Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. [Erratum: 2004 Sept. 23, v. 431, no. 7007, p. 485.]

• Published in: Nature 2004-09, Vol.431 (7005), p.200-205
• Main Authors: Um, S.H, Frigerio, F, Watanabe, M, Picard, F, Joaquin, M, Sticker, M, Fumagalli, S, Allegrini, P.R, Kozma, S.C, Auwerx, J
• Format: Article
• Language: English
• Subjects: Adipocytes - metabolism; adipose tissue; age; Aging - physiology; animal proteins; Animals; Biochemistry, Molecular Biology; Biological and medical sciences; blood glucose; Blood Glucose - analysis; blood lipids; Diabetes; Diet; Dietary Fats - pharmacology; Enzyme Activation; enzyme activity; enzyme deficiencies; Fasting - blood; Fasting - physiology; Fatty Acids, Nonesterified - blood; free fatty acids; Gene Deletion; high fat diet; hormonal regulation; Humanities and Social Sciences; Hypersensitivity; Insulin; Insulin - pharmacology; insulin receptor substrate 1; Insulin Receptor Substrate Proteins; Insulin Resistance - genetics; Insulin Resistance - physiology; letter; Life Sciences; Lipolysis; Male; Medical sciences; Medical treatment; Metabolic diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Nutrients; Obesity; Obesity - blood; Obesity - chemically induced; Obesity - genetics; Obesity - metabolism; overeating; Oxidation-Reduction; Phosphoproteins - metabolism; Phosphorylation; Receptor, Insulin - metabolism; Ribosomal Protein S6 Kinases, 70-kDa - deficiency; Ribosomal Protein S6 Kinases, 70-kDa - genetics; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Science; Science (multidisciplinary); Signal Transduction - drug effects
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature02866

Elucidating the signalling mechanisms by which obesity leads to impaired insulin action is critical in the development of therapeutic strategies for the treatment of diabetes. Recently, mice deficient for S6 Kinase 1 (S6K1), an effector of the mammalian target of rapamycin (mTOR) that acts to integrate nutrient and insulin signals, were shown to be hypoinsulinaemic, glucose intolerant and have reduced β-cell mass. However, S6K1-deficient mice maintain normal glucose levels during fasting, suggesting hypersensitivity to insulin, 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 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. Moreover, wild-type mice on a high fat diet as well as K/K Ay and ob/ob (also known as Lep/Lep) micetwo genetic models of obesityhave 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.