1. Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland
2. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, and Institut Clinique de la Souris, Génopole Strasbourg, 67404 Illkirch, France
3. Novartis Pharma AG, Klybeckstrasse 141, 4057 Basel, Switzerland
4. Present address: Laval Hospital Research Center, 2725 chemin Ste-Foy, Ste-Foy, Quebec G1V 4G5, Canada (F.P.); Genome Research Institute, University of Cincinnati, 2180 E. Galbraith Road, Cincinnati, Ohio 45237, USA (S.C.K.)

Correspondence to: George Thomas¹ Email: gthomas@fmi.ch

Abstract

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 -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 -oxidation. However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-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 resistance^{4, 5}. Moreover, wild-type mice on a high fat diet as well as K/K A^y 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.

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