Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity.

OBESITY; INSULIN; DIABETES; RAPAMYCIN; GLUCOSE; ALLERGIES; AGE; DIET

Elucidating the signalling mechanisms by which obesity leads to impaired insulin action is critical in the development of therapeutic strategies for the treatment of diabetes1. Recently, mice deficient for S6 Kinase 1 (S6K1), an effector of the mammalian target of rapamycin (mTOR) that acts to integrate nutrient and insulin signals2, were shown to be hypoinsulinaemic, glucose intolerant and have reduced β-cell mass3. However, S6K1- deficient mice maintain normal glucose levels during fasting, suggesting hypersensitivity to insulin3, raising the question of their metabolic fate as a function of age and diet. Here, we report that S6K1-deficient mice are protected against obesity owing to enhanced β-oxidation. However on a high fat diet, levels of glucose and free fatty acids still rise in S6Kl-deficient mice, resulting in insulin receptor desensitization. Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance4,5. Moreover, wild-type mice on a high fat diet as well as K/KAy and ob/ob (also known as Lep/Lep) mice-two genetic models of obesity—have markedly elevated S6K1 activity and, unlike S6K1-deficient mice, increased phosphorylation of IRS1 S307 and S636/S639. Thus under conditions of nutrient satiation S6K1 negatively regulates insulin signalling. [ABSTRACT FROM AUTHOR]

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