The link between nutritional status and insulin sensitivity is dependent on the adipocyte-specific peroxisome proliferator-activated receptor-γ2 isoform

The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR) is critically required for adipogenesis. PPART gamma exists as two isoforms, gamma 1 and gamma 2. PPAR gamma 2 is the more potent adipogenic isoform in vitro and is normally restricted to adipose tissues, where it is regulated more by nutritional state than PPAR gamma 1. To elucidate the relevance of the PPAR gamma 2 in vivo, we generated a mouse model in which the PPAR gamma 2 isoform was specifically disrupted. Despite similar weight, body composition, food intake, energy expenditure, and adipose tissue morphology, male mice lacking the gamma 2 iso-form were more insulin resistant than wild-type animals when fed a regular diet. These results indicate that insulin resistance associated with ablation of PPAR gamma 2 is not the result of lipodystrophy and suggests a specific role for PPAR gamma 2 in maintaining insulin sensitivity independently of its effects on adipogenesis. Furthermore, PPAR gamma 2 knockout mice fed a high-fat diet did not become more insulin resistant than those on a normal diet, despite a marked increase in their mean adipocyte cell size. These findings suggest that PPAR gamma 2 is required for the maintenance of normal insulin sensitivity in mice but also raises the intriguing notion that PPAR gamma 2 may be necessary for the adverse effects of a high-fat diet on carbohydrate metabolism.