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The hormone resistin links obesity to diabetes

Abstract

Diabetes mellitus is a chronic disease that leads to complications including heart disease, stroke, kidney failure, blindness and nerve damage. Type 2 diabetes, characterized by target-tissue resistance to insulin, is epidemic in industrialized societies and is strongly associated with obesity; however, the mechanism by which increased adiposity causes insulin resistance is unclear. Here we show that adipocytes secrete a unique signalling molecule, which we have named resistin (for resistance to insulin). Circulating resistin levels are decreased by the anti-diabetic drug rosiglitazone, and increased in diet-induced and genetic forms of obesity. Administration of anti-resistin antibody improves blood sugar and insulin action in mice with diet-induced obesity. Moreover, treatment of normal mice with recombinant resistin impairs glucose tolerance and insulin action. Insulin-stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment. Resistin is thus a hormone that potentially links obesity to diabetes.

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Figure 1: Cloning and identification of resistin.
Figure 2: Resistin expression is adipocyte-specific.
Figure 3: Resistin circulates in blood and is regulated by feeding and rosiglitazone.
Figure 4: Resistin levels are elevated in obesity.
Figure 5: Neutralization of resistin improves hyperglycaemia and insulin resistance in mice.
Figure 6: Resistin impairs glucose tolerance and insulin action in mice.
Figure 7: Resistin antagonizes insulin-stimulated glucose transport in vitro .

References

  1. Nathan, D. M. Long-term complications of diabetes mellitus. New Eng. J. Med. 328, 1676–1685 ( 1993).

    Article  CAS  PubMed  Google Scholar 

  2. Taylor, S. I. Deconstructing type 2 diabetes. Cell 97, 9–12 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Kopelman, P. G. Obesity as a medical problem. Nature 404, 635–643 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Kahn, C. R., Vicent, D. & Doria, A. Genetics of non-insulin-dependent (type II) diabetes mellitus. Annu. Rev. Med. 47, 509– 531 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Boden, G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 46, 1–10 ( 1997).

    Article  Google Scholar 

  6. Hotamisligil, G. S. The role of TNFα and TNF receptors in obesity and insulin resistance. J. Int. Med. 245, 621– 625 (1999).

    Article  CAS  Google Scholar 

  7. Spiegelman, B. M. & Flier, J. S. Adipogenesis and obesity: rounding out the big picture. Cell 87, 377–389 (1996).

    Article  CAS  PubMed  Google Scholar 

  8. Mohamed-Ali, V., Pinkney, J. H. & Coppack, S. W. Adipose tissue as an endocrine and paracrine organ. Int. J. Obes. Relat. Metab. Disord. 22, 1145–1158 (1998).

    Article  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  10. Shimomura, I., Hammer, R. E., Ikemoto, S., Brown, M. S. & Goldstein, J. L. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401, 73–76 ( 1999).

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Moller, D. E. Potential role of TNFα in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol. Metab. 11, 212–217 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Henry, R. R. Thiazolidinediones. Endocrinol. Metab. Clin. North Am. 26, 553–573 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Lehmann, J. M. et al. An antidiabetic thiazolidinedione is a high affinity ligand for the nuclear peroxisome proliferator-activated receptor γ (PPARγ). J. Biol. Chem. 270, 12953– 12956 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Tontonoz, P., Hu, E., Graves, R. A., Budavari, A. I. & Spiegelman, B. M. mPPARγ2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 8, 1224– 1234 (1994).

    Article  CAS  PubMed  Google Scholar 

  15. Chawla, A., Schwarz, E. J., Dimaculangan, D. D. & Lazar, M. A. Peroxisome proliferator-activated receptor γ (PPARγ): Adipose predominant expression and induction early in adipocyte differentiation. Endocrinology 135, 798–800 (1994).

    Article  CAS  PubMed  Google Scholar 

  16. Barak, Y. et al. PPARγ is required for placental, cardiac, and adipose tissue development. Mol. Cell 4, 585– 595 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Rosen, E. D. et al. PPARγ is required for the differentiation of adipose tissue in vivo and in vitro. Mol. Cell 4, 611–617 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Tontonoz, P., Hu, E. & Spiegelman, B. M. Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 79, 1147–1156 (1994).

    Article  CAS  PubMed  Google Scholar 

  19. Willson, T. M., Brown, P. J., Sternbach, D. D. & Henke, B. R. The PPARs: from orphan receptors to drug discovery. J. Med. Chem. 2000, 527–550 ( 2000).

    Article  Google Scholar 

  20. Mukherjee, R. et al. Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists. Nature 386, 407– 410 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  21. Barroso, I. et al. Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus, and hypertension. Nature 402, 880–883 ( 1999).

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Kubota, N. et al. PPARγ mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol. Cell 4, 597 –609 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Miles, P. D., Barak, Y., He, W., Evans, R. M. & Olefsky, J. M. Improved insulin-sensitivity in mice heterozygous for PPAR-γ deficiency. J. Clin. Invest. 105, 287–292 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Holcomb, I. N. et al. FIZZ1, a novel cysteine-rich secretedprotein associated with pulmonary inflammation, defines a new gene family. EMBO J. 19, 4046–4055 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Steppan, C. M. et al. A family of tissue-specific resistin-like molecules. Proc. Natl Acad. Sci. USA (in the press).

  26. VanHeek, M. et al. Diet-induced obese mice develop peripheral, but not central, resistance to leptin. J. Clin. Invest. 99, 385–390 (1997).

    Article  CAS  Google Scholar 

  27. Ahima, R. S. et al. Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  28. Seed, B. PPARγ and colorectal carcinoma: conflicts in a nuclear family. Nature Med. 4, 1004–1005 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Tontonoz, P., Nagy, L., Alvarez, J. G., Thomazy, V. A. & Evans, R. M. PPARγ promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93, 241 –252 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Shao, D. & Lazar, M. A. PPARγ, C/EBPα, cell cycle status and the commitment to adipocyte differentiation. J. Biol. Chem. 272, 21473–21478 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Huang, E. Y. et al. Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway. Genes Dev. 14, 45–54 ( 2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Speicher, D. W. & Reim, D. in Current Protocols in Protein Science (eds Coligan, J. E., Dunn, B. M., Ploegh, H. L., Speicher, D. W. & Wingfield, P. T.) 11.10.11–11.10.38 (John Wiley & Sons, New York, 1997).

    Google Scholar 

  33. Hausdorff, S. F. et al. Identification of wortmannin-sensitive targets in 3T3-L1 adipocytes. J. Biol. Chem. 274, 24677– 24684 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Nakai, K. & Horton, P. PSORT: a program for detecting sorting signals in proteins and predicting their subcellular localization. Trends Biochem. Sci. 24, 34–36 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Nielsen, H., Engelbrecht, J., Brunak, S. & von Heijne, G. Identification of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites. Protein Engng 10, 1–6 (1997).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank D. Shao for help with the early stages of this project, and M. Brown, M. S. Brown, J. Cunningham, T. Lawrence, M. Birnbaum, J. Stephens, A. Swick and the Lazar laboratory for discussions. We acknowledge D. Reim and D. Speicher of the Wistar Protein Microchemistry/MS Facility for sequence analysis; H. Collins and the Radioimmunoassay Core of the Penn Diabetes Center and J. Moffett; and G. Swain, and the Morphology Core of the Penn Center for the Molecular Study of Digestive Diseases. This work was supported by NIDDK grants to M.A.L., and by the Penn Diabetes Center. C.M.S. was supported by an unrestricted postdoctoral research fellowship from Pfizer. E.J.B. was supported by a student research fellowship from the American Diabetes Association. R.R.B. is a trainee of the Medical Scientist Training Program.

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Correspondence to Mitchell A. Lazar.

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Steppan, C., Bailey, S., Bhat, S. et al. The hormone resistin links obesity to diabetes. Nature 409, 307–312 (2001). https://doi.org/10.1038/35053000

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