The molecular mechanisms by which obesity leads to impaired insulin action are not well understood. However, recent studies, particularly in mice deficient for key components of the insulin-signaling pathway, have begun to provide molecular insights and potential models to study the role of obesity in the development of type 2 diabetes. Here we provide preliminary data in the mouse, showing that one such component, ribosomal protein S6 kinase 1 (S6K1), plays not only a positive role in insulin-induced anabolic responses associated with cell growth, but also a negative role. This negative role is revealed under conditions of nutrient satiation and is most likely mediated through the phosphorylation of specific residues on insulin receptor substrate 1 (IRS1). Phosphorylation at these sites is known to dampen phosphatidylinositide-3OH kinase (PI3K) binding to IRS1, reduce glucose uptake and lead to insulin resistance. However, the sites of phosphorylated in IRS1 are not S6K1 phosphorylation sites, but sites regulated by the mammalian Target Of Rapamycin (mTOR) an immediate upstream kinase involved in the phosphorylation and activation of S6K1. Our hypothesis is that nutrient activation of S6K1 negatively regulates insulin action by promoting mTOR phosphorylation of IRS1, leading to insulin resistance. Our research plan is to (i) identify the IRS1 phosphorylation sites mediated by mTOR, (ii) determine the mechanism by which absence of S6K1 reduces IRS1 phosphorylation by mTOR, and (iii) measure the extent to which S6K1 contributes to the development of diet-induced insulin resistance in the mouse. Given that nutrient satiation drives S6K1 activation and is intimately associated with obesity and insulin resistance, it is important to determine the extent to which S6K1 contributes to these pathologies. Obesity has become a worldwide epidemic, not only leading to type 2 diabetes, but is also a major cause of cancer and cardiovascular deaths. This epidemic has arisen because of the dramatic rise in food intake, which is due to the fact that food is abundant, tasteful, and inexpensive. That man was a scavenger until recent times has accentuated this effect, such that genetic traits to secure and retain food have prevailed over those that suppressed food intake. Thus, if S6K1 is a critical player in these diseases the development of a small molecule inhibitor to S6K1 may act to improve the quality of life of those suffering from insulin resistance. ? ? ?
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