Molecular mechanism of visceral obesity controlled by endothelial cell-related growth factors and the search for a new strategy of adipogenecity control

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Metabolic syndrome is known to induce various metabolic disorders such as diabetes mellitus and atherosclerotic diseases based on visceral obesity. In order to control the adiposity, we aimed at the relationship between angiogenesis and adipogenesity. The PI3K signaling pathway in vascular endothelial cells is important for systemic angiogenesis and glucose metabolism. To evaluate the systemic pathway of angiogenesis under PI3K signal, we generated endothelial cell specific PDK1 knock out mice using Cre-loxP system and investigated the degree of impaired angiogenesis of skeletal muscles under the normo-and hyperglycemia status. In normoglycemic status, VEPDK1KO mice manifested enhanced glucose tolerance and whole-body insulin sensitivity with a reduced volume of epididymal adipose tissues. These results provide the in vivo evidence that lowered angiogenesis through the deletion of PDK1 signaling not only interferes with thegrowth of adipose tissue but also induces increased energy expe … More nditure due to amelioration of the adipocytokine profile.The diabetic VEPDK1KO mice generated by genetic cross with db gene, however, demonstrated a significant impairment of glucose metabolism and systemic insulin sensitivity was diminished by approximately 39% in 12-week-old db-KO mice during the insulin tolerance test(3U/kg) despite of a reduced adiposity. Plasma high molecular weight adiponectin was elevated and mRNA expression of PECAM-1 and VEGF in epigonadal adipose tissue was decreased in db-KO compared with the control mice by 32% and 47%, respectively. Protein expressions of the β subunit of the insulin receptors and mRNA expressions of PECAM-1 in the skeletal muscle were decreased by approximately 47% and 23%, respectively, in db-KO. Nevertheless, those in the liver were comparable in both groups. We concluded that a complete lack of endothelial PDK1 induces the defects of angiogenesis in adipose tissues and skeletal muscle, which lead to deterioration of systemic insulin sensitivity in mice with genetic susceptibility to diabetes.Furthermore, protein expression of VCAM1, located in PI3K signal and regulated by PDK1, was significantly up-regulated by 2.4 times higher in Gastro of STZ-KO than in that of the control KO mice, but no significant difference was observed between two groups in the liver. VEGF, VEGF receptor, and HIF1 gene expressions in both Gastro and liver were not different between STZ-KO and the control-KO. These results indicated that ablation of PDK1 in vascular endothelial cells in diabetic state induces the lower vascularization and VCAM1-upregulation in skeletal muscle but not in the liver, and the underlying mechanism may be totally different from the reported angiogenic factors, including VEGF and HIF.Our results clearly indicate that PI3K signaling pathway in vascular endothelial cells plays an important role on adiposity and angiogenesis, and adipose tissue-specific ablation of PDK1 in endothelial cells may reduce visceral fat and contribute on an amelioration of dismetabolism induced by metabolic syndrome. Less