Brain insulin and leptin resistance in obesity

肥胖症中的脑胰岛素和瘦素抵抗

• 批准号: 6951103
• 负责人: KEVIN D NISWENDER
• 金额: $ 28.39万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6951103
• 关键词: biochemistry; biological signal transduction; body composition; coenzyme A; dietary lipid; enzyme activity; enzyme linked immunosorbent assay; hormone sensitivity /resistance; hypothalamus; immunocytochemistry; insulin; insulin receptor; insulin sensitivity /resistance; laboratory rat; leptin; long chain fatty acid; nuclear magnetic resonance spectroscopy; obesity; phosphatidylinositol 3 kinase; phosphorylation; western blottings

DESCRIPTION (provided by applicant): Obesity is recognized as a serious worldwide threat to human health. Evidence indicates that over the course of hours and days caloric intake is closely matched to energy expenditure in normal individuals, such that body weight remains stable over time. This regulation occurs via a classical endocrine feedback loop in which the "adiposity signals" insulin and leptin are secreted in proportion to body fat mass and interact with regulatory neurons found in the hypothalamic arcuate nucleus (ARC). Human obesity and the best animal model thereof, diet-induced obesity (DIO) are fundamentally different, leading to the hypothesis that acquired hypothalamic resistance to the adiporegulatory effects of insulin and leptin results in impaired body fat mass regulation. Previously we have demonstrated that the ability of both insulin and leptin to regulate feeding is dependent upon the activation of phosphatidylinositol 3-kinase (PI3K) in ARC neurons; this pathway is the major mode of insulin action in peripheral tissues and has been identified as a "target" of insulin resistance via accumulation of long chain fatty acyl CoA molecules (LC-CoA). We have generated preliminary data demonstrating both behavioral (food intake) and biochemical (PI3K) hypothalamic insulin and leptin resistance in obese DIO animals and that mechanisms implicated in peripheral insulin resistance may also be responsible for central resistance. We propose: Aim 1: To determine the time-course of central insulin and leptin (vs peripheral) resistance in DIO. Aim 2: To determine if the accumulation of hypothalamic long-chain fatty acyl CoA molecules in DIO coincides with behavioral and/or biochemical resistance. Aim 3: To determine if insulin and leptin regulation of FOXO proteins in hypothalamus is disrupted in DIO. Aim 4: To determine if genetic enhancement of the hypothalamic PI3K pathway enhances insulin and leptin sensitivity and attenuates DIO.

描述（由申请人提供）：肥胖被认为是对人类健康的严重威胁。有证据表明，在整个小时和几天的过程中，热量摄入量与正常人的能量消耗密切相匹配，因此体重随着时间的流逝而保持稳定。该调节是通过经典的内分泌反馈回路进行的，其中“肥胖信号”胰岛素和瘦素是按人体脂肪质量比例分泌的，并与下丘脑弧形核（ARC）中发现的调节神经元相互作用。人类肥胖症及其最佳动物模型，饮食诱导的肥胖症（DIO）在根本上是不同的，导致假设是获得了对胰岛素和瘦素的脂肪调节作用的下丘脑耐药性导致体内脂肪质量调节受损。以前，我们已经证明，胰岛素和瘦素调节喂养的能力取决于弧神经元中磷脂酰肌醇3-激酶（PI3K）的激活。该途径是外周组织中胰岛素作用的主要方式，已通过积累长链脂肪酰基COA分子（LC-COA）被确定为胰岛素抵抗的“靶标”。我们已经产生了初步数据，这些数据证明了肥胖dio动物中的行为（食物摄入量）和生化（PI3K）下丘脑胰岛素和瘦素耐药性，并且与周围胰岛素耐药性有关的机制也可能负责中央抵抗力。我们建议： 目的1：确定DIO中中央胰岛素和瘦素（VS外周）耐药的时间顺序。 目的2：确定下丘脑长链脂肪酰基CoA分子在DIO中是否与行为和/或生化耐药相吻合。 目的3：确定下丘脑中FOXO蛋白的胰岛素和瘦素调节是否在DIO中被破坏。 目标4：确定下丘脑PI3K途径的遗传增强是否增强胰岛素和瘦素敏感性并减轻DIO。