Leptin and peripheral glucose metabolism

瘦素与外周葡萄糖代谢

• 批准号: 7997436
• 负责人: Ruth B Harris
• 金额: $ 33.4万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7997436
• 关键词: 20 year old; Acceleration; Address; Adipocytes; Adipose tissue; Adult; Animal Feed; Animals; Biological Assay; Body Weight decreased; Body fat; Cell Proliferation; Chemicals; Chromatography; Chronic Disease; Classification; Data; Deposition; Development; Dose; Eating; Economics; Endogenous Factors; Energy Metabolism; Environmental Risk Factor; Epidemic; Fatty acid glycerol esters; Feedback; Food; Fractionation; Funding; Grant; Hormones; Hypothalamic structure; Incidence; Individual; Infusion procedures; Inhibition of Cell Proliferation; Investigation; Leptin; Leptin resistance; Life Style; Lipid Mobilization; Liver; Location; Measures; Mediating; Metabolic; Metabolism; Minority; Mus; Mutation; National Health and Nutrition Examination Survey; Obesity; Outcome; Overweight; Parabiosis; Pathway interactions; Peripheral; Phenotype; Physiological; Population; Procedures; Progress Reports; Prosencephalon; Proteins; Proteomics; Publishing; Rattus; Regulation; Resistance; Risk; Satiation; Serum; Shotguns; Signal Transduction; Staging; System; Testing; Tissues; Weight; Weight Gain; Zucker Rats; age group; base; cofactor; cytokine; db/db mouse; energy balance; glucose metabolism; hindbrain; human subject; in vitro Assay; innovation; leptin receptor; lipid biosynthesis; mortality; prevent; receptor; research study; response

DESCRIPTION (provided by applicant): The incidence of overweight and obesity continue to escalate in all age groups of the US population. Because excess adiposity is associated with increased risk for chronic disease and mortality it is essential that we develop an understanding of the physiological mechanisms that are in place to regulate adiposity and how environmental factors can make these mechanisms ineffectual. This proposal focuses on how the adipocyte derived cytokine leptin modifies whole body energy metabolism and adipocyte metabolism. It appears that there are at least three different stages of leptin responsiveness in experimental animals treated with physiological doses of the hormone: a) leptin sensitivity that facilitates a loss of body fat in response to leptin b) partial leptin resistance that leads to an increase in adiposity in response to leptin and c) full leptin resistance that prevents any metabolic response to peripherally administered leptin. This proposal focuses on the second condition. The first Specific Aim will examine the mechanistic basis of fat gain in rats that are partially leptin resistant. The proposed studies will test the hypothesis that when peripherally administered leptin is unable to increase activity of leptin receptors located in the forebrain, but can stimulate receptors in the hindbrain and/or periphery, then there is a shift in energy balance and metabolic status that favors fat deposition. Successful completion of this Aim will determine the conditions required and mechanisms responsible for acceleration of body fat gain in conditions of partial leptin-resistance. These studies will provide important new information on how environmental factors decrease the efficacy of mechanisms responsible for the regulation of body fat content and may even promote weight gain. The second Specific Aim includes studies that will identify the location of leptin receptors responsible for the accretion of fat in partially leptin resistant animals. Successful completion of this Aim will provide opportunities to modulate activity of endogenous factors that lead to the accumulation of white fat, and thus prevent, or reverse, obesity. PUBLIC HEALTH RELEVANCE: Because excessive adiposity is associated with a significant increase in risk for a large number of chronic diseases the epidemic of obesity represents a major economic and societal burden. Studies described in this proposal will examine how leptin, a cytokine that is released from adipose tissue, promotes fat gain in conditions of partial leptin resistance. This will provide important new information on how environmental factors modify mechanisms responsible for regulating the size of body fat stores and may even promote weight gain.

描述（由申请人提供）：在美国人口的所有年龄段，超重和肥胖的发生率继续升级。由于过量肥胖与慢性疾病和死亡率的增加有关，因此我们必须了解对调节肥胖的生理机制的理解，以及环境因素如何使这些机制无效。该提案的重点是脂肪细胞衍生的细胞因子瘦素如何修饰全身能量代谢和脂肪细胞代谢。看来，用激素的生理剂量治疗的实验动物中至少存在三个不同的瘦素反应能力：a）瘦素敏感性促进对瘦素的耐药性降低体内脂肪的损失，而瘦素耐药性会导致对瘦素的耐脂蛋白抗反应的脂肪增加，从而使瘦素的抗反应量增加，以应对所有效应。该提案的重点是第二条件。第一个具体目的将检查部分抗瘦素的大鼠的脂肪增加的机理基础。拟议的研究将检验以下假设：当外周施用的瘦素无法增加位于前脑中的瘦素受体的活性，但可以刺激后脑和/或周围的受体，那么能量平衡和代谢状态就会发生变化，使脂肪沉积有利。成功完成此目标将确定在部分瘦素抗性条件下导致体内脂肪增加所需的条件和机制。这些研究将提供有关环境因素如何降低负责调节体内脂肪含量的机制功效的重要新信息，甚至可能促进体重增加。第二个特定目的包括研究，这些研究将确定瘦素受体的位置，这些瘦素受体在部分耐瘦素的动物中促进脂肪。成功完成此目标将为调节内源性因素的活动提供机会，从而导致白脂肪的积累，从而预防或逆转肥胖。公共卫生相关性：因为过度肥胖与大量慢性疾病的风险显着增加有关，因此肥胖的流行代表了主要的经济和社会负担。该提案中描述的研究将检查瘦素是一种从脂肪组织释放的细胞因子如何促进部分瘦素耐药性的脂肪增加。这将提供有关环境因素如何修改负责调节体内脂肪储存量的机制的重要新信息，甚至可能促进体重增加。