The mitochondria of obese individuals are different from those of lean individuals. Alterations in mitochondrial morphology, impaired mitochondrial bioenergetics, increased mitochondrial lipid peroxides, decreased ATP content, and mitochondrial dysfunction further increase the risks of developing metabolic complications [78, 79]. In comparison to those of lean individuals, mitochondria in obese individuals have lower energy-generating capacities, less clearly defined inner membranes, and reduced fatty acid oxidation. These differences might promote the development and progression of obesity and might also have therapeutic implications [80, 81]. Impaired mitochondrial function could account for the insulin resistance that is closely associated with increased lipid content in the muscles of patients with type 2 diabetes. Altered mitochondrial function is the major factor that leads to increased muscular lipid accumulation and decreased insulin sensitivity [80, 81]. More recently, a model was created in which the amount of mitochondrial activity in adipocytes and hepatocytes can be altered based on the properties of the mitochondrial protein mitoNEET, which is located at the outer membrane [70]. Despite the prevalence of obesity in this model, mitoNEET overexpression during periods of high caloric intake resulted in systemwide improvements in insulin sensitivity, thereby providing a model of a “metabolically healthy” obese state with minimal tissue lipotoxicity that is similar to the clinically observed condition [82]. Alterations in mitoNEET expression might modulate ROS concentrations and mitochondrial iron transport into the matrix [70, 82, 83]. The mitochondrial fusion protein mitofusin-2 (Mfn-2), another useful protein in studies of mitochondrial dysfunction, regulates cellular metabolism and controls mitochondrial metabolism. In cultured cells, mitochondrial metabolism was activated in Mfn-2 gain-of-function experiments, whereas Mfn-2 loss-of-function reduced glucose oxidation, mitochondrial membrane potential, oxygen consumption, and mitochondrial proton leakage [84]. It is defective in the muscles of obese and type 2 diabetes patients in which mitochondrial size is reduced [71].

Therefore, a detailed characterisation of the proteins involved in mitochondrial fusion and fission and studies of the mechanisms that regulate these two processes are relevant to human pathology and might have a great therapeutic potential to improve metabolism and to decrease the generation of oxidative stress and excessive inflammatory response [85].

Apoptosis is another basic process to consider in metabolic diseases. Excess food intake leads to mitochondrial dysfunction and higher apoptotic susceptibility. Mitochondria specialise in energy production and cell killing. Only 13 proteins are encoded by the mitochondrial DNA, a circular molecule of 16 Kb. The remaining necessary proteins are encoded in the nuclear DNA [86]. Mitochondria are composed of outer and inner specialised membranes that define two separate components, the matrix and the intermembrane space [87]. Mitochondria regulate apoptosis in response to cellular stress signals and determine whether cells live or die [88]. Thus, it is conceivable that the availability or ingestion of nutrients could be a main candidate in the regulation of cell death and that mitochondria could have been selected as a nutrient sensor and effector. This could explain the influence of apoptosis-related proteins on mitochondrial respiration [89].

A common laboratory finding is that the morphology of the mitochondria changes when mice are supplied with a high-fat diet (Figure 7) and that optimal mitochondrial performance is achieved under conditions of calorie restriction. Excess food intake impairs respiratory capacities, likely through mTOR, and increases the susceptibility of the cell to apoptosis and additional stress [90, 91]. Of note, apoptotic protein levels are increased in the adipocytes of obese humans, and the depletion of proapoptotic proteins protects against liver steatosis and insulin resistance in mice fed a high-fat, high-cholesterol diet [92]. These conditions are relevant to the development of metabolic syndrome, as nutritional imbalances in Western diets lead to mitochondrial dysfunction and higher susceptibilities to inflammation, apoptosis, and aging [22].

5. AMP-Activated Protein Kinase (AMPK) Not Only Influences Metabolism in Adipocytes but Also Suppresses the Proinflammatory Environment

AMPK has anti-inflammatory actions that are independent of its effects on glucose and lipid metabolism [93]. The action of AMPK is not necessarily identical in all tissues. In adipose tissues, the role of AMPK is largely unknown because laboratory techniques to explore the action of this kinase in terminally differentiated adipocytes have not been fully established. Several agents have been used to activate AMPK experimentally, including AICAR (5′-aminoimidazole-4-carboxamide ribonucleoside), metformin, rosiglitazone, resveratrol and other polyphenols, statins, and several adipocytokines. In adipocytes, AMPK appears to increase the insulin-stimulated uptake of glucose, likely by increasing the expression of GLUT4, yet inhibits glucose metabolism [94]. Studies of the effects of AMPK on lipolysis in adipocytes have been controversial; some authors have reported an antilipolytic effect, while others have suggested that AMPK stimulates lipolysis [95, 96]. However, the activation of AMPK by metformin in human adipose tissues increases the phosphorylation of acetyl-CoA carboxylase (ACC) and decreases the expression of lipogenic genes, leading to reductions in malonyl-CoA, which is the precursor for fatty acid synthesis; malonyl-CoA also regulates fatty acid oxidation through the inhibition of carnitine palmitoyl-transferase 1, the rate-limiting enzyme for fatty acid entry into the mitochondria [97, 98]. Adipose tissue secretes adipocytokines, which influence metabolic and inflammatory pathways through the recruitment of macrophages and the consequent transition from the M2 state to M1 [7, 41]. These actions contribute to the development of disease (Figure 8). Conversely, adiponectin has been reported to induce adipose macrophages to switch to the anti-inflammatory M2 state [99]. AMPK is anti-inflammatory, as it inhibits the synthesis of proinflammatory cytokines and promotes the expression of IL-10 in macrophages; adiponectin and leptin levels may also be regulated by AMPK [100] (Figure 8). Finally, brown adipocytes contain high numbers of mitochondria that express UCP1, which permit thermogenesis. Exposure to cold temperatures stimulates AMPK and may play a role in the differentiation of fatty oxidising brown adipose tissue, thus leading to greater energy expenditure [101]. Therefore, we hypothesise that the chronic manipulation of the AMPK/mechanistic target of rapamycin (mTOR) pathway might represent a therapeutic approach for preventing noncommunicable diseases (Figure 8). Metformin, along with salicylate, polyphenols, and rapamycin, has a long history of safe and effective use, but other modulators are currently under development and will likely permit the design of tissue-specific activators of this pathway.

The first therapeutic approaches to metabolic disturbances are reduced caloric ingestion and increased physical activity. The effects are based mainly on weight reduction, but usefulness in other common complications remains incompletely explored [102]. Bariatric surgery is also effective, even in “metabolically healthy” patients [103, 104]. The effectiveness of surgery for the treatment of metabolic disturbances is surprisingly higher than expected, and mechanisms associated with surgical effects are not completely understood.

Insulin resistance and mitochondrial dysfunction appear to be the most significant alternative therapeutic targets. Metabolic abnormalities are associated with inflammation. Normally, glycolysis yields pyruvate, which is further oxidised in the mitochondria. When oxygen becomes limiting, mitochondrial oxidative metabolism is restricted. The induction of an inflammatory response is an energy-intensive process, and the involved cells rapidly switch from resting to highly active states. This is observed in diseases such as cancer, atherosclerosis, or autoimmune diseases, and mechanistic insights suggest the common involvement of the transcription factor hypoxia-inducible factor 1α, AMPK, and the mTOR pathway. In addition, the activation of sirtuins, which act as NAD+ sensors that connect nutrition and metabolism to chromatin structure, is anti-inflammatory [105] (Figure 8).

The use of metformin, an AMPK activator used extensively to treat type 2 diabetes, has been indicated for other metabolic conditions based on the rationale that insulin-sensitising agents might be effective [106], and the mode of action of metformin has guided our own experiments on cancer, aging, and viral infection [65, 107, 108]. We have shown that the beneficial effects of this biguanide class drug, which was initially obtained from Galega officinalis, are universal in patients with metabolic complications and negligible in patients without such complications. The primary effect is thought to be the suppression of hepatic glucose production and hepatic lipogenesis [109]. Metformin activates AMPK in hepatocytes, resulting in the phosphorylation and inactivation of ACA, a rate-limiting enzyme in lipogenesis [110], and theoretically might be useful and safe in the treatment of NAFLD [111]. Surprisingly, the beneficial clinical effects seem to be limited, despite the effects of metformin on insulin resistance, most likely because long-term treatment is an absolute requirement for the prevention of progressive disease. Our own current experiments in animal models suggest new insights into this phenomenon. Metformin activates AMPK, but AMPK deficiency does not abolish the effects of metformin on hepatic glucose production, indicating that the role of AMPK is dispensable, as indicated previously [112]. This suggests that the overall effect of metformin is mediated through actions on mitochondrial function through decreases in the hepatic energy state and intracellular ATP content. Other studies suggest that metformin inhibits Complex I of the mitochondrial respiratory chain, but the exact mechanisms and pathways involved are unclear [113]. Sirtuin 3 (SIRT 3), a member of the family of nicotinamide adenine dinucleotide (NAD+) dependent deacetylase proteins, is a crucial regulator of mitochondrial function that controls the global acetylation of the organelle (all sirtuins regulate energy production and the cell cycle; Figure 8). SIRT3 induces the activity of Complex I and promotes oxidative phosphorylation. In SIRT3 knockout mice, mitochondrial proteins are hyperacetylated, and cellular ATP levels are reduced, effects that are aggravated by fasting [114]. As a complement, peroxisome proliferator-activated receptor gamma coactivator 1-alpha induces the expression of SIRT3 in the liver [115]. Therefore, mitochondrial function appears to be the key target of metformin; reductions in ATP production may mediate the hepatic and antihyperglycemic actions of the drug and downregulate SIRT3 expression [116]. However, metformin distinctively regulates the expression of different sirtuin family members [117, 118]. In summary, metformin acts against both insulin resistance and mitochondrial dysfunction and is currently an attractive candidate agent of choice in the management of metabolic disorders. We have recently reviewed this complex scenario and found the following: (1) the unique ability of metformin to activate AMPK while leading to the increased utilisation of energy occurs because metformin inhibits AMP deaminase; and (2) in metabolic tissues, metformin can inhibit cell growth by functionally mimicking the effects of a multitargeted antifolate [119].

Based on these and other findings, we have also demonstrated that plant-derived phenolic compounds interact with numerous targets and multiple deregulated signalling pathways that may be useful in the management of metabolic conditions [120123]. The proposed mechanisms are direct antioxidant activity, attenuation of endoplasmic reticulum stress, blockade of proinflammatory cytokines, and blockade of transcription factors related to metabolic diseases [120]. Most polyphenols modulate oxidative stress and inflammatory responses through relevant actions in the process of macrophage recruitment. Interactions between the chemokine/cytokine network and bioenergetics, likely through the mTOR pathway, may also represent potential mechanisms for the prevention of metabolic disturbances [121]. Moreover, polyphenols attenuate the metabolic effects of high-fat, high-cholesterol diets when administered continuously at high doses, and we have described beneficial actions associated with the expression of selected microRNAs [122].

Inflammation lies at the heart of many diseases because the entire body is under metabolic stress, which induces symptoms and causes morbidity. Targeting altered metabolic pathways in inflammation may enhance our understanding of disease pathogenesis and point the way to new therapies. As mentioned, metformin, polyphenols, AICAR, salicylates, and corticoids all activate the AMPK/mTOR pathway. New compounds such as A-769662 are under scrutiny. Finally, rapamycin, which is also known as sirolimus and was first isolated from Streptomyces hygroscopicus, and several derivative compounds, including everolimus, temsirolimus, ridaforolimus, umirolimus, and zotarolimus, have been approved for a variety of uses, including posttransplantation therapy, the prevention of restenosis following angioplasty, and as a treatment for certain forms of cancer. Drugs that inhibit the mTOR pathway could one day be used widely to slow aging and reduce age-related pathologies in humans [124]. The development of chemical inhibitors of mTOR, as well as drugs that target other components of the mTOR pathway, promises to aid research greatly while also providing drugs with potential therapeutic value.

7. Perspectives and Implications

Obesity, metabolic alterations, and age-related diseases are complex conditions that require a multifaceted approach that includes action on both the chemokine network and energy metabolism [123, 125]. The underlying mechanisms are far from being understood [126] although the association between obesity and insulin resistance seems to be well substantiated. However, obesity is not distributed normally throughout the population, and type 2 diabetes mellitus is not associated closely with increased body weight; also, the relationship with noncommunicable diseases is not straightforward. A working hypothesis is that adipose tissue has a limited maximum capacity to increase in mass. Once the adipose tissue has reached the expansion limit, fat is deposited in the liver and muscle tissues and causes insulin resistance. This process is also associated with the activation of macrophages, oxidative stress, and inflammation which produce cytokines that have negative effects on insulin sensitivity, induce the secretion of adipokines that cause insulin resistance, and suppress those that promote insulin sensitivity. However, a host of other mechanisms must be involved because metabolic responses are different among patients with maximum adipose tissue expansion. A more popular and recent hypothesis suggests a differential effect of lipophagy, which implies a tissue-selective autophagy with cellular consequences from the mobilisation of intracellular lipids. Defective lipophagy is linked to fatty liver tissues and obesity and might be the basis for age-related metabolic syndrome [127]. Increased adipose tissue autophagy may be responsible for more efficient storage. Autophagy also affects metabolism, oxidation, and proinflammatory cytokine production. Very recent evidence suggests that autophagy is increased in the adipose tissues of obese patients [128]. Inexpensive and well-tolerated molecules such as chloroquine, metformin, and polyphenols already exist and could be used to fine-tune the metabolic alterations derived from an excess of energy and, more specifically, to modulate autophagy in the liver. Whether these therapies will dampen the genetic expression of factors that affect the development of noncommunicable diseases remains to be ascertained.


The Unitat de Recerca Biomèdica is currently being supported by Grants from the Fondo de Investigación Sanitaria (FIS PI08/1032, PI11/00130). E. Rodríguez-Gallego is the recipient of a fellowship from the Generalitat de Catalunya (2012FI_B 00389), and M. Riera-Borrull is the recipient of a fellowship from the Universitat Rovira i Virgili (2010PFR-URV-B2-58).


  1. K. Strong, C. Mathers, S. Leeder, and R. Beaglehole, “Preventing chronic diseases: how many lives can we save?” The Lancet, vol. 366, no. 9496, pp. 1578–1582, 2005. View at: Publisher Site | Google Scholar
  2. M. Cecchini, F. Sassi, J. A. Lauer, Y. Y. Lee, V. Guajardo-Barron, and D. Chisholm, “Tackling of unhealthy diets, physical inactivity, and obesity: health effects and cost-effectiveness,” The Lancet, vol. 376, no. 9754, pp. 1775–1784, 2010. View at: Publisher Site | Google Scholar
  3. T. A. Gaziano, G. Galea, and K. S. Reddy, “Scaling up interventions for chronic disease prevention: the evidence,” The Lancet, vol. 370, no. 9603, pp. 1939–1946, 2007. View at: Publisher Site | Google Scholar
  4. E. A. H. Sims, “Are there persons who are obese, but metabolically healthy?” Metabolism, vol. 50, no. 12, pp. 1499–1504, 2001. View at: Publisher Site | Google Scholar
  5. N. Stefan, K. Kantartzis, J. Machann et al., “Identification and characterization of metabolically benign obesity in humans,” Archives of Internal Medicine, vol. 168, no. 15, pp. 1609–1616, 2008. View at: Publisher Site | Google Scholar
  6. G. Iacobellis, M. C. Ribaudo, A. Zappaterreno, C. V. Iannucci, and F. Leonetti, “Prevalence of uncomplicated obesity in an Italian obese population,” Obesity Research, vol. 13, no. 6, pp. 1116–1122, 2005. View at: Google Scholar
  7. A. Rull, J. Camps, C. Alonso-Villaverde, and J. Joven, “Insulin resistance, inflammation, and obesity: role of monocyte chemoattractant protein-1 (orCCL2) in the regulation of metabolism,” Mediators of Inflammation, vol. 2010, Article ID 326580, 11 pages, 2010. View at: Publisher Site | Google Scholar
  8. J. B. Meigs, I. Lipinska, S. Kathiresan et al., “Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the framingham heart study,” Circulation, vol. 116, no. 11, pp. 1234–1241, 2007. View at: Publisher Site | Google Scholar
  9. D. Dowell and T. A. Farley, “Prevention of non-communicable diseases in New York City,” The Lancet, vol. 380, no. 9855, pp. 1787–1792, 2012. View at: Publisher Site | Google Scholar
  10. D. M. Arduíno, A. R. Esteves, and S. M. Cardoso, “Mitochondria drive autophagy pathology via microtubule disassembly: a new hypothesis for Parkinson disease,” Autophagy, vol. 9, no. 1, pp. 112–114, 2013. View at: Google Scholar
  11. H. Kumar, H. W. Lim, S. V. More et al., “The role of free radicals in the aging brain and Parkinson's disease: convergence and parallelism,” International Journal of Molecular Science, vol. 13, no. 8, pp. 10478–10504, 2012. View at: Publisher Site | Google Scholar
  12. G. Medina-Gómez, “Mitochondria and endocrine function of adipose tissue,” Best Practice & Research Clinical Endocrinology & Metabolism, vol. 26, no. 6, pp. 791–804, 2012. View at: Publisher Site | Google Scholar
  13. G. Pagano, G. Castello, and F. V. Pallardó, “Sjøgren's syndrome-associated oxidative stress and mitochondrial dysfunction: prospects for chemoprevention trials,” Free Radical Research, vol. 47, no. 2, pp. 71–73, 2013. View at: Publisher Site | Google Scholar
  14. J. Ouyang, M. Wu, C. Huang, L. Cao, and G. Li, “Overexpression of oxidored-nitro domain containing protein 1 inhibits human nasopharyngeal carcinoma and cervical cancer cell proliferation and induces apoptosis: involvement of mitochondrial apoptotic pathways,” Oncology Reports, vol. 29, no. 1, pp. 79–86, 2013. View at: Google Scholar
  15. L. D. Osellame, T. S. Blacker, and M. R. Duchen, “Cellular and molecular mechanisms of mitochondrial function,” Best Practice & Research Clinical Endocrinology & Metabolism, vol. 26, no. 6, pp. 711–723, 2012. View at: Publisher Site | Google Scholar
  16. I. Enache, A. L. Charles, J. Bouitbir et al., “Skeletal muscle mitochondrial dysfunction precedes right ventricular impairment in experimental pulmonary hypertension,” Molecular and Cellular Biochemistry, vol. 373, no. 1-2, pp. 161–170, 2013. View at: Publisher Site | Google Scholar
  17. L. W. Chol, “Metabolic syndrome,” Singapore Medical Journal, vol. 52, no. 11, pp. 779–785, 2011. View at: Google Scholar
  18. M. R. Souza, F. D. Mde, J. E. Medeiros-Filho, and M. S. Araújo, “Metabolic syndrome and risk factors for non-alcoholic fatty liver disease,” Arquivos de Gastroenterologia, vol. 49, no. 1, pp. 89–96, 2012. View at: Google Scholar
  19. M. S. Mirza, “Obesity, visceral fat and NAFLD: querying the role of adipokines in the progression of nonalcoholic fatty liver disease,” ISRN Gastroenterology, vol. 2011, Article ID 592404, 11 pages, 2011. View at: Publisher Site | Google Scholar
  20. G. Tarantino, S. Savastano, and A. Colao, “Hepatic steatosis, low-grade chronic inflammation and hormone/growth factor/adipokine imbalance,” World Journal of Gastroenterology, vol. 16, no. 38, pp. 4773–4783, 2010. View at: Publisher Site | Google Scholar
  21. C. Vernochet and C. R. Kahn, “Mitochondria, obesity and aging,” Aging, vol. 4, no. 12, pp. 1–2, 2012. View at: Google Scholar
  22. F. Pintus, G. Floris, and A. Rufini, “Nutrient availability links mitocondria, apoptosis and obesity,” Aging, vol. 4, no. 11, pp. 1–8, 2012. View at: Google Scholar
  23. M. M. Rogge, “The role of impaired mitochondrial lipid oxidation in obesity,” Biological Research for Nursing, vol. 10, no. 4, pp. 356–373, 2009. View at: Publisher Site | Google Scholar
  24. M. Vinaixa, M. A. Rodríguez, A. Rull et al., “Metabolomic assessment of the effect of dietary cholesterol in the progressive development of fatty liver disease,” Journal of Proteome Research, vol. 9, no. 5, pp. 2527–2538, 2010. View at: Publisher Site | Google Scholar
  25. A. Rull, M. Vinaixa, M. Ángel Rodríguez et al., “Metabolic phenotyping of genetically modified mice: an NMR metabonomic approach,” Biochimie, vol. 91, no. 8, pp. 1053–1057, 2009. View at: Publisher Site | Google Scholar
  26. J. Joven, A. Rull, N. Ferré et al., “The results in rodent models of atherosclerosis are not interchangeable. The influence of diet and strain,” Atherosclerosis, vol. 195, no. 2, pp. e85–e92, 2007. View at: Publisher Site | Google Scholar
  27. M. Tous, N. Ferré, J. Camps, F. Riu, and J. Joven, “Feeding apolipoprotein E-knockout mice with cholesterol and fat enriched diets may be a model of non-alcoholic steatohepatitis,” Molecular and Cellular Biochemistry, vol. 268, no. 1-2, pp. 53–58, 2005. View at: Publisher Site | Google Scholar
  28. P. Lindström, “β-cell function in obese-hyperglycemic mice [ob/ob mice],” Advances in Experimental Medicine and Biology, vol. 654, pp. 463–477, 2010. View at: Publisher Site | Google Scholar
  29. S. de Ferranti and D. Mozaffarian, “The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences,” Clinical Chemistry, vol. 54, no. 6, pp. 945–955, 2008. View at: Publisher Site | Google Scholar
  30. L. Xu, X. Ma, B. Cui, X. Li, G. Ning, and S. Wang, “Selection of reference genes for qRT-PCR in high fat diet-induced hepatic steatosis mice model,” Molecular Biotechnology, vol. 48, no. 3, pp. 255–262, 2011. View at: Publisher Site | Google Scholar
  31. M. V. Machado, J. Coutinho, F. Carepa, A. Costa, H. Proença, and H. Cortez-Pinto, “How adiponectin, leptin, and ghrelin orchestrate together and correlate with the severity of nonalcoholic fatty liver disease,” European Journal of Gastroenterology and Hepatology, vol. 24, no. 10, pp. 1166–1172, 2012. View at: Publisher Site | Google Scholar
  32. J. C. Cohen, J. D. Horton, and H. H. Hobbs, “Human fatty liver disease: old questions and new insights,” Science, vol. 332, no. 6037, pp. 1519–1523, 2011. View at: Publisher Site | Google Scholar
  33. M. J. Pagliassotti, “Endoplasmic reticulum stress in nonalcoholic fatty liver disease,” Annual Review of Nutrition, vol. 32, pp. 17–33, 2012. View at: Publisher Site | Google Scholar
  34. J. V. Neel, “Diabetes mellitus a “thrifty” genotype rendered detrimental by ‘progress’?” The American Journal of Human Genetics, vol. 14, pp. 352–353, 1962. View at: Google Scholar
  35. J. V. Neel, “Update to ‘The study of natural selection in primitive and civilized human populations’,” Human Biology, vol. 61, no. 5-6, pp. 811–823, 1989. View at: Google Scholar
  36. A. R. Frisancho, “Reduced rate of fat oxidation: a metabolic pathway to obesity in the developing nations,” The American Journal of Human Biology, vol. 15, no. 4, pp. 522–532, 2003. View at: Publisher Site | Google Scholar
  37. J. R. Speakman, “A novel non-adaptive scenario explaining the genetic pre-disposition to obesity: the “predation release” hypothesis,” Cell Metabolism, vol. 6, no. 1, pp. 5–12, 2007. View at: Publisher Site | Google Scholar
  38. J. R. Speakman and S. O'Rahilly, “Fat: an evolving issue,” Disease Models and Mechanisms, vol. 5, no. 5, pp. 569–573, 2012. View at: Publisher Site | Google Scholar
  39. B. Rius, C. López-Vicario, A. González-Périz et al., “Resolution of inflammation in obesity-induced liver disease,” Frontiers in Immunology, vol. 3, article 257, 2012. View at: Publisher Site | Google Scholar
  40. A. Paul, L. Calleja, J. Camps et al., “The continuous administration of aspirin attenuates atherosclerosis in apolipoprotein E-deficient mice,” Life Sciences, vol. 68, no. 4, pp. 457–465, 2000. View at: Publisher Site | Google Scholar
  41. M. Tous, N. Ferré, A. Rull et al., “Dietary cholesterol and differential monocyte chemoattractant protein-1 gene expression in aorta and liver of apo E-deficient mice,” Biochemical and Biophysical Research Communications, vol. 340, no. 4, pp. 1078–1084, 2006. View at: Publisher Site | Google Scholar
  42. L. Masana, M. Camprubi, P. Sarda, R. Sola, J. Joven, and P. R. Turner, “The mediterranean-type diet: is there a need for further modification?” The American Journal of Clinical Nutrition, vol. 53, no. 4, pp. 886–889, 1991. View at: Google Scholar
  43. A. P. Rolo, J. S. Teodoro, and C. M. Palmeira, “Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis,” Free Radical Biology and Medicine, vol. 52, no. 1, pp. 59–69, 2012. View at: Publisher Site | Google Scholar
  44. B. Mlinar and J. Marc, “New insights into adipose tissue dysfunction in insulin resistance,” Clinical Chemistry and Laboratory Medicine, vol. 29, no. 12, pp. 1925–1935, 2011. View at: Google Scholar
  45. C. N. Lumeng, J. L. Bodzin, and A. R. Saltiel, “Obesity induces a phenotypic switch in adipose tissue macrophage polarization,” Journal of Clinical Investigation, vol. 117, no. 1, pp. 175–184, 2007. View at: Publisher Site | Google Scholar
  46. M. E. Shaul, G. Bennett, K. J. Strissel, A. S. Greenberg, and M. S. Obin, “Dynamic, M2-like remodeling phenotypes of CD11c+ adipose tissue macrophages during high-fat diet—induced obesity in mice,” Diabetes, vol. 59, no. 5, pp. 1171–1181, 2010. View at: Publisher Site | Google Scholar
  47. J. M. Wentworth, G. Naselli, W. A. Brown et al., “Pro-inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity,” Diabetes, vol. 59, no. 7, pp. 1648–1656, 2010. View at: Publisher Site | Google Scholar
  48. A. Rull, R. Beltrán-Debón, G. Aragonès et al., “Expression of cytokine genes in the aorta is altered by the deficiency in MCP-1: effect of a high-fat, high-cholesterol diet,” Cytokine, vol. 50, no. 2, pp. 121–128, 2010. View at: Publisher Site | Google Scholar
  49. M. L. Batista, S. B. Peres, M. E. McDonald et al., “Adipose tissue inflammation and cancer cachexia: possible role of nuclear transcription factors,” Cytokine, vol. 57, no. 1, pp. 9–16, 2012. View at: Publisher Site | Google Scholar
  50. A. Rull, J. C. Escolà-Gil, J. Julve et al., “Deficiency in monocyte chemoattractant protein-1 modifies lipid and glucose metabolism,” Experimental and Molecular Pathology, vol. 83, no. 3, pp. 361–366, 2007. View at: Publisher Site | Google Scholar
  51. B. Coll, C. Alonso-Villaverde, and J. Joven, “Monocyte chemoattractant protein-1 and atherosclerosis: Is there room for an additional biomarker?” Clinica Chimica Acta, vol. 383, no. 1-2, pp. 21–29, 2007. View at: Publisher Site | Google Scholar
  52. B. Westermann, “Mitochondrial fusion and fission in cell life and death,” Nature Reviews Molecular Cell Biology, vol. 11, no. 12, pp. 872–884, 2010. View at: Publisher Site | Google Scholar
  53. D. C. Chan, “Mitochondrial fusion and fission in mammals,” Annual Review of Cell and Developmental Biology, vol. 22, pp. 79–99, 2006. View at: Publisher Site | Google Scholar
  54. D. H. Margineantu, W. G. Cox, L. Sundell, S. W. Sherwood, J. M. Beechem, and R. A. Capaldi, “Cell cycle dependent morphology changes and associated mitochondrial DNA redistribution in mitochondria of human cell lines,” Mitochondrion, vol. 1, no. 5, pp. 425–435, 2002. View at: Publisher Site | Google Scholar
  55. A. E. Frazier, C. Kiu, D. Stojanovski, N. J. Hoogenraad, and M. T. Ryan, “Mitochondrial morphology and distribution in mammalian cells,” Biological Chemistry, vol. 387, no. 12, pp. 1551–1558, 2006. View at: Publisher Site | Google Scholar
  56. B. Westermann, “Bioenergetic role of mitochondrial fusion and fission,” Biochimica et Biophysica Acta, vol. 1817, no. 10, pp. 1833–1838, 2012. View at: Publisher Site | Google Scholar
  57. J. C. Chang, S. J. Kou, W. T. Lin, and C. S. Liu, “Regulatory role of mitochondria in oxidative stress and atherosclerosis,” World Journal of Cardiology, vol. 2, no. 6, pp. 150–159, 2010. View at: Publisher Site | Google Scholar
  58. D. C. Chan, “Mitochondria: dynamic organelles in disease, aging, and development,” Cell, vol. 125, no. 7, pp. 1241–1252, 2006. View at: Publisher Site | Google Scholar
  59. K. C. Fearon, D. J. Glass, and D. C. Guttridge, “Cancer cachexia: mediators, signaling, and metabolic pathways,” Cell Metabolism, vol. 16, no. 2, pp. 153–166, 2012. View at: Publisher Site | Google Scholar
  60. F. S. Lira, L. C. Carnevali, N. E. Zanchi, R. V. T. Santos, J. M. Lavoie, and M. Seelaender, “Exercise intensity modulation of hepatic lipid metabolism,” Journal of Nutrition and Metabolism, vol. 2012, Article ID 809576, 8 pages, 2012. View at: Publisher Site | Google Scholar
  61. S. Lokireddy, I. W. Wijesoma, S. Teng et al., “The ubiquitin ligase mul1 induces mitophagy in skeletal muscle in response to muscle-wasting stimuli,” Cell Metabolism, vol. 16, no. 5, pp. 613–624, 2012. View at: Publisher Site | Google Scholar
  62. M. Banasch, M. Ellrichmann, A. Tannapfel, W. E. Schmidt, and O. Goetze, “The non-invasive 13C-methionine breath test detects hepatic mitochondrial dysfunction as a marker of disease activity in non-alcoholic steatohepatitis,” European Journal of Medical Research, vol. 16, no. 6, pp. 258–264, 2011. View at: Google Scholar
  63. W. Dröge and H. M. Schipper, “Oxidative stress and aberrant signaling in aging and cognitive decline,” Aging Cell, vol. 6, no. 3, pp. 361–370, 2007. View at: Publisher Site | Google Scholar
  64. M. E. Witte, J. J. G. Geurts, H. E. de Vries, P. van der Valk, and J. van Horssen, “Mitochondrial dysfunction: a potential link between neuroinflammation and neurodegeneration?” Mitochondrion, vol. 10, no. 5, pp. 411–418, 2010. View at: Publisher Site | Google Scholar
  65. J. A. Menendez, S. Cufi, C. Oliveras-Ferraros, L. Vellon, J. Joven, and A. Vazquez-Martin, “Gerosuppressant metformin: less is more,” Aging, vol. 3, no. 4, pp. 348–362, 2011. View at: Google Scholar
  66. S. I. Rattan, “Anti-ageing strategies: prevention or therapy? Showing ageing from within,” EMBO Reports, vol. 6, pp. S25–S29, 2005. View at: Google Scholar
  67. V. B. Saprunova, M. A. Lelekova, N. G. Kolosova, and L. E. Bakeeva, “SkQ1 slows development of age-dependent destructive processes in retina and vascular layer of eyes of wistar and OXYS rats,” Biochemistry, vol. 77, no. 6, pp. 648–658, 2012. View at: Publisher Site | Google Scholar
  68. T. F. Liu, C. M. Brown, M. El Gazzar et al., “Fueling the flame: bioenergy couples metabolism and inflammation,” Journal of Leukocyte Biology, vol. 92, no. 3, pp. 499–507, 2012. View at: Publisher Site | Google Scholar
  69. E. Profumo, B. Buttari, L. Petrone et al., “Redox imbalance of red blood cells impacts T lymphocyte homeostasis: implication in carotid atherosclerosis,” Journal of Thrombosis and Haemostasis, vol. 106, no. 6, pp. 1117–1126, 2011. View at: Publisher Site | Google Scholar
  70. C. M. Kusminski, W. L. Holland, K. Sun et al., “MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptative process that preserves insulin sensitivity in obesity,” Nature Medicine, vol. 18, no. 10, pp. 1539–1549, 2012. View at: Publisher Site | Google Scholar
  71. A. Zorzano, M. Liesa, and M. Palacín, “Role of mitochondrial dynamics proteins in the pathophysiology of obesity and type 2 diabetes,” International Journal of Biochemistry and Cell Biology, vol. 41, no. 10, pp. 1846–1854, 2009. View at: Publisher Site | Google Scholar
  72. C. Aguer and M. E. Harper, “Skeletal muscle mitochondrial energetics in obesity and type 2 diabetes mellitus: endocrine aspects,” Best Practice & Research Clinical Endocrinology & Metabolism, vol. 26, no. 6, pp. 805–819, 2012. View at: Publisher Site | Google Scholar
  73. Z. A. Ma, “The role of peroxidation of mitochondrial membrane phospholipids in pancreatic β-cell failure,” Current Diabetes Reviews, vol. 8, no. 1, pp. 69–75, 2012. View at: Publisher Site | Google Scholar
  74. C. Tang, K. Koulajian, I. Schuiki et al., “Glucose-induced beta cell dysfunction in vivo in rats: link between oxidative stress and endoplasmic reticulum stress,” Diabetologia, vol. 55, no. 5, pp. 1366–1379, 2012. View at: Publisher Site | Google Scholar
  75. A. Lde. Brondani, T. S. Assmann, G. C. Duarte, J. L. Gross, L. H. Canani, and D. Crispim, “The role of the uncoupling protein 1 (UCP1) on the development of obesity and type 2 diabetes mellitus,” Arquivos Brasileiros de Endocrinologia e Metabologia, vol. 56, no. 4, pp. 215–225, 2012. View at: Google Scholar
  76. A. Fedorenko, P. V. Lishko, and Y. Kirichok, “Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria,” Cell, vol. 151, no. 2, pp. 400–413, 2012. View at: Publisher Site | Google Scholar
  77. B. Cannon and J. Nedergaard, “Cell biology: neither brown nor white,” Nature, vol. 488, no. 7411, pp. 286–287, 2012. View at: Publisher Site | Google Scholar
  78. I. Grattagliano, O. de Bari, T. C. Bernardo, P. J. Oliveira, D. Q. Wang, and P. Portincasa, “Role of mitochondria in nonalcoholic fatty liver disease—from origin to propagation,” Clinical Biochemistry, vol. 45, no. 9, pp. 610–618, 2012. View at: Publisher Site | Google Scholar
  79. G. Serviddio, F. Bellanti, G. Vendemiale, and E. Altomare, “Mitochondrial dysfunction in nonalcoholic steatohepatitis,” Expert Review of Gastroenterology and Hepatology, vol. 5, no. 2, pp. 233–244, 2011. View at: Publisher Site | Google Scholar
  80. N. C. Sadler, T. E. Angel, M. P. Lewis et al., “Activity-based protein profiling reveals mitochondrial oxidative enzyme impairment and restoration in diet-induced obese mice,” PLoS ONE, vol. 7, no. 10, Article ID e47996, 2012. View at: Publisher Site | Google Scholar
  81. M. Carrer, N. Liu, C. E. Grueter et al., “Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 38, pp. 15330–15335, 2012. View at: Publisher Site | Google Scholar
  82. A. D. Karelis, M. Faraj, J. P. Bastard et al., “The metabolically healthy but obese individual presents a favorable inflammation profile,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 7, pp. 4145–4150, 2005. View at: Publisher Site | Google Scholar
  83. C. M. Kusminski and P. E. Scherer, “Mitochondrial dysfunction in white adipose tissue,” Trends in Endocrinology and Metabolism, vol. 23, no. 9, pp. 435–443, 2012. View at: Publisher Site | Google Scholar
  84. A. Zorzano, M. I. Hernández-Alvarez, M. Palacín, and G. Mingrone, “Alterations in the mitochondrial regulatory pathways constituted by the nuclear co-factors PGC-1α or PGC-1β and mitofusin 2 in skeletal muscle in type 2 diabetes,” Biochimica et Biophysica Acta, vol. 1797, no. 6-7, pp. 1028–1033, 2010. View at: Publisher Site | Google Scholar
  85. A. Zorzano, D. Sebastián, J. Segalés, and M. Palacín, “The molecular machinery of mitochondrial fusion and fission: an opportunity for drug discovery?” Current Opinion in Drug Discovery and Development, vol. 12, no. 5, pp. 597–606, 2009. View at: Google Scholar
  86. X. J. Chen and R. A. Butow, “The organization and inheritance of the mitochondrial genome,” Nature Reviews Genetics, vol. 6, no. 11, pp. 815–825, 2005. View at: Publisher Site | Google Scholar
  87. A. M. Distler, J. Kerner, and C. L. Hoppel, “Proteomics of mitochondrial inner and outer membranes,” Proteomics, vol. 8, no. 19, pp. 4066–4082, 2008. View at: Publisher Site | Google Scholar
  88. L. Galluzzi, I. Vitale, J. M. Abrams et al., “Molecular definitions of cell death subroutines: recommendations of the nomenclature committee on cell death 2012,” Cell Death and Differentiation, vol. 19, pp. 107–120, 2012. View at: Publisher Site | Google Scholar
  89. N. Joza, G. Y. Oudit, D. Brown et al., “Muscle-specific loss of apoptosis-inducing factor leads to mitochondrial dysfunction, skeletal muscle atrophy, and dilated cardiomyopathy,” Molecular and Cellular Biology, vol. 25, no. 23, pp. 10261–10272, 2005. View at: Publisher Site | Google Scholar
  90. J. R. Speakman and S. E. Mitchell, “Caloric restriction,” Molecular Aspects of Medicine, vol. 32, no. 3, pp. 159–221, 2011. View at: Publisher Site | Google Scholar
  91. A. Raffaello and R. Rizzuto, “Mitochondrial longevity pathways,” Biochimica et Biophysica Acta, vol. 1813, no. 1, pp. 260–268, 2011. View at: Publisher Site | Google Scholar
  92. N. Alkhouri, A. Gornicka, M. P. Berk et al., “Adipocyte apoptosis, a link between obesity, insulin resistance, and hepatic steatosis,” The Journal of Biological Chemistry, vol. 285, no. 5, pp. 3428–3438, 2010. View at: Publisher Site | Google Scholar
  93. I. P. Salt and T. M. Palmer, “Exploiting the anti-inflammatory effects of AMP-activated protein kinase activation,” Expert Opinion on Investigational Drugs, vol. 21, no. 8, pp. 1155–1167, 2012. View at: Publisher Site | Google Scholar
  94. J. G. Boyle, P. J. Logan, G. C. Jones et al., “AMP-activated protein kinase is activated in adipose tissue of individuals with type 2 diabetes treated with metformin: a randomised glycaemia-controlled crossover study,” Diabetologia, vol. 54, no. 7, pp. 1799–1809, 2011. View at: Publisher Site | Google Scholar
  95. J. E. Sullivan, K. J. Brocklehurst, A. E. Marley, F. Carey, D. Carling, and R. K. Beri, “Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell-permeable activator of AMP-activated protein kinase,” FEBS Letters, vol. 353, no. 1, pp. 33–36, 1994. View at: Publisher Site | Google Scholar
  96. W. Yin, J. Mu, and M. J. Birnbaum, “Role of AMP-activated protein kinase in cyclic AMP-dependent lipolysis in 3T3-L1 adipocytes,” The Journal of Biological Chemistry, vol. 278, no. 44, pp. 43074–43080, 2003. View at: Publisher Site | Google Scholar
  97. M. P. Gaidhu, S. Fediuc, and R. B. Ceddia, “5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside-induced AMP-activated protein kinase phosphorylation inhibits basal and insulin-stimulated glucose uptake, lipid synthesis, and fatty acid oxidation in isolated rat adipocytes,” The Journal of Biological Chemistry, vol. 281, no. 36, pp. 25956–25964, 2006. View at: Publisher Site | Google Scholar
  98. M. P. Gaidhu, S. Fediuc, N. M. Anthony et al., “Prolonged AICAR-induced AMP-kinase activation promotes energy dissipation in white adipocytes: novel mechanisms integrating HSL and ATGL,” Journal of Lipid Research, vol. 50, no. 4, pp. 704–715, 2009. View at: Publisher Site | Google Scholar
  99. A. T. Turer and P. E. Scherer, “Adiponectin: mechanistic insights and clinical implications,” Diabetologia, vol. 55, no. 9, pp. 2319–2326, 2012. View at: Publisher Site | Google Scholar
  100. S. Galic, M. D. Fullerton, J. D. Schertzer et al., “Hematopoietic AMPK β1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity,” Journal of Clinical Investigation, vol. 121, no. 12, pp. 4903–4915, 2011. View at: Publisher Site | Google Scholar
  101. R. Vila-Bedmar, M. Lorenzo, and S. Fernández-Veledo, “Adenosine 5′-monophosphate-activated protein kinase-mammalian target of rapamycin cross talk regulates brown adipocyte differentiation,” Endocrinology, vol. 151, no. 3, pp. 980–992, 2010. View at: Publisher Site | Google Scholar
  102. O. Horakova, D. Medrikova, E. M. van Schothorst et al., “Preservation of metabolic flexibility in skeletal muscle by a combined use of n-3 PUFA and rosiglitazone in dietary obese mice,” PLoS ONE, vol. 7, no. 8, Article ID e43764, 2012. View at: Publisher Site | Google Scholar
  103. V. T. To, T. P. Hüttl, R. Lang, K. Piotrowski, and K. G. Parhofer, “Changes in body weight, glucose homeostasis, lipid profiles, and metabolic syndrome after restrictive bariatric surgery,” Experimental and Clinical Endocrinology and Diabetes, vol. 120, no. 9, pp. 547–552, 2012. View at: Publisher Site | Google Scholar
  104. H. M. Heneghan, S. Nissen, and P. R. Schauer, “Gastrointestinal surgery for obesity and diabetes: weight loss and control of hyperglycemia,” Current Atherosclerosis Reports, vol. 14, no. 6, pp. 579–587, 2012. View at: Publisher Site | Google Scholar
  105. A. Luke, J. O’Neill, and D. Hardie, “Metabolism of inflammation limited by AMPK and pseudo-starvation,” Nature, vol. 493, pp. 346–355, 2013. View at: Publisher Site | Google Scholar
  106. C. Finelli and G. Tarantino, “Is there any consensus as to what diet of lifestyle approach is the right one for NAFLD patients?” Journal of Gastrointestinal and Liver Diseases, vol. 21, pp. 293–302, 2012. View at: Google Scholar
  107. J. Joven, J. Menéndez, L. Fernandez-Sender et al., “Metformin: a cheap and well-tolerated drug that provides benefits for viral infections,” HIV Medicine, 2012. View at: Publisher Site | Google Scholar
  108. S. Del Barco, A. Vazquez-Martin, S. Cufí et al., “Metformin: multi-faceted protection against cancer,” Oncotarget, vol. 2, no. 12, pp. 896–917, 2011. View at: Google Scholar
  109. B. Viollet, B. Guigas, N. Sanz Garcia, J. Leclerc, M. Foretz, and F. Andreelli, “Cellular and molecular mechanisms of metformin: an overview,” Clinical Science, vol. 122, no. 6, pp. 253–270, 2012. View at: Publisher Site | Google Scholar
  110. S. Nair, A. M. Diehl, M. Wiseman, G. H. Farr, and R. P. Perrillo, “Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial,” Alimentary Pharmacology and Therapeutics, vol. 20, no. 1, pp. 23–28, 2004. View at: Publisher Site | Google Scholar
  111. A. Duseja, A. Das, R. K. Dhiman et al., “Metformin is effective in achieving biochemical response in patients with nonalcoholic fatty liver disease (NAFLD) not responding to lifestyle interventions,” Annals of Hepatology, vol. 6, no. 4, pp. 222–226, 2007. View at: Google Scholar
  112. J. W. Haukeland, Z. Konopsi, H. B. Eggesbo et al., “Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial,” Scandinavian Journal of Gastroenterology, vol. 44, no. 7, pp. 853–860, 2009. View at: Google Scholar
  113. M. Foretz, S. Hébrard, J. Leclerc et al., “Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state,” Journal of Clinical Investigation, vol. 120, no. 7, pp. 2355–2369, 2010. View at: Publisher Site | Google Scholar
  114. M. R. Owen, E. Doran, and A. P. Halestrap, “Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain,” Biochemical Journal, vol. 348, no. 3, pp. 607–614, 2000. View at: Publisher Site | Google Scholar
  115. B. H. Ahn, H. S. Kim, S. Song et al., “A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 38, pp. 14447–14452, 2008. View at: Publisher Site | Google Scholar
  116. X. Kong, R. Wang, Y. Xue et al., “Sirtuin 3, a new target of PGC-1α, plays an important role in the suppression of ROS and mitochondrial biogenesis,” PLoS ONE, vol. 5, no. 7, Article ID e11707, 2010. View at: Publisher Site | Google Scholar
  117. M. Buler, S. M. Aatsinki, V. Izzi, and J. Hakkola, “Metformin reduces hepatic expression of SIRT3, the mitochondrial deacetylase controlling energy metabolism,” PLoS ONE, vol. 7, no. 11, Article ID e49863, 2012. View at: Publisher Site | Google Scholar
  118. P. W. Caton, N. K. Nayuni, J. Kieswich, N. Q. Khan, M. M. Yaqoob, and R. Corder, “Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5,” Journal of Endocrinology, vol. 205, no. 1, pp. 97–106, 2010. View at: Publisher Site | Google Scholar
  119. B. Corominas-Faja, R. Quirantes-Piné, C. Oliveras-Ferraros et al., “Metabolomic fingerprint reveals that metformin impairs one-carbon metabolism in a manner similar to the antifolate class of chemotherapy drugs,” Aging, vol. 4, no. 7, pp. 480–498, 2012. View at: Google Scholar
  120. R. Beltrán-Debón, A. Rull, F. Rodríguez-Sanabria et al., “Continuous administration of polyphenols from aqueous rooibos (Aspalathus linearis) extract ameliorates dietary-induced metabolic disturbances in hyperlipidemic mice,” Phytomedicine, vol. 18, no. 5, pp. 414–424, 2011. View at: Publisher Site | Google Scholar
  121. J. Joven, A. Rull, E. Rodríguez-Gallego et al., “Multifunctional targets of dietary polyphenols in disease: a case for the chemokine network and energy metabolism,” Food and Chemical Toxicology, vol. 51, pp. 267–279, 2013. View at: Publisher Site | Google Scholar
  122. J. Joven, E. Espinel, A. Rull et al., “Plant-derived polyphenols regulate expression of miRNA paralogs miR-103/107 and miR-122 and prevent diet-induced fatty liver disease in hyperlipidemic mice,” Biochimica et Biophysica Acta, no. 7, pp. 894–899, 1820. View at: Publisher Site | Google Scholar
  123. A. Segura-Carretero, M. A. Puertas-Mejía, S. Cortacero-Ramírez et al., “Selective extraction, separation, and identification of anthocyanins from Hibiscus sabdariffa L. using solid phase extraction-capillary electrophoresis-mass spectrometry (time-of-flight/ion trap),” Electrophoresis, vol. 29, no. 13, pp. 2852–2861, 2008. View at: Publisher Site | Google Scholar
  124. S. C. Johnson, P. S. Rabinovitch, and M. Kaeberlein, “mTOR is a key modulator of ageing and age-related disease,” Nature, vol. 493, pp. 338–345, 2013. View at: Publisher Site | Google Scholar
  125. M. Herranz-López, S. Fernández-Arroyo, A. Pérez-Sanchez et al., “Synergism of plant-derived polyphenols in adipogenesis: perspectives and implications,” Phytomedicine, vol. 19, no. 3-4, pp. 253–261, 2012. View at: Publisher Site | Google Scholar
  126. S. Virtue and A. Vidal-Puig, “It's not how fat you are, it's what you do with it that counts,” PLoS Biology, vol. 6, no. 9, article e237, 2008. View at: Publisher Site | Google Scholar
  127. R. Singh and A. M. Cuervo, “Lipophagy: connecting autophagy and lipid metabolism,” International Journal of Cell Biology, vol. 2012, Article ID 282041, 12 pages, 2012. View at: Publisher Site | Google Scholar
  128. H. J. Jansen, P. van Essen, T. Koenen, L. A. Joosten, M. G. Netea, and C. J. Tack, “Autophagy activity is up-regulated in adipose tissue of obese individuals and modulates proinflammatory cytokine expression,” Endocrinology, vol. 153, no. 12, pp. 5866–5874, 2012. View at: Publisher Site | Google Scholar

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