Brain insulin and leptin resistance in obesity

描述(申请人提供)：肥胖症被公认为严重威胁人类健康的世界性疾病。有证据表明，在几个小时和几天的过程中，正常个体的卡路里摄入量与能量消耗密切匹配，因此体重随着时间的推移保持稳定。这种调节是通过经典的内分泌反馈回路实现的，在该回路中，“肥胖信号”胰岛素和瘦素与身体脂肪质量成比例地分泌，并与下丘脑弓状核(ARC)中的调节神经元相互作用。人类肥胖及其最佳动物模型与饮食诱导肥胖(DIO)有着根本的不同，导致假设后天下丘脑抵抗胰岛素和瘦素的脂肪调节作用，导致体内脂肪质量调节受损。以前我们已经证明，胰岛素和瘦素调节摄食的能力依赖于ARC神经元中磷脂酰肌醇3-激酶(PI3K)的激活；这一途径是外周组织中胰岛素作用的主要方式，并已被确认为通过积累长链脂肪酰辅酶A分子(LC-CoA)而产生的胰岛素抵抗的靶点。我们已经生成了初步数据，表明肥胖DIO动物的行为(食物摄入)和生化(PI3K)胰岛素和瘦素抵抗，以及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： 目的1：确定DIO中枢性胰岛素和瘦素(VS外周)抵抗的时程。 目的2：确定下丘脑长链脂肪酰辅酶A分子在DIO中的积聚是否与行为和/或生化抵抗相一致。 目的：探讨胰岛素和瘦素对DIO大鼠下丘脑FOXO蛋白调控的影响。 目的：确定下丘脑PI3K通路的遗传增强是否增强了胰岛素和瘦素的敏感性，并减弱了DIO。

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.