The Role of Adipose Tissue and Adipokines in Obesity-Related Inflammatory Diseases

Table 2

Adipocytokines, chemokines, vascular proteins, and other proinflammatory markers produced in WAT and systemic sites and involved in the inflammatory-obesity responses.

Name	Cell type expression	Biological effects
Proinflammatory cytokines
IL-6: one the crucial pro-inflammatory mediator, secreted by several body’s cell types (monocytes, adipocytes, endothelial cells, fibroblasts, etc.) [10, 11]	Stromal vascular fraction: the 90% WAT IL-6 production comes from these cells. Under the obesity conditions, both adipocytes and macrophages are the principal responsible of WAT derived IL-6, although the stimuli for the induction of IL-6 production seem to be different.	Decreases insulin and leptin signaling; induces the hepatic release of acute-phase proteins, such as C-reactive protein, and the hypothalamic induction of fever; seems to have a controversial role in insulin resistance: it seems to impair hepatic signaling through the increased expression of SOCS-3 impairing the phosphorylation of insulin receptor substrate 1 (IRS-1) and the transcription factor PKB/Akt. Furthermore, down-regulates the expression of IRS-1 and Glucose transporter 4. In addition, SOCS-3 has the capacity to bind and to inhibit the insulin receptor and to induce the proteosomal degradation of IRS proteins. IL-6 also induces fatty acid oxidation and lipolysis [102]
TNF-α: another remarkable proinflammatory cytokine [10, 11]	Adipocytes and M1 macrophages	Induces IR and increases lipolysis in adipocytes; decreases adiponectin and increases IL-6 expression. TNF-$\alpha$ should also play an atherogenic role inducing an increased expression of adhesion molecules in vascular wall, increasing the scavenger receptor class A expression and oxidised LDL uptake in macrophages and stimulating their infiltration in vascular wall
IL-1: Another pro-inflammatory cytokine, member of IL-1 family (IL-1$\alpha$, IL-1$\beta$, and IL-1Ra) [10, 11]	M1 Macrophages	Induces fever, acute-phase proteins, proliferation of fibroblasts, smooth muscle cells, and production of antibodies, cytokines, and angiogenesis, metastasis, and cartilage breakdown. It also appears to affect glucose homeostasis and insulin sensitivity through central and peripheral mechanisms. IL-1 also mediates direct effects on adipocytes, decreasing the expression and the activity of LPL, increasing lypolisis and affecting adipocyte differentiation through inhibition of PPAR receptors
Anti-inflammatory cytokines
IL-1Ra: a cytokine antagonist able to limit inflammation, competing with IL-1 for binding to its receptor without inducing a signal [10, 11]	M2 macrophages and hepatic cells as an acute-phase protein under systemic inflammation stimuli	Produced in response to stress and by M2 macrophages to create an anti-inflammatory WAT milieu in physiological condition. High serum levels of IL-1Ra are associated with insulin resistance
IL-10: an anti-inflammatory cytokine inhibiting the production of several proinflammatory cytokines (IL-1, IL-6, and TNF-$\alpha$), chemokines and increasing the levels of anti-inflammatory cytokine such as IL-1Ra [10, 11]	Adipocytes and M2 macrophages	Produced by M2 macrophages to create an anti-inflammatory WAT milieu in physiological condition. In obesity, high levels of IL-10 have been observed
Proinflammatory chemokines
IL-8: a proinflammatory chemokine [10, 11]	Stromal vascular cells	Induces the migration of different cell blood types, such as monocytes, particularly in inflammatory conditions. In obesity, high IL-8 levels have been observed and increased levels of IL-8 mRNA have been detected principally in visceral WAT. They seem correlated to fat mass and BMI
Mcp-1 (CCL2): key chemokine involved in recruitment of monocytes/macrophages and in monocyte tissue infiltration. Its levels conspicuously increase under IL-1, TNF-$\alpha ,$ and LPS stimuli, while under normal conditions are undetectable [10, 11]	Adipocytes/M1 macrophages	Increases lipolysis and leptin secretion; decreasesinsulin-stimulated glucose uptake; (increased plasmaconcentrations in obesity; disturbs insulin sensitivity)
Adipokines associated with thrombosis and hypertension and other inflammatory markers
PAI-1: a serine protease inhibitor (serpin) with the physiological function to inhibit plasminogen activation [10, 11]	Stromal vascular cells with visceral WAT secretion more elevated than subcutaneous WAT	Inhibits plasminogen activation. Elevated PAI-1 levels determine a pathological condition characterised by hypofibrinolysis and a prothrombotic state It affects cellular matrix degradation, smooth muscle cell migration and angiogenesis, determining the development of atherosclerosis. In obese conditions, PAI-1 seems to contribute directly to obesity complications, such as atherothrombosis, insulin resistance and type 2 diabetes
Angiotensinogen (AGT): the precursor of vasoactive peptide angiotensin II (Ang II), a component of vasoconstrictor renin-angiotensin system (RAS) [10, 11]	Stromal vascular cells and adipocytes, with visceral WAT secretion more elevated than subcutaneous WA	Linked to vascular inflammation (increased plasmalevels in obesity) and increased blood pressure
C-reactive protein (CRP): one of the acute-phase proteins in inflammation. It is a member of short pentraxins produced in the liver in response of IL-6 [10, 11]	Hepatic cells, human mature adipocytes, but not preadipocytes, under inflammatory stimuli, including lipopolysaccharide (LPS), TNF- $\alpha$ , and resistin	Endothelial dysfunction, adhesion molecules expression, Tissue factor production, PAI-1upregulation, mononuclear cells recruitment, adhesion, activation and cytokine production, ROS and MMPs production, uptake of oxLDL, foam cells formation, proliferation, migration, ROS production, MMPs, MCP-1, and iNOS expression
Serum amyloid protein (SAA): constitute a family of lipoproteins involved in the transport of cholesterol and the host defence alarm system [10, 11].	Hepatic cells, adipocytes	SAA are not only inflammatory markers induced by IL-6, but also represent inflammatory mediators able to induce inflammatory events in leucocytes. In particular, SAA proteins can mediate chemotaxis of monocytes into WAT with hypertrophic adipocytes and at the same time to increase the expression of adhesion molecules in endothelial WAT cells. SSA proteins seem responsible of increased incidence of cardiovascular diseases in obese individuals. They are able to interact with high-density lipoprotein (HDL)-receptor competing with HDL, and thereby inhibit the HDL-mediated clearance of cholesterol, increasing the development of atherosclerotic lesions.