Integration of Long- and Short-Term Control of Feeding

本研究旨在探讨肥胖相关激素、胰岛素和瘦素以及营养相关信号在控制下丘脑弓状核关键神经元亚群中相互作用的机制(S)，并试图阐明这些相互作用如何影响饱腹感。假设胰岛素和瘦素都作用于ARC神经元，通过激活与胰岛素有关的细胞反应来减少食物摄入量 受体底物(IRS)-磷脂酰肌醇3-羟基激酶(PI3K)通路。瘦素和胰岛素被假设为减少食物摄入量的一个机制是通过加强对食物摄取产生的内源性信号的反应，包括CCK，这会加速饱腹感的开始。具体地说，我们假设下丘脑的下行投射将肥胖相关信号引发的反应联系到 对饱腹感信号做出反应的后脑回路。通过这一机制，建议持续减少体内脂肪储存(降低血浆胰岛素和瘦素水平)，以减弱对饱腹感信号的反应，从而增加进餐数量。具体目的1研究胰岛素或瘦素增强CCK反应的能力是否依赖于下丘脑PI3K信号。一个令人兴奋的新研究领域围绕着一种假设，即胰岛素和瘦素的急性神经元效应与细胞内长链脂肪酰辅酶A(LCFACoA)分子诱导的效应相一致。具体目标2-4将在我们的初步数据的基础上展开，表明LCFACoA含量受能量平衡变化和肥胖相关激素的调节，并将阐明这些影响的机制。具体目的5研究在ARC中LCFACoA的积累是否模仿瘦素的作用，以增强对饱腹感信号的反应。这些目标加在一起，有可能从根本上修改我们的 了解控制能量稳态和肥胖发病机制的信号网络，从而为正在进行的努力开发更成功的肥胖症治疗方法提供亟需的新方向。

This proposal investigates the mechanism(s) underlying the interactions between adiposity-related hormones, insulin and leptin, and nutrient-related signals in the control of key neuronal subsets in the hypothalamic arcuate nucleus (ARC), and seeks to clarify how these interactions influence the perception of satiety. Both insulin and leptin are hypothesized to act upon ARC neurons to reduce food intake via activation of cellular responses involving the insulin receptor substrate (IRS)-phosphatidylinositol 3-OH kinase (PI3K) pathways. One mechanism whereby leptin and insulin are hypothesized to reduce food intake is by potentiating the response to endogenous signals generated in response to food ingestion, including cholecystokinin (CCK), that hasten the onset of satiety. Specifically, we hypothesize that a descending projection from the hypothalamus links responses elicited by adiposity-related signals to hindbrain circuits that respond to satiety signals. Via this mechanism, a sustained reduction of body fat stores (which lowers plasma insulin and leptin levels) is proposed to attenuate the response to satiety signals and thereby increase meal size. Specific Aim 1 investigates whether the ability of insulin or leptin to potentiate the response to CCK is dependent on hypothalamic PI3K signaling. An exciting new area of study revolves around the hypothesis that acute neuronal effects of insulin and leptin converge on those induced by intracellular long chain fatty acyl CoA (LCFACoA) molecules. Specific Aims 2-4 will expand upon our preliminary data demonstrating that LCFACoA content is regulated by changes of energy balance and by adiposity-related hormones, and will clarify the mechanisms underlying these effects. Specific Aim 5 investigates whether accumulation of LCFACoA in the ARC mimics the effect of leptin to potentiate the response to satiety signals. Together, these aims have the potential to fundamentally revise our understanding of signaling networks controlling energy homeostasis and obesity pathogenesis, and will thereby provide much needed new direction for ongoing efforts to develop more successful approaches to obesity treatment.