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Resistin / Fizz3 Expression in Relation to Obesity and Peroxisome Proliferator–Activated Receptor-γ Action in Humans

Savage, David B., Sewter, Ciaran P., Klenk, Ellen S., Segal, David G., Vidal-Puig, Antonio, Considine, Robert V., O’Rahilly, Stephen·2001·Diabetes
DOI 10.2337/diabetes.50.10.2199
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Abstract

Recent studies in murine models suggest that resistin (also called Fizz3 [1]), a novel cysteine-rich protein secreted by adipocytes, may represent the long-sought link between obesity and insulin resistance (2). Furthermore, peroxisome proliferator–activated receptor-γ (PPAR-γ) agonists appear to inhibit resistin expression in murine adipocytes, providing a possible explanation for the mode of action of this class of insulin sensitizers (2). Using a fluorescent real-time reverse transcriptase–polymerase chain reaction–based assay, we found that resistin mRNA levels in whole adipose tissue samples were increased in morbidly obese humans compared with lean control subjects. However, in freshly isolated human adipocytes, resistin mRNA levels were very low and showed no correlation with BMI. Resistin mRNA was undetectable in preadipocytes, endothelial cells, and vascular smooth muscle cells, but it was readily detectable in circulating mononuclear cells. Although exposure of human mononuclear cells to PPAR-γ agonists markedly upregulated fatty acid–binding protein-4 expression, these agents had no effect on mononuclear cell resistin expression. Finally, resistin mRNA was undetectable in adipocytes from a severely insulin-resistant subject with a dominant-negative mutation in PPAR-γ (3). We conclude that the recently described relationships of murine resistin/Fizz3 expression with obesity, insulin resistance, and PPAR-γ action may not readily translate to humans. Further studies of this novel class of proteins are needed to clarify their roles in human metabolism.

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Crossref · 10.2337/diabetes.50.10.2199

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Citations

Cites

Research works printed but not linked: 15

  1. Holcomb IN, Kabakoff RC, Chan B, Baker TW, Gurney A, Henzel W, Nelson C, Lowman HB, Wright BD, Skelton NJ, Frantz GD, Tumas DB, Peale FV Jr, Shelton DL, Hebert CC: FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. Embo J 19:4046–4055, 2000 · DOI
  2. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA: The hormone resistin links obesity to diabetes. Nature 409:307–312, 2001 · DOI · Paper page
  3. Barroso I, Gurnell M, Crowley VEF, Agostini M, Schwabe JW, Soos MA, Maslen GL, Williams TDM, Lewis H, Schafer AJ, Chatterjee VKK, O’Rahilly S: Dominant negative mutations in human PPAR-γ associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402:880–883, 1999 · DOI · Paper page
  4. Way JM, Gorgun CZ, Tong Q, Uysal KT, Brown KK, Harrington WW, Oliver WR, Willson TM, Kliewer SA, Hotamisligil GS: Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists. J Biol Chem 276:25651–25653, 2001 · DOI
  5. Considine RV, Cooksey RC, Williams LB, Fawcett RL, Zhang P, Ambrosius WT, Whitfield RM, Jones R, Inman M, Huse J, McClain DA: Hexosamines regulate leptin production in human subcutaneous adipocytes. J Clin Endocrinol Metab 85:3551–3556, 2000 · DOI
  6. Adams M, Montague CT, Prins JB, Holder JC, Smith SA, Sanders L, Digby JE, Sewter CP, Lazar MA, Chatterjee VKK, O’Rahilly S: Activators of peroxisome proliferator-activated receptor gamma have depot-specific effects on human preadipocyte differentiation. J Clin Invest 100:3149–3153, 1997 · DOI
  7. Willson TM, Brown PJ, Sternbach DD, Henke BR: The PPARs: from orphan receptors to drug discovery (Review). J Med Chem 43:527–550, 2000 · DOI · Paper page
  8. Kim KH, Lee K, Moon YS, Sul HS: A cysteine-rich adipose-tissue specific secretory factor inhibits adipocyte differentiation. J Biol Chem 276:11252–11256, 2001 · DOI
  9. Montague CT, Prins JB, Sanders L, Digby JE, O’Rahilly S: Depot- and sex-specific differences in human leptin mRNA expression: implications for the control of regional fat distribution. Diabetes 46:342–347, 1997 · DOI
  10. Cianflone K, Maslowska M: Differentiation-induced production of ASP in human adipocytes. Eur J Clin Invest 25:817–825, 1995 · DOI
  11. Karlsson C, Lindell K, Ottoson M, Sjostrom L, Carlsson B, Carlsson LM: Human adipose tissue expresses angiotensinogen and enzymes required for its conversion to angiotensin II. J Clin Endocrinol Metab 83:3925–3929, 1998 · DOI
  12. Olefsky, J.M: Treatment of insulin resistance with peroxisome proliferator-activated receptor gamma agonists. J Clin Invest 46:467–472, 2000 · DOI
  13. Hotamisligil GS, Shargill NS, Spiegelman BM: Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259:87–91, 1993 · DOI · Paper page
  14. Montague CT, Prins JB, Sanders L, Zhang J, Sewter CP, Digby J, Byrne CD, O’Rahilly S: Depot-related gene expression in human subcutaneous and omental adipocytes. Diabetes 47:1384–1391, 1998 · DOI
  15. Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R: Effects of an engineered human anti–TNF-α antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 45:881–885, 1996 · DOI

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Metadata

Authors
Savage, D. B., Sewter, C. P., Klenk, E. S., Segal, D. G., Vidal-Puig, A., Considine, R. V., & O’Rahilly, S.
Affiliations
  • University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom
  • Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
Venue
Diabetes
Publisher
American Diabetes Association
Published
2001-10-01
Volume
50
Issue
10
Pages
2199-2202
ISSN
  • 0012-1797
  • 1939-327X
DOI
10.2337/diabetes.50.10.2199
Cited by
572
References
1
Language
en

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