Abstract
The peroxisome proliferator-activated receptor-γ (PPARγ) is a transcription factor that has a pivotal role in adipocyte differentiation and expression of adipocyte-specific genes1,3. The PPARγ1 and γ2 isoforms result from alternative splicing4 and have ligand-dependent and -independent activation domains. PPARγ2 has an additional 28 amino acids at its amino terminus that renders its ligand-independent activation domain 5-10-fold more effective than that of PPARγ1. Insulin stimulates the ligand-independent activation of PPARγ1 and γ2 (ref. 5), however, obesity and nutritional factors only influence the expression of PPARγ2 in human adipocytes6. Here, we report that a relatively common Pro12Ala substitution in PPARγ2 is associated with lower body mass index (BMI; P=0.027; 0.015) and improved insulin sensitivity among middle-aged and elderly Finns. A significant odds ratio (4.35, P=0.028) for the association of the Pro/Pro genotype with type 2 diabetes was observed among Japanese Americans. The PPARγ2 Ala allele showed decreased binding affinity to the cognate promoter element and reduced ability to transactivate responsive promoters. These findings suggest that the PPARγ2 Pro12Ala variant may contribute to the observed variability in BMI and insulin sensitivity in the general population.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Tontonoz, P., Hu, E. & Spiegelman, B.M. Stimulation of adipogenesis in fibroblasts by PPAR γ 2, a lipid-activated transcription factor. Cell 79, 1147–1156 (1994).
Tontonoz, P. Hu, E., Graves, R.A., Budavari, A.I. & Spiegelman, B.M. mPPAR γ 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 8, 1224– 1234 (1994).
Tontonoz, P. & Spiegelman, B.M. Regulation of adipocyte gene expression and differentiation by peroxisome proliferator activated receptor γ. Curr. Opin. Genet. Dev. 5, 571– 576 (1995).
Fajas, L. et al. The organization, promoter analysis, and expression of the human PPARγ gene. J. Biol. Chem. 272, 18779–18789 (1997).
Werman, A. et al. Ligand-independent activation domain in the N terminus of peroxisome proliferator-activated receptor γ (PPARγ). Differential activity of PARγ 1 and -2 isoforms and influence of insulin. J. Biol. Chem. 272, 20230–20235 (1997).
Vidal-Puig, A. et al. Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J. Clin. Invest. 99, 2416–2422 (1997).
Kahn, C.R. Diabetes. Causes of insulin resistance. Nature 373, 384–385 (1995).
Spiegelman, B.M. & Flier, J.S. Adipogenesis and obesity: rounding out the big picture. Cell 87, 377–389 (1996).
Auwerx, J., Martin, G., Guerre-Millo, M. & Staels, B. Transcription, adipocyte differentiation, and obesity. J. Mol. Med. 74, 347–352 (1996).
Hotamisligil, G.S., Shargill, N.S. & Spiegelman, B.M. Adipose expression of tumor necrosis factor-γ: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).
Kliewer, S.A. et al., A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation. Cell 83, 813–819 (1995).
Lehmann, J.M. et al., An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ). J. Biol. Chem. 270, 12953–12956 (1995).
Saltiel, A.R. & Olefsky, J.M. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 45, 1661–1669 (1996).
Bouchard, C. Genetics of obesity: an update on molecular markers. Int. J. Obes. Rel. Metab. Disord. 19, S10–S13 (1995).
Meirhaeghe, A. et al. A genetic polymorphism of the peroxisome proliferator-activated receptor γ gene influences plasma leptin levels in obese humans. Hum. Mol. Genet. 7, 435–440 (1998).
Laakso, M. et al. Atherosclerotic vascular disease and its risk factors in non-insulin-dependent diabetic and nondiabetic subjects in Finland. Diabetes Care 11, 449–463 (1988).
Fujimoto, W.Y., Bergstrom, R.W., Newell-Morris, L. & Leonetti, D.L. Nature and nurture in the etiology of type 2 diabetes mellitus in Japanese Americans. Diabetes Metab. Rev. 5, 607– 625 (1989).
Schoonjans, K. et al. PPARγ and PPARγ activators direct a distinct tissue specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J. 15, 5336– 5348 (1996).
Nolan, J.J., Ludvik, B., Beerdsen, P., Joyce, M. & Olefsky, J. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N. Engl. J. Med. 331, 1188–1193 (1994).
Burant, C.F. et al. Troglitazone action in independent of adipose tissue. J. Clin. Invest. 100, 2900–2908 (1997).
Reaven, G.M. Role of insulin resistance in human disease. Diabetes 37, 1595–1607 (1988).
Chagnon, Y.C., Perusse, L. & Bouchard, C. The human obesity gene map: the 1997 update. Obesity Res. 6, 76–92 (1998).
Norman, R.A. et al. Genomewide search for genes influencing percent body fat in Pima Indians: suggestive linkage at chromosome 11q21-q22. Am. J. Hum. Genet. 60, 166–173 (1997).
Beamer, B.A. et al. Chromosomal localization and partial genomic structure of the human peroxisome proliferator activated receptor-γ (hPPAR γ) gene. Biochem. Biophys. Res. Commun. 233, 756–759 (1997).
Hanis, C.L. et al. A genome-wide search for human non-insulin-dependent (type2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nature Genet. 13, 161–166 (1996).
Mykkänen, L., Laakso, M., Uusitupa, M. & Pyörälä, K. Prevalence of diabetes and impaired glucose tolerance in elderly subjects and their association with obesity and family history of diabetes. Diabetes Care 13, 1099–1105 (1990).
Nevin, D., Deeb, S. & Brunzell, J. The LPL gene in individuals with familial combined hyperlipidemia and decreased LPL activity. Arterioscler. Thromb. 14, 869–873 (1994).
Vu-Dac, N. et al. Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor. J. Clin. Invest. 96, 741–750 (1995).
Fried, M.G. & Crothers, D.M. CAP and RNA polymerase interactions with the lac binding stoichiometry and long range effects. Nucleic Acids Res. 11, 141–158 (1983).
Mykkanen, L. et al. Is there a sex difference in the association of plasma insulin level and insulin sensitivity with serum lipids and lipoproteins? Metabolism 43, 523–528 (1994).
Acknowledgements
We thank all subjects for their invaluable contribution to this project. We thank L. Iwasaki, R. Peng, D. Cayet, O. Vidal and R. Miettinen for excellent technical work and suggestions, and investigators and staff of the Japanese-American Community Diabetes Study for their assistance and support. We thank R. Heyman for the gift of BRL 49,653 and J. Purnell for helpful discussions. This work was supported by National Insitutes of Health grant HL30086 to S.D., INSERM and Association pour la Recherche contre le Cancer (ARC 6403) to J.A. and NIH grants DK 3117, 17047, 35816, HL 49293 and RR 00037 to W.F. We also thank NATO for a collaborative research grant number 940514 to S.D. and J.A. L.F. was a fellow of the Janssen Research Foundation and J.A. is a research director with CNRS.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Deeb, S., Fajas, L., Nemoto, M. et al. A Pro12Ala substitution in PPARγ2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 20, 284–287 (1998). https://doi.org/10.1038/3099
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/3099
This article is cited by
Association of Polymorphic Variants of TCF7L2 and PPARG Genes with Metabolic Markers in Patients with Early Disorders of Carbohydrate Metabolism
Bulletin of Experimental Biology and Medicine (2024)
Association between the MTNR1B, HHEX, SLC30A8, and TCF7L2 single nucleotide polymorphisms and cardiometabolic risk profile in a mixed ancestry South African population
Scientific Reports (2023)
Peroxisome proliferator-activated receptor γ Pro12 ala polymorphism and risk of cerebral stroke in type 2 diabetes mellitus egyptian patients
Journal of Diabetes & Metabolic Disorders (2022)
Diabetes: discovery of insulin, genetic, epigenetic and viral infection mediated regulation
The Nucleus (2022)
Associations among perfluorooctanesulfonic/perfluorooctanoic acid levels, nuclear receptor gene polymorphisms, and lipid levels in pregnant women in the Hokkaido study
Scientific Reports (2021)