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A Pro12Ala substitution in PPARγ2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity

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.

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Figure 1: Relative affinities of the Pro and Ala PPARγ2 isoforms to PPRE.
Figure 2: Comparison of the transactivation capacity of the Pro and Ala PPARγ2 isoforms in transient transfection assays3.

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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.

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Correspondence to Samir S. Deeb.

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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

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