Editors' ChoiceMetabolic Syndrome

Adapting to Aging and Metabolism

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Science Translational Medicine  21 Jul 2010:
Vol. 2, Issue 41, pp. 41ec116
DOI: 10.1126/scitranslmed.3001484

Obesity, metabolic syndrome, and type 2 diabetes are major public health issues, particularly in populations that have adapted a lifestyle of overnutrition and underactivity. At the core of these health conditions is insulin resistance, which also accelerates the aging process. Previous work has demonstrated that the adaptor protein p66shcA influences life span and body mass in mice; in addition, the protein participates in insulin signaling and promotes insulin-induced fat accumulation. So, could a targeted disruption in p66shcA both improve longevity and insulin sensitivity?

To address this question, Ranieri et al. investigated the molecular interactions of p66shcA with nutrient- and insulin-induced signaling pathways and evaluated the effect of p66shcA deletion in leptin-deficient LepOb/Ob mice—an established model of metabolic dysfunction from nutrient overload. Although both mice in which p66shcA was knocked out (p66KO) and wild-type (p66WT) mice became obese on an ad libitum diet, p66shcA deficiency was shown to exert a protective effect on fat accumulation independently of food consumption and also to extend survival. Moreover, p66shcA deficiency improved glucose tolerance in the p66KO animals and attenuated the development of insulin resistance independently of body weight. The authors further showed that p66shcA promoted serine phosphorylation (and thus inactivation) of the major insulin-signaling molecule IRS-1 by bridging it to the mTOR effector p70S6, a kinase previously associated with obesity-induced insulin resistance.

Collectively, these findings establish p66shcA as a major player in both the aging process as well as the metabolic response to nutrient overload. Furthermore, p66shcA may be an important molecular target in the prevention and treatment of obesity-induced insulin resistance and the rising prevalence of type 2 diabetes.

S. C. Ranieri et al., Mammalian life-span determinant p66shcA mediates obesity-induced insulin resistance. Proc. Natl. Acad. Sci. U.S.A. 12 July 2010 (10.1073/pnas.1008647107). [Abstract]

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