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

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 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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Figure 1: Reduced adiposity in S6K1-/- mice.
Figure 2: Increased mitochondria and resistance to diet-induced obesity.
Figure 3: Enhanced insulin sensitivity and insulin signalling in the absence of S6K1.
Figure 4: S6K1 activation in obesity.

References

  1. Saltiel, A. R. & Kahn, C. R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799–806 (2001)

    Article  ADS  CAS  Google Scholar 

  2. Fingar, D. C., Salama, S., Tsou, C., Harlow, E. & Blenis, J. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev. 16, 1472–1487 (2002)

    Article  CAS  Google Scholar 

  3. Pende, M. et al. Hypoinsulinaemia, glucose intolerance and diminished β-cell size in S6K1-deficient mice. Nature 408, 994–997 (2000)

    Article  ADS  CAS  Google Scholar 

  4. Zick, Y. Insulin resistance: a phosphorylation-based uncoupling of insulin signaling. Trends Cell Biol. 11, 437–441 (2001)

    Article  CAS  Google Scholar 

  5. Bouzakri, K. et al. Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. Diabetes 52, 1319–1325 (2003)

    Article  CAS  Google Scholar 

  6. Tanaka, T. et al. Activation of peroxisome proliferator-activated receptor delta induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc. Natl Acad. Sci. USA 100, 15924–15929 (2003)

    Article  ADS  CAS  Google Scholar 

  7. Luquet, S. et al. Peroxisome proliferator-activated receptor delta controls muscle development and oxidative capability. FASEB J. 17, 2299–2301 (2003)

    Article  CAS  Google Scholar 

  8. Dressel, U. et al. The peroxisome proliferator-activated receptor beta/delta agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells. Mol. Endocrinol. 17, 2477–2493 (2003)

    Article  CAS  Google Scholar 

  9. Patti, M. E. et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc. Natl Acad. Sci. USA 100, 8466–8471 (2003)

    Article  ADS  CAS  Google Scholar 

  10. Mootha, V. K. et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genet. 34, 267–273 (2003)

    Article  ADS  CAS  Google Scholar 

  11. Boden, G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 46, 3–10 (1997)

    Article  CAS  Google Scholar 

  12. Kahn, B. B. Type 2 diabetes: when insulin secretion fails to compensate for insulin resistance. Cell 92, 593–596 (1998)

    Article  CAS  Google Scholar 

  13. Le Marchand-Brustel, Y. et al. Fatty acid-induced insulin resistance: role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signalling. Biochem. Soc. Trans. 31, 1152–1156 (2003)

    Article  CAS  Google Scholar 

  14. Jiang, G. & Zhang, B. B. Pi 3-kinase and its up- and down-stream modulators as potential targets for the treatment of type II diabetes. Front. Biosci. 7, d903–d907 (2002)

    Article  CAS  Google Scholar 

  15. Radimerski, T., Montagne, J., Hemmings-Mieszczak, M. & Thomas, G. Lethality of Drosophila lacking TSC tumor suppressor function rescued by reducing dS6K signaling. Genes Dev. 16, 2627–2632 (2002)

    Article  CAS  Google Scholar 

  16. Kahn, B. B. & Flier, J. S. Obesity and insulin resistance. J. Clin. Invest. 106, 473–481 (2000)

    Article  CAS  Google Scholar 

  17. Proietto, J., Filippis, A., Nakhla, C. & Clark, S. Nutrient-induced insulin resistance. Mol. Cell. Endocrinol. 151, 143–149 (1999)

    Article  CAS  Google Scholar 

  18. Greiwe, J. S., Kwon, G., McDaniel, M. L. & Semenkovich, C. F. Leucine and insulin activate p70 S6 kinase through different pathways in human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 281, E466–E471 (2001)

    Article  CAS  Google Scholar 

  19. Patti, M. E. Nutrient modulation of cellular insulin action. Ann. NY Acad. Sci. 892, 187–203 (1999)

    Article  ADS  CAS  Google Scholar 

  20. Hara, K. et al. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J. Biol. Chem. 273, 14484–14494 (1998)

    Article  CAS  Google Scholar 

  21. Patti, M. E., Brambilla, E., Luzi, L., Landaker, E. J. & Kahn, C. R. Bidirectional modulation of insulin action by amino acids. J. Clin. Invest. 101, 1519–1529 (1998)

    Article  CAS  Google Scholar 

  22. Dennis, P. B. et al. Mammalian TOR: a homeostatic ATP sensor. Science 294, 1102–1105 (2001)

    Article  ADS  CAS  Google Scholar 

  23. Tremblay, F. & Marette, A. Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells. J. Biol. Chem. 276, 38052–38060 (2001)

    CAS  PubMed  Google Scholar 

  24. Iwatsuka, H., Shino, A. & Suzuoki, Z. General survey of diabetic features of yellow KK mice. Endocrinol. Jpn 17, 23–35 (1970)

    Article  CAS  Google Scholar 

  25. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994)

    Article  ADS  CAS  Google Scholar 

  26. Manning, B. D. & Cantley, L. C. Rheb fills a GAP between TSC and TOR. Trends Biochem. Sci. 28, 573–576 (2003)

    Article  CAS  Google Scholar 

  27. Picard, F. et al. SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Cell 111, 931–941 (2002)

    Article  CAS  Google Scholar 

  28. Doty, F. D., Entzminger, G. Jr, Hauck, C. D. & Staab, J. P. Practical aspects of birdcage coils. J. Magn. Reson. 138, 144–154 (1999)

    Article  ADS  CAS  Google Scholar 

  29. Marette, A., Tulp, O. L. & Bukowiecki, L. J. Mechanism linking insulin resistance to defective thermogenesis in brown adipose tissue of obese diabetic SHR/N-cp rats. Int. J. Obes. 15, 823–831 (1991)

    CAS  PubMed  Google Scholar 

  30. Hirosumi, J. et al. A central role for JNK in obesity and insulin resistance. Nature 420, 333–336 (2002)

    Article  ADS  CAS  Google Scholar 

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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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Correspondence to George Thomas.

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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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