Deeb S S, Fajas L, Nemoto M, Pihlajamäki J, Mykkänen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx J
Department of Medicine, University of Washington, Seattle 98195, USA.
Nat Genet. 1998 Nov;20(3):284-7. doi: 10.1038/3099.
The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcription factor that has a pivotal role in adipocyte differentiation and expression of adipocyte-specific genes. The PPARgamma1 and gamma2 isoforms result from alternative splicing and have ligand-dependent and -independent activation domains. PPARgamma2 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 PPARgamma1. Insulin stimulates the ligand-independent activation of PPARgamma1 and gamma2 (ref. 5), however, obesity and nutritional factors only influence the expression of PPARgamma2 in human adipocytes. Here, we report that a relatively common Pro12Ala substitution in PPARgamma2 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 PPARgamma2 Ala allele showed decreased binding affinity to the cognate promoter element and reduced ability to transactivate responsive promoters. These findings suggest that the PPARgamma2 Pro12Ala variant may contribute to the observed variability in BMI and insulin sensitivity in the general population.
过氧化物酶体增殖物激活受体γ（PPARγ）是一种转录因子，在脂肪细胞分化和脂肪细胞特异性基因的表达中起关键作用。PPARγ1和γ2亚型是由可变剪接产生的，具有配体依赖性和非依赖性激活域。PPARγ2在其氨基末端有额外的28个氨基酸，使其非配体依赖性激活域比PPARγ1的激活域有效5至10倍。胰岛素刺激PPARγ1和γ2的非配体依赖性激活（参考文献5），然而，肥胖和营养因素仅影响人脂肪细胞中PPARγ2的表达。在此，我们报告，在中年和老年芬兰人中，PPARγ2中相对常见的Pro12Ala替代与较低的体重指数（BMI；P = 0.027；0.015）和改善的胰岛素敏感性相关。在日裔美国人中观察到Pro/Pro基因型与2型糖尿病关联的显著优势比（4.35，P = 0.028）。PPARγ2 Ala等位基因显示与同源启动子元件的结合亲和力降低，以及反式激活反应性启动子的能力降低。这些发现表明，PPARγ2 Pro12Ala变体可能导致普通人群中观察到的BMI和胰岛素敏感性的变异性。
