Inhibitory effect of a proline-to-alanine substitution at codon 12 of peroxisome proliferator-activated receptor-gamma 2 on thiazolidinedione-induced adipogenesis.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear hormone receptor superfamily of transcription factors and appears to be a key regulator of adipogenesis. Members of the thiazolidinedione class of insulin-sensitizing agents act as high-affinity ligands for PPARgamma, indicating that PPARgamma is also important in systemic insulin action. To determine whether Pro(12) --> Ala (P12A) mutation in PPARgamma gene contributes to the development of obesity or insulin sensitivity, we examined the effects of the P12A mutation on the function of PPARgamma by expression of the mutant protein in COS or 3T3-L1 cells. The abilities of the P12A mutant of PPARgamma to mediate both transcriptional activation of a luciferase reporter gene construct containing the peroxisome proliferator response element and adipogenesis induced by a thiazolidinedione drug were reduced compared with those of the wild-type protein. These results suggest that the P12A substitution in PPARgamma gene may be associated with abnormalities of adipose tissue formation and insulin sensitivity.