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Molecular Medicine of Leptin Regulation of Energy Metabolism and Its Medical Application

瘦素调节能量代谢的分子医学及其医学应用

基本信息

批准号：
15390294
负责人：
OGAWA Yoshihiro
金额：
$ 9.34万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Leptin is an important adipocytokine that acts directly on the hypothalamus, thereby regulating food intake and energy expenditure. Because leptin receptor is expressed not only in the hypothalamus but in a variety of peripheral tissues and leptin is capable of activating the JAK/STAT signaling pathway, suggesting that leptin works as a proinflammatory cytokine in peripheral target tissues.1)Leptin as an antidiabetic agent in insulin-deficient diabetes : We showed that after streptozotocin injection, both transgenic skinny mice overexpressing leptin and their non-transgenic littermates developed marked hyperglycemia as a result of severe hypoinsulinemia (termed diabetic TGM and diabetic WT, respectively). Diabetic TGM became normoglycemic, when treated with insulin at such doses that did not improve hyperglycemia in diabetic WT. This study suggests that leptin can be used as an adjunct of insulin therapy in insulin-deficient diabetes, thereby providing an insight into the therapeutic implication of leptin as an anti-diabetic agent.2)Pathonhvsioloizic role of leptin in ischemia-induced retinal neovascularization : Using the mouse retinopathy of prematurity model, we showed that leptin stimulates ischemia-induced retinal neovascularization possibly through the upregulation of endothelial VEGF. These observations suggest that leptin antagonism may offer a novel therapeutic strategy to prevent or treat diabetic retinopathy.3)Diagnostic role of leptin in as a biomarker of atherosclerosis : Given that leptin and adiponectin are important mediators linking adiposity and atherosclerosis in the adipovascular axis, we demonstrated that leptin/adiponectin ratio is strongly correlated with pulse-wave velocity, a direct measure of arterial stiffness. We, therefore, postulate that the ratio may serve as a potential atherogenic index in obese type 2 diabetic patients.

瘦素是一种重要的脂肪细胞因子，直接作用于下丘脑，从而调节食物摄入和能量消耗。由于瘦素受体不仅在下丘脑中表达，而且在多种外周组织中表达，并且瘦素能够激活JAK/STAT信号通路，这表明瘦素在外周靶组织中作为促炎细胞因子起作用。1）瘦素作为胰岛素缺乏型糖尿病的抗糖尿病剂：我们发现在注射链脲佐菌素后，过度表达瘦素的转基因瘦小鼠和它们的非转基因同窝出生的小鼠都由于严重的低胰岛素血症而发展出显著的高血糖症（分别称为糖尿病TGM和糖尿病WT）。当以不能改善糖尿病WT高血糖的剂量接受胰岛素治疗时，糖尿病TGM变得血糖正常。本研究提示，瘦素可作为胰岛素治疗的辅助药物，用于治疗胰岛素缺乏型糖尿病，从而为瘦素作为抗糖尿病药物的治疗意义提供了新的思路。2）瘦素在缺血诱导的视网膜新生血管形成中的病理学作用：利用早产儿视网膜病变模型，我们发现瘦素可能通过上调内皮细胞VEGF来刺激缺血诱导的视网膜新生血管形成。这些观察结果表明，瘦素拮抗剂可能提供一种新的治疗策略，以预防或治疗糖尿病视网膜病变。3）瘦素作为动脉粥样硬化的生物标志物的诊断作用：鉴于瘦素和脂联素是脂肪血管轴中肥胖和动脉粥样硬化的重要介质，我们证明瘦素/脂联素比值与脉搏波速度密切相关，脉搏波速度是动脉硬度的直接测量。因此，我们推测该比值可作为肥胖2型糖尿病患者潜在的致动脉粥样硬化指标。