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

已知代谢综合征可导致多种代谢紊乱，如糖尿病和基于内脏肥胖的动脉粥样硬化性疾病。为了控制肥胖，我们针对血管生成与成脂之间的关系进行了研究。血管内皮细胞中的PI3K信号通路对全身血管生成和糖代谢具有重要作用。为了评估PI3K信号下血管生成的系统途径，我们利用Cre-loxP系统构建了内皮细胞特异性的PDK1基因敲除小鼠，并观察了正常血糖和高血糖状态下骨骼肌血管生成的受损程度。在正常血糖状态下，VEPDK1KO小鼠表现出糖耐量和全身胰岛素敏感性的增强，附睾脂肪组织的体积减少。这些结果提供了体内证据，即通过缺失PDK1信号而导致的血管生成减少不仅干扰了脂肪组织的生长，而且还导致能量消耗…增加然而，通过与db基因进行基因杂交而产生的糖尿病VEPDK1KO小鼠表现出显著的葡萄糖代谢障碍，在12周龄的db-KO小鼠中，在胰岛素耐量试验(3U/kg)中，尽管脂肪减少，但全身胰岛素敏感性降低了约39%。Db-KO组大鼠血浆高分子脂联素水平升高，肾上腺脂肪组织PECAM-1和VEGFmRNA表达水平较对照组分别降低32%和47%。Db-KO组大鼠骨骼肌胰岛素受体β亚单位的蛋白表达和PECAM1的表达分别下降约47%和23%。然而，在两组中，肝脏中的那些是可比的。我们的结论是，内皮PDK1的完全缺失导致脂肪组织和骨骼肌血管生成的缺陷，导致糖尿病遗传易感性小鼠全身胰岛素敏感性的恶化。此外，位于PI3K信号中的受PDK1调控的VCAM1的蛋白表达在STZ-KO组显著上调2.4倍，但在肝脏中两组之间没有显著差异。血管内皮生长因子及其受体和HIF1基因在胃和肝脏中的表达在STZ-KO组和对照-KO组均无差异。这些结果表明，在糖尿病状态下，去除血管内皮细胞中的PDK1可导致骨骼肌而不是肝脏中血管生成和VCAM1上调，其潜在机制可能与已报道的血管生成因子，包括血管内皮生长因子和血管生成因子完全不同。我们的结果清楚地表明，血管内皮细胞中的PI3K信号通路在肥胖和血管生成中起重要作用，脂肪组织特异性去除内皮细胞中的PDK1可能减少内脏脂肪，有助于改善代谢综合征引起的代谢紊乱。较少

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