Brain insulin and leptin resistance in obesity

描述（由申请人提供）：肥胖被认为是对人类健康的严重全球性威胁。有证据表明，在正常个体中，在数小时和数天的过程中，热量摄入与能量消耗密切匹配，使得体重随时间保持稳定。这种调节通过经典的内分泌反馈回路发生，其中“肥胖信号”胰岛素和瘦素与体脂量成比例地分泌，并与下丘脑弓状核（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）是根本不同的，导致下丘脑对胰岛素和瘦素的脂肪调节作用的获得性抵抗导致体脂量调节受损的假设。先前我们已经证明胰岛素和瘦素调节进食的能力依赖于ARC神经元中磷脂酰肌醇3-激酶（PI 3 K）的激活;该途径是外周组织中胰岛素作用的主要模式，并且已经被鉴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”。我们已经产生了初步的数据，表明肥胖DIO动物的行为（食物摄入）和生化（PI 3 K）下丘脑胰岛素和瘦素抵抗，外周胰岛素抵抗的机制也可能是中枢抵抗的原因。我们建议： 目的1：研究DIO患者中枢胰岛素和瘦素抵抗的时程变化。 目标二：确定DIO中下丘脑长链脂肪酰CoA分子的积累是否与行为和/或生化抗性一致。 目的3：确定胰岛素和瘦素对下丘脑FOXO蛋白的调节是否在DIO中被破坏。 目的4：确定下丘脑PI 3 K通路的遗传增强是否增强胰岛素和瘦素敏感性并减弱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.