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

内皮细胞相关生长因子控制内脏肥胖的分子机制及寻找脂肪生成新策略

• 批准号: 21591153
• 负责人: KAKU Kohei
• 金额: $ 2.83万
• 依托单位: Kawasaki Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21591153/
• 关键词: メタボリックシンドローム; 血管内皮細胞特異的PDK1欠損; 高血糖マウス; 血管新生; インスリン抵抗性; 骨格筋; 内臓脂肪; HIF1; VCAM1; db/dbマウス; VEGF; アディポネクチン; 脂肪細胞小型化

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

已知代谢综合征可诱发各种代谢紊乱，例如糖尿病和基于内脏肥胖的动脉粥样硬化疾病。为了控制肥胖，本研究旨在探讨血管生成与肥胖的关系。血管内皮细胞中的PI 3 K信号通路对于系统性血管生成和葡萄糖代谢是重要的。为了研究PI 3 K信号下血管生成的系统性途径，我们利用Cre-loxP系统建立了内皮细胞特异性PDK 1基因敲除小鼠模型，并研究了正常和高血糖状态下骨骼肌血管生成受损的程度。在血糖正常状态下，VEPDK 1 KO小鼠表现出葡萄糖耐量和全身胰岛素敏感性增强，附睾脂肪组织体积减少。这些结果提供了体内证据，即通过PDK 1信号转导的缺失降低血管生成不仅干扰脂肪组织的生长，而且诱导能量消耗增加。 ...更多信息 然而，通过与db基因遗传杂交产生的糖尿病VEPDK 1 KO小鼠表现出葡萄糖代谢的显着损害，并且12周龄db-KO小鼠的全身胰岛素敏感性在胰岛素耐受性测试期间降低了约39%（3U/kg）尽管肥胖减少。与对照组小鼠相比，db-KO小鼠的血浆高分子量脂联素升高，上性腺脂肪组织中PECAM-1和VEGF的mRNA表达分别降低了32%和47%。在db-KO中，骨骼肌中胰岛素受体β亚基的蛋白表达和PECAM-1的mRNA表达分别降低约47%和23%。然而，两组中肝脏中的那些相当。我们的结论是，完全缺乏内皮细胞PDK 1可诱导脂肪组织和骨骼肌血管生成缺陷，从而导致糖尿病遗传易感性小鼠全身胰岛素敏感性下降。此外，位于PI 3 K信号并受PDK 1调节的VCAM 1蛋白表达在STZ-KO小鼠的Gastro中显著上调，是对照KO小鼠的2.4倍，而肝组织中两组间无显著性差异。STZ-KO和对照-KO之间胃和肝脏中的VEGF、VEGF受体和HIF 1基因表达没有差异。这些结果表明，在糖尿病状态下，血管内皮细胞中的PDK 1的消融诱导骨骼肌中的血管化降低和VCAM 1-上调，而不是在肝脏中，并且潜在的机制可能与已报道的血管生成因子（包括VEGF和HIF）完全不同。我们的结果清楚地表明，血管内皮细胞中的PI 3 K信号通路在肥胖和血管生成中起重要作用。脂肪组织特异性消融内皮细胞中的PDK 1可能减少内脏脂肪，并有助于改善代谢综合征诱导的代谢异常。少

项目成果

Molecular mechanism by which pioglitazone preserves pancreatic {beta} cells in obese diabetic mice : Evidence for acute and chronic actions as a PPARγ agonist.

吡格列酮保护肥胖糖尿病小鼠胰腺 {β} 细胞的分子机制：作为 PPARγ 激动剂的急性和慢性作用的证据。

• 发表时间: 2010
• 期刊: Am J Physiol Endocrinol Metab.
• 作者: Kanda Y;et al
• 通讯作者: et al

Molecular Analysis of db Gene-related Pancreatic beta Cell Dysfunction ; Evidence for a Compensatory Mechanism Inhibiting Development of Diabetes in the db Gene Heterozygote

db基因相关的胰腺β细胞功能障碍的分子分析；

• 发表时间: 2009
• 期刊: Endocr J
• 影响因子: 2
• 作者: Kanda Y;Shimoda M;Tawaramoto K;Hamamoto S;Tatsumi F;Kawasaki F;Hashiramoto M;Nakashima K;Matsuki M;Kaku K
• 通讯作者: Kaku K

Ablation of vascular endothelial phosphoinositide-dependent protein kinase 1 deteriorates the volume of blood flow in skeletal muscle

血管内皮磷酸肌醇依赖性蛋白激酶 1 的消融会恶化骨骼肌的血流量

• 发表时间: 2010
• 作者: Tawaramoto K;Hashiramoto M;Kotani K;Ogawa W;Tatsumi F;Hamamoto S;Shimoda M;Kanda Y;Kasuga M;Kaku K
• 通讯作者: Kaku K

肥満2型糖尿病での血管内皮細胞PDK1欠損は筋肉内血管新生を低下させ、全身インスリン抵抗性を増悪させる

肥胖2型糖尿病患者血管内皮细胞PDK1缺乏会减少肌内血管生成并加剧全身胰岛素抵抗

• 发表时间: 2009
• 作者: 俵本和仁;柱本満;小谷光;小川渉;辰巳文則;濱本純子;下田将司;菅田有紀子;春日雅人;加来浩平
• 通讯作者: 加来浩平

Self-inducible secretion of glucagon-like peptide-1 (GLP-1) that allows MIN6 cells to maintain insulin secretion and insure cell survival

• DOI: 10.1016/j.mce.2011.11.008
• 发表时间: 2012-02
• 期刊: Molecular and Cellular Endocrinology
• 影响因子: 4.1
• 作者: Koji Nakashima;M. Shimoda;Sumiko Hamamoto;F. Tatsumi;H. Hirukawa;K. Tawaramoto;Y. Kanda;K. Kaku