Role of resistin in insulin resistance

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Resistin is a recently discovered polypeptide that is secreted by mouse adipocytes and has been implicated in the development of insulin resistance. Resistin was first described in 2001, when a search for genes that are induced during adipocyte differentiation but downregulated in mature adipocytes during exposure to thiazolidinediones led to the discovery of a protein the investigators named resistin, for "resistance to insulin" (43). Administration of resistin in normal mice impairs glucose tolerance and insulin action. Furthermore, immunoneutralization of resistin improved blood glucose and insulin action in animal models of obesity-induced insulin resistance. In rodents, administration of thiazolidinedione drugs reverses insulin resistance. These drugs also reduce gene and protein expression of resistin in some studies (44) but not in others (45). These initial data suggested that resistin, at least in part, may explain how adiposity leads to insulin resistance and may also explain the antidiabetic effects of thiazolidinedione drugs. The molecular mechanism for the action of resistin is unknown. A recent study in mice suggested that resistin selectively impairs the inhibitory action of insulin on hepatic glucose production (44). However, the role of resistin in obesity-associated insulin resistance has become controversial because the biology of resistin is different in humans than in rodents and additional evidence has suggested that obesity and insulin resistance are associated with decreased resistin expression (45-47).

Whether resistin is expressed in human adipose tissue is not clear. McTernan et al. found such expression and reported that resistin is relatively highly expressed in the omental visceral fat and the abdominal subcutaneous fat, with lower expression in subcutaneous fat on the thigh (48). This finding is in contrast to the findings of Savage et al. and Nagaev et al., who did not detect resistin in human adipose tissue (49,50). Whereas resistin is expressed mainly in adipocytes in mice (43), Fain et al. reported that most of the resistin secreted by human fat explants is derived from nonadipocytes (51). The reason for the differences in these studies is unclear. Human resistin is only 59% similar to the mouse protein, and this may portend important differences in the endocrine functions of adipocytes and resistin between rodents and humans (52). Furthermore, insulin and TNF-a, both elevated in obesity, have been found to inhibit resistin expression, which may explain the low levels of resistin found in the recent studies of obesity diabetes.

The initial suggestion that resistin may be the link between obesity and insulin resistance is being challenged. The role of resistin in normal and abnormal physiology remains elusive. Studies from knockout mice and better characterization of resistin changes in humans should help determine whether this adipokine is a cause of insulin resistance or simply a bystander. Also, it will important to understand the similarities and differences between mouse and human resistin and mechanisms of obesity-related insulin resistance.

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