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

The peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a transcription factor that has a pivotal role in adipocyte differentiation and expression of adipocyte-specific genes(1-3) The PPAR gamma 1 and gamma 2 isoforms result from alternative splicing(4) and have ligand-dependent and -independent activation domains. PPAR gamma 2 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 PPAR gamma 1. Insulin stimulates the ligand-independent activation of PPAR gamma 1 and gamma 2 (ref. 5), however, obesity and nutritional factors only influence the expression of PPAR gamma 2 in human adipocytes(6). Here, we report that a relatively common Pro12Ala substitution in PPAR gamma 2 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 PPAR gamma 2 Ala allele showed decreased binding affinity to the cognate promoter element and reduced ability to transactivate responsive promoters. These findings suggest that the PPAR gamma 2 Pro12Ala variant may contribute to the observed variability in BMI and insulin sensitivity in the general population.