Brain insulin and leptin resistance in obesity

描述（由申请人提供）：肥胖是公认的严重威胁人类健康的全球性问题。有证据表明，在数小时和数天的过程中，热量摄入与正常个体的能量消耗密切匹配，因此体重在一段时间内保持稳定。这种调节通过一个经典的内分泌反馈回路发生，在这个回路中，“肥胖信号”胰岛素和瘦素的分泌与体脂量成比例，并与下丘脑弓状核（ARC）中的调节神经元相互作用。人类肥胖与其最佳动物模型饮食性肥胖（DIO）有着根本的不同，这导致了一种假说，即获得性下丘脑对胰岛素和瘦素的脂肪调节作用的抵抗导致了身体脂肪量调节的受损。先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；该途径是外周组织中胰岛素作用的主要模式，并已被确定为胰岛素抵抗的“靶标”，通过长链脂肪酰基辅酶a分子（LC-CoA）的积累。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，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:

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.