Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity (original) (raw)

Nature volume 431, pages 200–205 (2004)Cite this article

A Corrigendum to this article was published on 23 September 2004

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 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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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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  1. Frédéric Picard
    Present address: Laval Hospital Research Center, 2725 chemin Ste-Foy, Ste-Foy, Quebec, G1V 4G5, Canada
  2. Sara C. Kozma
    Present address: Genome Research Institute, University of Cincinnati, 2180 E. Galbraith Road, Cincinnati, Ohio, 45237, USA

Authors and Affiliations

  1. Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058, Basel, Switzerland
    Sung Hee Um, Francesca Frigerio, Manel Joaquin, Melanie Sticker, Stefano Fumagalli, Sara C. Kozma & George Thomas
  2. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, and Institut Clinique de la Souris, Génopole Strasbourg, 67404, Illkirch, France
    Mitsuhiro Watanabe, Frédéric Picard & Johan Auwerx
  3. Novartis Pharma AG, Klybeckstrasse 141, 4057, Basel, Switzerland
    Peter R. Allegrini

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  1. Sung Hee Um
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  2. Francesca Frigerio
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  3. Mitsuhiro Watanabe
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  11. George Thomas
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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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