Mammalian life-span determinant p66shcA mediates obesity-induced insulin resistance.

Obesity and metabolic syndrome result from excess calorie intake and genetic\r\npredisposition and are mechanistically linked to type II diabetes and accelerated\r\nbody aging; abnormal nutrient and insulin signaling participate in this\r\npathologic process, yet the underlying molecular mechanisms are incompletely\r\nunderstood. Mice lacking the p66 kDa isoform of the Shc adaptor molecule live\r\nlonger and are leaner than wild-type animals, suggesting that this molecule may\r\nhave a role in metabolic derangement and premature senescence by overnutrition.\r\nWe found that p66 deficiency exerts a modest but significant protective effect on\r\nfat accumulation and premature death in lepOb/Ob mice, an established genetic\r\nmodel of obesity and insulin resistance; strikingly, however, p66 inactivation\r\nimproved glucose tolerance in these animals, without affecting\r\n(hyper)insulinaemia and independent of body weight. Protection from insulin\r\nresistance was cell autonomous, because isolated p66KO preadipocytes were\r\nrelatively resistant to insulin desensitization by free fatty acids in vitro.\r\nBiochemical studies revealed that p66shc promotes the signal-inhibitory\r\nphosphorylation of the major insulin transducer IRS-1, by bridging IRS-1 and the \r\nmTOR effector p70S6 kinase, a molecule previously linked to obesity-induced\r\ninsulin resistance. Importantly, IRS-1 was strongly up-regulated in the adipose\r\ntissue of p66KO lepOb/Ob mice, confirming that effects of p66 on tissue\r\nresponsiveness to insulin are largely mediated by this molecule. Taken together, \r\nthese findings identify p66shc as a major mediator of insulin resistance by\r\nexcess nutrients, and by extension, as a potential molecular target against the\r\nspreading epidemic of obesity and type II diabetes.