The study for molecular mechanisms of obesity, insulin resistance and atherosclerosis in the PPAR gamma deficient mice

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1. Focusing on the fact that heterozygous PPARgamma deficient mice were protected from the development of obesity and insulin resistance under a high-fat diet, we compared the differences of the gene expression in white adipose tissues between PPARgamma deficient mice and wild-type mice under a high-fat diet by using DNA chip. Adiponectin as well as leptin expression was higher in the PPARgamma deficient mice than in the wild-type mice. These data suggested that adiponectin may be an insulin-sensitizing hormone secreted by adipose tissue. In fact, administration of adiponectin increases fatty acid combustion in muscle, thereby ameliorating insulin resistance in obese mice. These observations indicate that the replenishment of adiponectin might provide a novel treatment modality for insulin resistance and type 2 diabetes.2. PPARgamma is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). We identified a synthetic RXR antagonist, HX531 … More and investigated whether functional, antagonism toward PPARgamma/RXR could be used to treat obesity and type 2 diabetes. Administration of the RXR antagonist HX531 decreases TG content in white adipose tissue, skeletal muscle, and the liver due to increased leptin effects and increased fatty acid combustion and energy dissipation, thereby ameliorating obesity and insulin resistance. Our data suggest that appropriate functional antagonism of PPARgamma/RXR may be a logical approach to protect against obesity and related diseases such as type 2 diabetes.3. A Pro12Ala polymorphism has been detected in the human PPARgamma2 gene. Since this amino acid substitution causes a reduction in the transcriptional activity of PPARgamma, this polymorphism may be associated with increased insulin sensitivity and decreased risk of type 2 diabetes. To investigate this hypothesis, we performed a case-control study of the Pro12Ala PPARgamma2 polymorphism in Japanese diabetic and non-diabetic subjects. The frequency of Ala12 was significantly lower in the diabetic group than in the control group. In an overweight or obese group, subjects with Ala12 were more insulin sensitive than those without Ala12. These results suggest that the PPARgamma is a thrifty gene and that the Pro12Ala PPARgamma2 polymorphism protects against type 2 diabetes in the Japanese population.4. We investigated the role of PPARgamma in the development of atherosclerosis using heterozygous PPARgamma deficient (PPARγ+/-) mice. When we placed a cuff around the femoral artery to induce inflammation of the adventitia and subsequent neointimal formation, the PPARgamma+/- mice showed 2 fold more neointimal formation than the wild-type mice 2 weeks after cuff placement. Moreover, endothelium-dependent vascular relaxation was significantly impaired in the PPARγ+/- mice compared with the wild-type mice and the expression of endothelial nitric oxide synthase (eNOS) was significantly lower in the PPARgamma+/- mice than in the wild-type mice. These data suggested that PPAR amma plays a crucial role in the regulation of vascular endothelial function and the protection from inflammation induced neointimal formation. Less