Brain insulin and leptin resistance in obesity

肥胖症中的脑胰岛素和瘦素抵抗

• 批准号: 7256342
• 负责人: KEVIN D NISWENDER
• 金额: $ 30.28万
• 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/7256342
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acyl Coenzyme A; Address; Adenoviruses; Adipose tissue; Animal Model; Animals; Attenuated; Behavioral; Biochemical; Blood Circulation; Body Weight; Body fat; Brain; Caenorhabditis elegans; Chronic; Coenzyme A; Complement; Data; Defect; Development; Diet; Disease; Dominant-Negative Mutation; Down-Regulation; Eating; Endocrine; Energy Intake; Energy Metabolism; Epidemic; Family; Fatty acid glycerol esters; Feedback; Figs - dietary; Fire - disasters; Gene Targeting; Genetic; Genetic Enhancement; Genetic Transcription; Genomics; Health; Homeostasis; Hormones; Hour; Human; Hyperphagia; Hypothalamic structure; Impairment; Individual; Insulin; Insulin Resistance; Intervention; Laboratories; Lead; Leptin; Leptin resistance; Lesion; Maintenance; Measures; Mediating; Mediator of activation protein; Medical; Membrane Potentials; Metabolic; Modeling; Morbidity - disease rate; Mus; Neurons; Numbers; Obesity; Pathogenesis; Pathway interactions; Peripheral; Peripheral Resistance; Phosphorylation; Physiological; Play; Population; Prevalence; Primary Lesion; Proteins; Proto-Oncogene Proteins c-akt; Rat-1; Rate; Rattus; Receptor Signaling; Regulation; Resistance; Role; Series; Serine; Signal Pathway; Signal Transduction; Stream; Structure of nucleus infundibularis hypothalami; System; Technology; Testing; Time; Tissues; Transcriptional Regulation; Tyrosine; Work; attenuation; base; cost; day; feeding; gene therapy; in vivo; insulin sensitivity; insulin signaling; mortality; neural circuit; transcription factor

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）：肥胖被认为是全球范围内对人类健康的严重威胁。有证据表明，正常人在数小时和数天内的热量摄入与能量消耗密切相关，因此体重随着时间的推移保持稳定。这种调节通过经典的内分泌反馈环路发生，其中“肥胖信号”胰岛素和瘦素按身体脂肪量的比例分泌，并与下丘脑弓状核（ARC）中的调节神经元相互作用。人类肥胖与其最好的动物模型饮食诱导肥胖（DIO）有着本质上的不同，这导致了这样的假说：下丘脑对胰岛素和瘦素的脂肪调节作用产生抵抗，导致体脂量调节受损。之前我们已经证明，胰岛素和瘦素调节进食的能力取决于 ARC 神经元中磷脂酰肌醇 3-激酶 (PI3K) 的激活；该途径是胰岛素在外周组织中作用的主要模式，并已被确定为通过长链脂肪酰辅酶 A 分子 (LC-CoA) 积累的胰岛素抵抗的“靶标”。我们已经生成了初步数据，证明肥胖 DIO 动物的行为（食物摄入）和生化（PI3K）下丘脑胰岛素和瘦素抵抗，并且与外周胰岛素抵抗有关的机制也可能是中枢抵抗的原因。我们建议： 目标 1：确定 DIO 中中枢胰岛素和瘦素（相对于外周）抵抗的时程。 目标 2：确定 DIO 中下丘脑长链脂肪酰辅酶 A 分子的积累是否与行为和/或生化耐药性一致。 目标 3：确定 DIO 中胰岛素和瘦素对下丘脑 FOXO 蛋白的调节是否受到干扰。 目标 4：确定下丘脑 PI3K 通路的基因增强是否会增强胰岛素和瘦素敏感性并减弱 DIO。