Peroxisome proliferator-activated receptor-gamma (PPAR gamma) 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 PPAR gamma, indicating that PPAR gamma is also important in systemic insulin action, To determine whether Pro(12) --> Ala (P12A) mutation in PPAR gamma gene contributes to the development of obesity or insulin sensitivity, we examined the effects of the P12A mutation on the function of PPAR gamma by expression of the mutant protein in COS or 3T3-L1 cells. The abilities of the P12A mutant of PPAR gamma 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 PPAR gamma gene may be associated with abnormalities of adipose tissue formation and insulin sensitivity.