Modulation of obesity and insulin resistance by the redox enzyme and adaptor protein p66shc

Initially reported as a longevity-related protein, the 66 kDa isoform of the mammalian Shc1 locus has been implicated in several metabolic pathways, being able to act both as an adaptor protein and as a redox enzyme capable of generating reactive oxygen species (ROS) when it localizes to the mitochondrion. Ablation of p66(Shc) has been shown to be protective against obesity and the insurgence of insulin resistance, but not all the studies available in the literature agree on these points. This review will focus in particular on the role of p66(Shc) in the modulation of glucose homeostasis, obesity, body temperature, and respiration/energy expenditure. In view of the obesity and diabetes epidemic, p66(Shc) may represent a promising therapeutic target with enormous implications for human health.