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IL-6 is a pleiotropic cytokine produced by adipose tissue, immune cells (91), and contracting muscle fibers (92). It functions by activating various signaling cascades via binding to receptors, which exist in both membrane-bound and soluble forms. It has been shown to have multiple, sometimes contradictory, physiological effects on the periphery, particularly muscle, liver, and endothelium.

Visceral depots release two to three times as much IL-6 as subcutaneous adipocytes

(93), and high levels of this cytokine are found circulating in the serum. It has been estimated that up to 35% comes from adipose tissue (88); thus, the majority of circulating IL-6 is derived from nonadipose sources.

As an inflammatory molecule, IL-6 is involved in the immune system's host defense to tissue injury. As mentioned earlier, it is thought that IL-6 expression in adipose tissue is induced in a paracrine fashion by other proinflammatory molecules, such as TNF-a

(94), though whether IL-6 itself is proinflammatory or anti-inflammatory in adipose tissue is still unclear (95). Both higher circulating levels of IL-6 and increased adipose tissue concentrations are associated with obesity. Furthermore, weight loss results in a decrease in IL-6 serum concentrations (96). Importantly, in obesity, unlike other situations, IL-6 is chronically elevated, and this chronic elevation may result in detrimental alterations in systemic metabolism.

Higher concentrations of adipose tissue IL-6 are associated with insulin resistance (96). In a study that carefully examined adipose tissue and systemic insulin sensitivity, including measures of serum fatty acids, IL-6, and TNF-a in the lean and obese, insulin resistance was most highly correlated with serum measures of IL-6. Additionally, serum IL-6 correlated with serum measurements of fatty acids (69). However, it is currently unclear as to whether this is merely a reflection of the correlation between insulin resistance and inflammation, or is in fact a causal relationship. One possible effect of IL-6 may be indirect in the sense that IL-6 has been reported to decrease adiponectin levels (96). Additionally, IL-6 can increase lipolysis (97). Another possibility is that IL-6 can inhibit insulin by increasing the cellular expression of suppressor of cytokine signaling (SOCS)-3, a negative regulator of both leptin and insulin signaling. IL-6-induced SOCS-3 expression has been demonstrated in skeletal muscle, adipocytes (98), and hepatocytes (99). In vivo experiments further confirm that IL-6 decreases insulin sensitivity in the liver (100).

As with type 2 diabetes, there is some evidence that IL-6 has a role in the early pathogenesis of cardiovascular disease. This inflammatory cytokine is reported to be an independent marker of increased mortality in patients with unstable coronary artery disease (101). Furthermore, increased serum IL-6 concentrations tend to parallel dyslipidemia (102). A partial explanation may be the increase in adipocyte lipolysis, as noted above. It is known that IL-6 infusion in humans results in higher serum FFA (103). However, the exact role that the cytokine plays, and whether it is more than simply a reflection of the correlation between atherosclerosis and inflammation, is still to be determined.

Similar to observations for TNF-a, serum levels of IL-6 are also correlated with obesity-associated sleep apnea and have been implicated in its pathogenesis (104-107). Increased cytokine levels and associated sleep disturbances have been proposed to be consequences of metabolic syndrome (108).

In summary, adipose tissue and serum levels of IL-6 increase with obesity. There is evidence that IL-6 has some anti-inflammatory actions, perhaps as a brake to inflammatory states. In certain situations, IL-6 has been suggested to have beneficial effects on systemic metabolism. However, obesity is associated with chronic elevations of IL-6 that may promote adipocyte lipolysis, insulin resistance, and other metabolic alterations.

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