Molecular pathogenesis and mechanism of vidseral obesity

肥胖，尤其是内脏脂肪堆积是糖尿病、血脂异常、高血压和动脉粥样硬化性血管疾病等多种生活方式相关疾病发生的共同基础。在本研究中，我们对脂肪组织的生物学功能和肥胖相关疾病的分子发病机制进行了研究。我们已经证明，脂肪组织不仅是一个储存能量的器官，而且还是一个内分泌器官，在循环中产生和分泌各种生物物质。其中，腹内脂肪组织高分泌纤溶酶原激活物抑制物1和肝素结合的EGF样生长因子被认为直接影响血管壁的功能和代谢，并在血管疾病的发生发展中发挥作用。A…在脂肪组织中特异性地、大量地合成了更多的Dionectin。与PAI-1和HB-μ不同，肥胖者血浆脂联素浓度明显降低，尤以内脏型肥胖者为甚。大鼠血管内皮损伤时，损伤的血管壁上可见脂联素。该蛋白抑制单核细胞与内皮细胞的黏附和血管平滑肌细胞的增殖，这是动脉粥样硬化病变的最初变化。通过对脂联素基因的分析，发现冠心病患者存在错义突变。这些数据表明，脂联素对动脉粥样硬化性血管疾病具有潜在的保护作用，内脏肥胖症中发现的低脂联素血症可能在动脉粥样硬化性疾病的发生发展中起作用。多种证据支持AQPap在脂肪细胞中作为甘油通道的作用：1)AQPap在卵母细胞中表达时表现出甘油通透性，2)禁食诱导AQPap mRNA的表达，激活细胞中甘油的释放，3)汞离子减少细胞中甘油的释放，从而抑制AQP家族的功能。肥胖小鼠脂肪组织中AQPap表达增强，甘油浓度升高。在内脏脂肪堆积过程中，大量甘油通过门静脉流入肝脏，可能干扰肝脏的葡萄糖代谢，提示内脏肥胖时多种脂肪特异性基因表达发生改变。这些都可能导致内脏肥胖症的发展。较少

Obesity, especially accumulation of intra-abdomicl visreal fat is a common basis of the development of various life-style-related diseases including diabetes mellitus, dyslipoproteinemia, hypertension and atherosclerotic vascular diseases. In he current study, we investigted the biological functions of adipose tissue and molecular pathogenesis of obesity-related diseases. We have demonstrated that adipose tissue is not solely an energy-storing organ but also an endocrine organ producing and secreting a variety of biological substances in the circulation. Among them, hypersecretion of plasminogen activator inhibitor type 1 and heparin binding EGF-like growth factor form intra-abdominal adipose tissue were considered to affect the function and metabolism of vascular walls directly and to play roles in the development of vascular diseases.In this study, we especially focused on a novel collagen-like plasma protein, adiponectin and a member of aquaporin family, aquaporin adipose (AQPap). A … More dionectin was specifically and abundantly synthesized in adipose tissue. The protein was present in the circulation with the concentration of 5-10μg/ml. Different from thecases of PAI-1 and HB-EGF, plasma adiponectin concentrations were markedly reduced in obesity, especially in visceral obesity. When the vascular endothelium was injured in rats, adiponectin was observed in the injured vascular wall. The protein suppressed monocyte-adhesion to endothelial cells and proliferation of vascular smooth muscle cells, which are the initial changes of atherosclerotic lesion. By the analysis of adiponectin gene, we found missense mutation in subjects with coronary artery disease. These data suggest that adiponectin has potential protective activity against atherosclerotic vascular diseases and hypoadiponectin-emia found in visceral obesity may play a role in the development of atherosclerotic diseases.We investigated the function of AQPap in adipocytes. Several lenes of enidences supported that AQPap works as a glycerol channel in adipocytes; 1) AQPap exhibited glycerol permeability when it was expressed in oocytes, 2) expression of AQPap mRNA was induced by fasting in which glycerol release from the cell was activated, 3) glycerol release from the cells was reduced by mercuty ion, which inhibits the function of AQP family. Expression of AQPap was augumented and glycerol concentration in adipose tissue was increased in obese mice. In visceral fat accumulation, large amount of glycerol were drained into the liver via portal vein, may disturb glucose metabolism in liver.In conclusion, the expressions of various adipose-specific genes are altered in visceral obesity. These might contribute to the development of disorders in visceral obesity. Less