The significance of adipocvte-specific glycerol channel, aquaporin adipose for life-style related diseases.

代谢综合征集胰岛素抵抗、血压升高和血脂异常为一体，是世界范围内心血管疾病的常见病因。然而，代谢综合征的分子基础仍不清楚。由营养过剩和缺乏运动引起的腹内脂肪组织积聚位于代谢综合征的上游。脂肪组织一直被认为是一种简单的能量储存器官。我们的团队明确了组织是一个巨大的内分泌器官，表达各种生物活性物质的基因，并将其定义为“脂肪细胞因子”。通过研究，我们发现了多种新的脂肪细胞表达基因。本研究以脂肪细胞因子为研究对象，阐明代谢综合征的分子机制。脂联素是一种大量存在于血浆中的脂肪细胞衍生蛋白。内脏脂肪患者血浆脂联素水平降低。脂联素缺乏小鼠的血压水平几乎正常。当给老鼠喂食高盐食物时，它们的血压水平升高。内源性一氧化氮合成酶（eNOS）和前列环素合成酶在KO小鼠主动脉中表达增强。腺病毒介导的脂联素补充降低了脂联素KO小鼠的血压水平。这种效应被L-NAME（一种eNOS特异性抑制剂）所抵消，提示脂联素缺乏引起的盐敏感性高血压是由NO缺乏和血管内皮细胞功能障碍引起的。一系列研究表明，脂联素缺乏可加重心脏再灌注损伤、心肌肥厚和血管血栓形成。临床研究表明，血浆脂联素降低（低脂联素血症）与冠状动脉病变的复杂性、冠状动脉痉挛和外周动脉病变有关。低脂联素血症增加2型糖尿病患者心血管事件和心肌梗死后不良心脏事件的风险，也与慢性肾脏疾病患者的心血管风险相关。改善生活方式包括戒烟对纠正低脂联素血症很重要。我们发现，阻断脂肪血管紧张素受体可降低脂肪组织中的活性氧，恢复血浆脂联素水平。我们还通过对缺乏水通道蛋白7的小鼠的分析显示了一种新的肥胖机制，我们已经证明水通道蛋白7是脂肪细胞中的甘油通道分子。这些基础和临床研究将对代谢综合征的研究领域产生影响。少

Metabolic syndrome clusters insulin resistance, elevated blood pressure and dyslipidemia, and is a common cause of cardiovascular diseases in the world. The molecular basis of the metabolic syndrome, however, remained unclear. Accumulation of intra-abdominal adipose tissue caused by overnutrition and physical inactivity locates upstream of the metabolic syndrome. Adipose tissue had been regarded as a simple energy storage organ. Our team clarified the tissue is a huge endocrine organ to express genes for various bioactive substances, and concepualized as 'adipocytokines'. Through the study, we discovered various novel adipocyte-expressed genes. In this study, we focused adipocytokines to clarify molecular mechanism of the metabolic syndrome. Adiponectin is an adipocyte-derived protein present abundantly in plasma. Plasma level of adiponectin is decreased in subjectes with visceral fat. Blood pressure levels of adiponectin deficient mice were almost normal. When the mice were fed with h … More igh salt-diet, their blood pressure levels were elevated. The expression of endogenous nitric oxide synthetase (eNOS) and prostacyclin synthetase was augmented in the aorta of the KO mice. Adenovirus-mediated supplementation of adiponectin lowered blood pressure level of adiponectin KO mice. The effect was cancelled by the administration of L-NAME, which is a specific inhibitor of eNOS, suggesting salt-sensitive hypertension in adiponectin deficiency is caused by lack of NO and vascular endothelial cell dysfunction. A series of studies revealed that adiponectin deficiency worsened cardiac reperfusion injury, cardiac hypertrophy and vascular thrombosis. Clinical studies demonstrated that decreased plasma adiponectin (hypoadiponectinemia) is related to complexity of coronary artery lesion, coronary spasm and peripheral artery disease. Hypoadiponectinemia increased a risk of cardiovascular events in type 2 diabetic subjects and adverse cardiac events after myocardial infarction, also related to cardiovascular risks of the patients with chronic renal disease. Improvement of life-style including cessation of smoking is important to correct hypoadiponectinemia. We demonstrated blockade of adipose angiotensin receptor decreased reactive oxygen species in adipose tissue and recovered plasma adiponectin level. We also showed a novel mechanism of obesity through the analyses of the mice with lack of aquaporin 7, which we had demonstrated as a glycerol channel molecule in adipocyte. These basic and clinical studies will give an impact on the research field of the metabolic syndrome. Less