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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

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

  2. 2

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

  3. 3

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

  4. 4

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

  5. 5

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

  6. 6

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

  7. 7

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

  8. 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).

  9. 9

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

  10. 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).

  11. 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).

  12. 12

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

  13. 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).

  14. 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).

  15. 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).

  16. 16

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

  17. 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).

  18. 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).

  19. 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).

  20. 20

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

  21. 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).

  22. 22

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

  23. 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).

  24. 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).

  25. 25

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

  26. 26

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

  27. 27

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

  28. 28

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

  29. 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).

  30. 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).

  31. 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).

  32. 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).

  33. 33

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

  34. 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).

  35. 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).

Download references


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.

Author information


  1. Division of Endocrinology, Departments of Medicine and Genetics, Diabetes, and Metabolism, and The Penn Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    • Claire M. Steppan
    • , Shannon T. Bailey
    • , Savitha Bhat
    • , Elizabeth J. Brown
    • , Ronadip R. Banerjee
    • , Christopher M. Wright
    • , Hiralben R. Patel
    • , Rexford S. Ahima
    •  & Mitchell A. Lazar


  1. Search for Claire M. Steppan in:

  2. Search for Shannon T. Bailey in:

  3. Search for Savitha Bhat in:

  4. Search for Elizabeth J. Brown in:

  5. Search for Ronadip R. Banerjee in:

  6. Search for Christopher M. Wright in:

  7. Search for Hiralben R. Patel in:

  8. Search for Rexford S. Ahima in:

  9. Search for Mitchell A. Lazar in:

Corresponding author

Correspondence to Mitchell A. Lazar.

About this article

Publication history



Issue Date


Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.