Molecular pathogenesis and mechanism of vidseral obesity

肥胖，尤其是腹腔内可见脂肪的积累，是各种生活方式相关疾病（包括糖尿病、脂蛋白异常血症、高血压和动脉粥样硬化性血管疾病）发展的共同基础。在目前的研究中，我们探讨了脂肪组织的生物学功能和肥胖相关疾病的分子发病机制。我们已经证明，脂肪组织不仅是一个能量储存器官，也是一个内分泌器官，在循环中产生和分泌多种生物物质。其中，1型纤溶酶原激活物抑制剂和肝素结合egf样生长因子在腹腔脂肪组织中的高分泌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。在这项研究中，我们特别关注了一种新的胶原样血浆蛋白脂联素和水通道蛋白家族成员水通道蛋白脂肪（AQPap）。更多的薯蓣粘连素是在脂肪组织中特异而丰富地合成的。该蛋白在循环中存在，浓度为5-10μg/ml。与PAI-1和HB-EGF病例不同，肥胖患者血浆脂联素浓度明显降低，尤其是内脏型肥胖患者。当大鼠血管内皮损伤时，在损伤血管壁上观察到脂联素的变化。该蛋白抑制单核细胞粘附内皮细胞和血管平滑肌细胞的增殖，这是动脉粥样硬化病变的初始变化。通过对脂联素基因的分析，我们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，在内脏肥胖中发现的低脂联素血症可能在动脉粥样硬化性疾病的发展中发挥作用。我们研究了AQPap在脂肪细胞中的功能。一些证据支持AQPap在脂肪细胞中作为甘油通道起作用；1) AQPap在卵母细胞中表达时表现出甘油渗透性，2)禁食激活细胞释放甘油，诱导AQPap mRNA表达，3)汞离子抑制AQP家族功能，减少细胞释放甘油。肥胖小鼠AQPap表达增加，脂肪组织中甘油浓度升高。在内脏脂肪堆积过程中，大量甘油经门静脉排入肝脏，可能干扰肝脏的葡萄糖代谢。总之，各种脂肪特异性基因的表达在内脏型肥胖中发生了改变。这些可能会导致内脏性肥胖疾病的发展。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