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）：美国人口所有年龄段的超重和肥胖发生率持续上升。由于过度肥胖与慢性疾病和死亡风险增加有关，因此我们必须了解调节肥胖的生理机制以及环境因素如何使这些机制失效。该提案重点关注脂肪细胞来源的细胞因子瘦素如何改变全身能量代谢和脂肪细胞代谢。在用生理剂量的激素治疗的实验动物中，瘦素反应似乎至少存在三个不同的阶段：a）瘦素敏感性，促进对瘦素的反应而减少体内脂肪；b）部分瘦素抵抗，导致瘦素增加c) 瘦素完全抵抗，防止对外周施用的瘦素产生任何代谢反应。本提案主要针对第二个条件。第一个具体目标将检查部分瘦素抵抗的大鼠脂肪增加的机制基础。拟议的研究将检验以下假设：当外周施用瘦素无法增加位于前脑的瘦素受体的活性，但可以刺激后脑和/或外周的受体时，能量平衡和代谢状态会发生变化，有利于脂肪沉积。成功完成这一目标将确定在部分瘦素抵抗的情况下加速体脂增加所需的条件和机制。这些研究将提供关于环境因素如何降低负责调节身体脂肪含量的机制的功效，甚至可能促进体重增加的重要新信息。第二个具体目标包括确定瘦素受体位置的研究，该受体负责部分瘦素抵抗动物中脂肪的增加。成功完成这一目标将为调节导致白色脂肪积累的内源性因素的活动提供机会，从而预防或逆转肥胖。公共卫生相关性：由于过度肥胖与大量慢性病风险显着增加相关，肥胖的流行造成了重大的经济和社会负担。该提案中描述的研究将研究瘦素（一种从脂肪组织释放的细胞因子）如何在部分瘦素抵抗的情况下促进脂肪增加。这将提供关于环境因素如何改变负责调节身体脂肪储存大小的机制，甚至可能促进体重增加的重要新信息。