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Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3

Abstract

Leptin is an adipocyte-derived hormone that regulates energy balance and neuroendocrine function primarily by acting on specific hypothalamic pathways1,2. Resistance to the weight reducing effects of leptin is a feature of most cases of human and rodent obesity1,2, yet the molecular basis of leptin resistance is poorly understood. We have previously identified suppressor of cytokine signaling-3 (Socs3) as a leptin-induced negative regulator of leptin receptor signaling and potential mediator of leptin resistance3,4,5. However, due to the non-viability of mice with targeted disruption of Socs3 (ref. 6), the importance of Socs3 in leptin action in vivo was unclear. To determine the functional significance of Socs3 in energy balance in vivo we undertook studies in mice with heterozygous Socs3 deficiency (Socs3+/−). We report here that Socs3+/− mice display greater leptin sensitivity than wild-type control mice: Socs3+/− mice show both enhanced weight loss and increased hypothalamic leptin receptor signaling in response to exogenous leptin administration. Furthermore, Socs3+/− mice are significantly protected against the development of diet-induced obesity and associated metabolic complications. The level of Socs3 expression is thus a critical determinant of leptin sensitivity and obesity susceptibility in vivo and this molecule is a potential target for therapeutic intervention.

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Figure 1: Enhanced weight-reducing effect of exogenous leptin in Socs3+/− mice.
Figure 2: Enhanced hypothalamic leptin-mediated Stat3 phosphorylation in Socs3+/− mice.
Figure 3: Protection against diet-induced obesity and improved metabolic parameters in mixed background Socs3+/− mice.
Figure 4: Attenuation of diet-induced obesity and enhanced insulin sensitivity in C57Bl/6 Socs3+/− mice.

References

  1. Ahima, R.S. & Flier, J.S. Leptin. Annu. Rev. Physiol. 62, 413–437 (2000).

    Article  Google Scholar 

  2. Friedman, J.M. & Halaas, J.L. Leptin and the regulation of body weight in mammals. Nature 395, 763–770 (1998).

    Article  Google Scholar 

  3. Bjørbæk, C., Elmquist, J.K., Frantz, J.D., Shoelson, S.E. & Flier, J.S. Identification of Socs3 as a potential mediator of central leptin resistance. Mol. Cell 4, 619–625 (1998).

    Article  Google Scholar 

  4. Bjørbæk, C., El-Haschimi, K., Frantz, J.D. & Flier, J.S. The role of Socs3 in leptin signaling and leptin resistance. J. Biol. Chem. 274, 30059–30065 (1999).

    Article  Google Scholar 

  5. Bjørbæk, C. et al. SOCS-3 mediates feedback inhibition of the leptin receptor via Tyr 985. J. Biol. Chem. 275, 40649–40657 (2000).

    Article  Google Scholar 

  6. Marine, J.C. et al. Socs3 is essential in the regulation of fetal liver erythropoiesis. Cell 98, 617–627 (1999).

    Article  Google Scholar 

  7. Krebs, D.L. & Hilton, D.J. SOCS proteins: negative regulators of cytokine signaling. Stem Cells 19, 378–387 (2001).

    Article  Google Scholar 

  8. Eyckerman, S., Broekaert, D., Verhee, A., Vandekerckhove, J. & Tavernier, J. Identification of the Y985 and Y1077 motifs as Socs3 recruitment sites in the murine leptin receptor. FEBS Lett. 486, 33–37 (2000).

    Article  Google Scholar 

  9. Halaas, J.L. et al. Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc. Natl. Acad. Sci. USA. 94, 8878–8883 (1997).

    Article  Google Scholar 

  10. Frederich, R.C. et al. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat. Med. 1, 1311–1314 (1995).

    Article  Google Scholar 

  11. Schwartz, M.W., Woods, S.C., Porte, D. Jr., Seeley, R.J. & Baskin, D.G. Central nervous system control of food intake. Nature 404, 661–671 (2000).

    Article  Google Scholar 

  12. Tartaglia, L.A. The leptin receptor. J. Biol. Chem. 272, 6093–6096 (1997).

    Article  Google Scholar 

  13. Scarpace, P.J. et al. Leptin-induced leptin resistance reveals separate roles for the anorexic and thermogenic responses in weight maintenance. Endocrinology 143, 3026–3035 (2002).

    Article  Google Scholar 

  14. Lin, S., Thomas, T.C., Storlien, L.H. & Huang, X.F. Development of high fat diet-induced obesity and leptin resistance in C57BL/6J mice. Int. J. Obes. Relat. Metab. Disord. 24, 639–646 (2000).

    Article  Google Scholar 

  15. El-Haschimi, K., Pierroz, D.D., Hileman, S.M., Bjørbæk, C. & Flier, J.S. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J. Clin. Invest. 105, 1827–1832 (2000).

    Article  Google Scholar 

  16. Wang, Z. et al. Leptin resistance of adipocytes in obesity: role of suppressors of cytokine signaling. Biochem. Biophys. Res. Commun. 277, 20–26 (2000).

    Article  Google Scholar 

  17. Emanuelli, B et al. Socs3 is an insulin-induced negative regulator of insulin signaling. J. Biol. Chem. 275, 15985–15991 (2000).

    Article  Google Scholar 

  18. Bruning, J.C. et al. Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122–2125 (2000).

    Article  Google Scholar 

  19. Spanswick, D., Smith, M.A., Mirshamsi, S., Routh, V.H. & Ashford, M.L.J. Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat. Neurosci. 3, 757–758 (2000).

    Article  Google Scholar 

  20. Spanswick, D., Smith, M.A., Groppi, V.E., Logan, S.D. & Ashford, M.J.L. Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature 390, 521–525 (1997).

    Article  Google Scholar 

  21. Kim, Y.B., Uotani, S., Pierroz, D.D., Flier, J.S. & Kahn, B.B. In vivo administration of leptin activates signal transduction directly in insulin-sensitive tissues: overlapping but distinct pathways from insulin. Endocrinology 141, 2328–2339 (2000).

    Article  Google Scholar 

  22. Shi, H., Tzameli, I., Bjørbæk, C.B. & Flier, J.S. Suppressor of cytokine signaling-3 is a physiologic regulator of adipocyte insulin signaling. J. Biol. Chem. (in the press).

  23. Heymsfield, S.B. et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. J. Am. Med. Assoc. 282, 1568–1575 (1999).

    Article  Google Scholar 

  24. Caro, J.F. et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 348, 159–161 (1996).

    Article  Google Scholar 

  25. Elchebly, M. et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283, 1544–1548 (1999).

    Article  Google Scholar 

  26. Klaman, L.D. et al. Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol. Cell Biol. 20, 5479–5489 (2000).

    Article  Google Scholar 

  27. Zabolotny, J.M. et al. PTP1B regulates leptin signal transduction in vivo. Dev. Cell 2, 489–495 (2002).

    Article  Google Scholar 

  28. Cheng, A. et al. Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Dev. Cell 2, 497–503 (2002).

    Article  Google Scholar 

  29. Salmon, D.M. & Flatt, J.P. Effect of dietary fat content on the incidence of obesity among ad libitum fed mice. Int. J. Obes. 9, 443–449 (1985).

    PubMed  Google Scholar 

Download references

Acknowledgements

Funded by grants from the National Institutes of Health (to J.S.F and C.B.), Takeda Chemical Industries (to J.S.F.), The Wellcome Trust, UK and the Royal College of Physicians, UK (to J.K.H.) and the Sigrid Jusélius Foundation (to L.J.O.). We thank J. Ihle for access to the Socs3+/− mice and H. Shi, K. Inouye and P. Pissios for their assistance in aspects of these studies.

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Correspondence to Jeffrey S Flier.

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Supplementary Fig. 1

Food intake and hypothalamic neuropeptides in leptin-infused wild-type and Socs3+/− mice. (PDF 14 kb)

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Howard, J., Cave, B., Oksanen, L. et al. Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat Med 10, 734–738 (2004). https://doi.org/10.1038/nm1072

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