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The nuclear receptor peroxisome proliferator-activated receptor-[gamma] (PPAR[gamma]) is critically required for adipogenesis. PPAR[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 isoform 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., Peroxisome proliferator-activated receptor-[gamma] (PPAR[gamma]) plays a central role in adipogenesis and insulin sensitivity. PPAR[gamma] is expressed as two isoforms, PPAR[gamma]1 and PPAR[gamma]2, which differ only in that PPAR[gamma]2 has 30 [...]