Study of Leptin Receptor Deficiency in Fat

脂肪瘦素受体缺陷的研究

• 批准号: 6821161
• 负责人: ALLAN Z ZHAO
• 金额: $ 26.05万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6821161
• 关键词: adipocytes; bioenergetics; cell surface receptors; endocrine disorder; fatty acid transport; gene expression; genetically modified animals; hormone regulation /control mechanism; hypothalamus; insulin sensitivity /resistance; laboratory mouse; leptin; lipid metabolism; mitogen activated protein kinase; oxygen consumption; phosphatidylinositol 3 kinase; triglycerides

DESCRIPTION (provided by applicant): A prevailing dogma of leptin research field has attributed the regulation of body weight by leptin exclusively to the hypothalamus of central nervous system (CNS). Here, we demonstrate and propose to further evaluate a genetic example that leptin regulates body weight by DIRECT regulation of fat metabolism in adipocytes in addition to its functions in the hypothalamus. Recently, using a Technical Knock-out (TKO) system, we have engineered a mouse model to display adipocyte-selective deficiency of the leptin receptors. These mutant mice are hereafter referred to as TKO-OBR mice, short for technical knockout of OB-receptors. TKO-OBR mice maintained normal levels of leptin receptors in the hypothalamus. However, the mutant mice developed increased adiposity, hyperinsulinemia, hypertriglyceridemia, impaired glucose tolerance and insulin sensitivity, as well as elevated triglyceride levels in livers and skeletal muscle. A variety of genes involved in regulating fat and glucose metabolism are dysregulated in the white adipose tissue of the mutant mice, such as TNFalpha, AdipoQ, leptin, fatty acid synthase, SREBP-1, glycerol kinase, and beta3-adrenergic receptor. Furthermore, the mutant mice are significantly more sensitive to high-fat feeding with regards to developing obesity and severe insulin resistance than their wild-type littermates. In summary, we have provided the first unequivocal genetic example demonstrating the physiological importance of a direct peripheral effect of leptin in vivo. In this application, we propose a series of studies to further understand the molecular mechanisms by which leptin regulates adiposity and insulin sensitivity through its direct actions in adipocytes. We believe that these studies will provide a possible molecular linkage between adipocyte-selective leptin receptor deficiency and type 2 diabetes.

描述（由申请人提供）：瘦素研究领域的普遍教条归因于瘦素专门对体重的调节，专为中枢神经系统下丘脑（CNS）。在这里，我们证明并建议进一步评估一个遗传例子，即瘦素通过直接调节脂肪细胞中脂肪代谢除了下丘脑的功能外调节体重。最近，使用技术敲除（TKO）系统，我们设计了一种小鼠模型来显示瘦素受体的脂肪细胞选择性缺陷。这些突变小鼠以下称为tko-obr小鼠，缺乏ob受体的技术敲除。 TKO-OBR小鼠在下丘脑中保持正常的瘦素受体水平。然而，突变小鼠的肥胖，高胰岛素血症，高甘油三酯血症，葡萄糖耐受性降低和胰岛素敏感性以及肝脏和骨骼肌的甘油三酸酯水平升高。在突变小鼠的白色脂肪组织中，参与调节脂肪和葡萄糖代谢的各种基因失调，例如tnfalpha，adipoq，leptin，leptin，脂肪酸合酶，SREBP-1，甘油酶，甘油激酶和beta3-Adren酶和beta3-Adren蛋白酶。此外，与野生型同窝仔相比，突变小鼠对肥胖和严重的胰岛素抵抗的高脂喂养更为敏感。总而言之，我们提供了第一个明确的遗传例子，证明了瘦素在体内直接外周效应的生理重要性。在此应用中，我们提出了一系列研究，以进一步了解瘦素通过其在脂肪细胞中的直接作用来调节脂肪和胰岛素敏感性的分子机制。我们认为，这些研究将在脂肪细胞选择性瘦素受体缺乏症和2型糖尿病之间提供可能的分子联系。