Peroxisome proliferator-activated receptor ␥ (PPAR␥) is a nuclear receptor that plays a pivotal role in obesity and diabetes. PPAR␥ has two isoforms, PPAR␥1 and PPAR␥2. We investigated the functional differences between PPAR␥1 and PPAR␥2 by selectively disrupting PPAR␥2 in mice. In contrast to the embryonic lethality of PPAR␥-deficient mice, PPAR␥2 ؊/؊ mice survived. Although normal development was identified in other tissues we examined, PPAR␥2 ؊/؊ mice exhibited an overall reduction in white adipose tissue, less lipid accumulation, and decreased expression of adipogenic genes in adipose tissue. In addition, insulin sensitivity was impaired in male PPAR␥2 ؊/؊ mice, with dramatically decreased expression of insulin receptor substrate 1 and glucose transporter 4 in the skeletal muscle, but thiazolidinediones were able to normalize this insulin resistance. Consistent with in vivo data, PPAR␥2 ؊/؊ mouse embryonic fibroblasts showed a dramatically reduced capacity for adipogenesis in vitro compared with wildtype mouse embryonic fibroblasts. Taken together, our data demonstrate that PPAR␥2 deficiency impairs the development of adipose tissue and insulin sensitivity. PPAR␥2 ؊/؊ mice may provide a tool to study the role of PPAR␥2 in obesity and diabetes.adipogenesis ͉ obesity ͉ diabetes

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PFKFB3 is the gene that codes for the inducible isoform of 6-phosphofructo-2-kinase (iPFK2), a key regulatory enzyme of glycolysis. As one of the targets of peroxisome proliferatoractivated receptor ␥ (PPAR␥), PFKFB3/iPFK2 is up-regulated by thiazolidinediones. In the present study, using PFKFB3/iPFK2-disrupted mice, the role of PFKFB3/iPFK2 in the anti-diabetic effect of PPAR␥ activation was determined. In wild-type littermate mice, PPAR␥ activation (i.e. treatment with rosiglitazone) restored euglycemia and reversed high fat diet-induced insulin resistance and glucose intolerance. In contrast, PPAR␥ activation did not reduce high fat diet-induced hyperglycemia and failed to reverse insulin resistance and glucose intolerance in PFKFB3 ؉/؊ mice. The lack of anti-diabetic effect in PFKFB3 ؉/؊ mice was associated with the inability of PPAR␥ activation to suppress adipose tissue lipolysis and proinflammatory cytokine production, stimulate visceral fat accumulation, enhance adipose tissue insulin signaling, and appropriately regulate adipokine expression. Similarly, in cultured 3T3-L1 adipocytes, knockdown of PFKFB3/iPFK2 lessened the effect of PPAR␥ activation on stimulating lipid accumulation. Furthermore, PPAR␥ activation did not suppress inflammatory signaling in PFKFB3/iPFK2-knockdown adipocytes as it did in control adipocytes. Upon inhibition of excessive fatty acid oxidation in PFKFB3/iPFK2-knockdown adipocytes, PPAR␥ activation was able to significantly reverse inflammatory signaling and proinflammatory cytokine expression and restore insulin signaling. Together, these data demonstrate that PFKFB3/iPFK2 is critically involved in the anti-diabetic effect of PPAR␥ activation.