摘要：

The peroxisome proliferator-activated receptor-γ (PPARγ) is a transcription factor that has a pivotal role in adipocyte differen- tiation and expression of adipocyte-specific genes 1-3 . 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), how- ever, obesity and nutritional factors only influence the expres- sion of PPARγ2 in human adipocytes 6 . Here, we report that a relatively common Pro12Ala substitution in PPARγ2 is associ- ated 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 sensi- tivity in the general population. Dysregulation of adipose tissue metabolism may predispose to the development of insulin resistance and type 2 diabetes 7-10 . Fatty acids and eicosanoids bind to PPARγ and stimulate activa- tion of target genes involved in adipocyte differentiation and glucose homeostasis 11-13 . Signalling through PPARγ1 and γ2 could have a considerable physiological impact on energy bal- ance and BMI. A substantial fraction of variability in human obesity is genetically determined 14 , therefore, we hypothesized that genetic variation in PPARγ may constitute a predisposing factor for obesity and the associated insulin resistance. We screened the gene (PPARG) encoding PPARγ in Japanese Ameri- cans and Finns for variants associated with this phenotype. PPARG spans more than 100 kb and is composed of 9 exons 4 . We observed a CφιG variant (which creates an HgaI site) predicting the substitution of Ala for Pro at position 12 in the PPARγ2-spe- cific exon B, and a synonymous CφιT substitution in exon 6. We previously found an association between the synonymous poly- morphism and leptin levels among obese subjects from north- ern France 15 . In this report, we describe the functional consequence and association of the Pro12Ala substitution with BMI, insulin sensitivity and type 2 diabetes. The first group of Finnish men and women that we screened was drawn randomly from a population-based study 16 and was comprised of 333 middle-aged non-diabetic individuals that included 38 with impaired glucose tolerance. The PPARγ2 Ala allele (frequency of 0.12) in this group was associated with lower

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