TNF-a was first shown by Hotamisligil et al. to be overexpressed in adipose tissue from several strains of obese rodents (24). Weisberg et al. have shown that macrophages are the main source of TNF-a in adipose tissue (14). TNF-a expression is higher in visceral fat (VF) of rodents than in subcutaneous (sc) fat (25). In addition, TNF-a has been shown to impair insulin signaling in cultured cells by three separate molecular mechanisms. TNF-a activates serine/threonine kinases that phosphorylate and impair the function of key elements in the insulin signaling pathway (26). First, TNF-a mediates a serine phosphorylation of IRS-1 (27). This alteration impairs insulin signaling by making IRS-1 resistant to subsequent insulin-stimulated tyrosine phosphorylation. Second, TNF-a phosphorylates and activates a protein tyrosine phosphatase that normally terminates insulin action, thus playing a role in the self-limiting nature of insulin signaling (28). Third, TNF-a phosphorylates and inactivates the protein phosphate PP-1 at site 2, resulting in its inactivation (29). This action of TNF-a opposes the action of insulin, whereby glucose storage is promoted by phosphorylating PP-1 at site 1 and activating it.
The above findings led to the popular theory that TNF-a of adipose origin is secreted into the circulation, from where it reaches targets such as muscle and liver and causes insulin resistance. However, circulating levels of TNF-a are very low compared with the concentrations required to induce insulin resistance when infused into rats (30) and tissue levels of TNF-a are several orders of magnitude higher than circulating levels (31). Whereas some studies have shown that circulating TNF-a is elevated in obese and insulin-resistant subjects (32), others have not (33).
We hypothesize that locally produced TNF-a may contribute to insulin resistance in one of two ways. First, obesity may cause insulin resistance in by increasing TNF-a expression in targets such as muscle. Support for this concept is our report that diet-induced obesity in rats is accompanied by reduced insulin-stimulated glucose transport in skeletal muscle, together with an increase in muscle expression of TNF-a (34). Alternatively, obesity may increase TNF-a expression in adipose tissue, leading to the release into the circulation of other cytokines that are capable of causing systemic insulin resistance.
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