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 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 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 resistance4,5. Moreover, wild-type mice on a high fat diet as well as K/K Ay 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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Acknowledgements
We thank T. Opgenorth and C. Rondinone for sharing their results before publication; G. S. Hotamisligil, S. Y. Kim and D. J. Withers for their critical reading of the manuscript; and S. Cinti, P. B. Dennis, A. Dulloo, L. Fajas, A. Greenberg, B. M. Spiegelman, G. Solinas, J. Tanti and M. Wymann for discussions. We are also grateful to M.-F. Champy, W. Theilkaes, N. Messaddeq, I. Obergfoell and J. F. Spetz for the blood analysis, studies with MRI, technical assistance with electron microscopy, for photography and for assistance in the animal experiments, respectively. Work in the laboratory of J.A. is supported by grants from CNRS, INSERM, ULP, Hôpital Universitaire de Strasbourg, NIH, EMBO and the European community, and the laboratory of S.C.K. and G.T. is supported by the Novartis Institutes for Biomedical Research and a grant from the Swiss Cancer League.
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Supplementary information
Supplementary Figure 1
Reduced adiposity in S6K1-/- mice. (PDF 720 kb)
Supplementary Figure 2
Increased mitochondria and resistance to diet-induced obesity. (PDF 277 kb)
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Um, S., Frigerio, F., Watanabe, M. et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431, 200–205 (2004). https://doi.org/10.1038/nature02866
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DOI: https://doi.org/10.1038/nature02866
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