Integration of Long- and Short-Term Control of Feeding

饲喂长短期控制一体化

• 批准号: 7663936
• 负责人: Michael W Schwartz
• 金额: $ 27.01万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7663936
• 关键词: 1-Phosphatidylinositol 3-Kinase; 5-(tetradecyloxy)-2-furancarboxylic acid; Acetyl-CoA Carboxylase; Acute; Acyl Coenzyme A; Address; Adipocytes; Animals; Anorexia; Area; Attenuated; Biological; Biology; Body Weight; Body Weight decreased; Body fat; Brain; Brain Stem; Cholecystokinin; Cloning; Complement; Consumption; Coupled; Data; Dose; Eating; Energy Intake; Energy Metabolism; FOS gene; Fasting; Feedback; Figs - dietary; Food; Frequencies; Gas Chromatography; Gene Expression; Genes; Genomics; Glucose; Goals; Homeostasis; Hormones; Hypothalamic structure; Immunohistochemistry; Individual; Infusion procedures; Ingestion; Insulin; Insulin Receptor; Intervention; Intracarotid Infusion; Leptin; Letters; Link; Literature; Liver; Malonyl Coenzyme A; Measures; Mediating; Membrane; Metabolism; Methods; Mitochondria; Modeling; Neurons; Neuropeptide Gene; Nucleus solitarius; Nutrient; ORALIT; Obesity; Pathogenesis; Pathway interactions; Peptides; Perception; Peripheral; Pharmaceutical Preparations; Phosphatidylinositols; Plasma; Potassium; Principal Investigator; Process; Rattus; Receptor Gene; Recovery; Reporting; Research Personnel; Satiation; Signal Transduction; Signaling Molecule; Stimulus; Stomach; Structure of nucleus infundibularis hypothalami; System; Testing; Time; Tissue Extracts; Tissues; Universities; Washington; Weight; Work; base; cellular targeting; energy balance; feeding; food consumption; gene therapy; glucose metabolism; hindbrain; inhibitor/antagonist; insulin signaling; kinase inhibitor; leptin receptor; obesity treatment; oxidation; prevent; programs; receptor; response; role model; size; tandem mass spectrometry

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.

该提案研究了在控制下丘脑神经座核（ARC）中关键神经元亚群中与脂肪相关的激素，胰岛素和瘦素以及与营养相关的信号之间相互作用之间相互作用的机制，并试图阐明这些相互作用如何影响Sateetie的感知。假设胰岛素和瘦素都作用于弧神经元，以通过激活涉及胰岛素的细胞反应来减少食物摄入 受体底物（IRS） - 磷脂酰肌醇3-OH激酶（PI3K）途径。假设瘦素和胰岛素可以减少食物摄入的一种机制是增强对食物摄入的内源信号的反应，包括胆囊基蛋白（CCK），从而加快了其中料的发作，从而加快了其中料的摄入。具体而言，我们假设来自下丘脑链接的下降投影是由肥胖相关信号引起的响应 响应饱腹感信号的后脑电路。通过这种机制，提出了体内脂肪储存的持续减少（降低血浆胰岛素和瘦素水平），以减轻对饱腹感信号的反应，从而增加餐食的大小。具体目标1研究胰岛素或瘦素增强对CCK反应的能力是否取决于下丘脑PI3K信号传导。一个令人兴奋的新研究领域围绕以下假设：胰岛素和瘦素的急性神经元作用对细胞内长链脂肪脂肪酰基COA（LCFACOA）分子诱导的急性神经元作用。具体目标2-4将在我们的初步数据上扩展，表明LCFACOA含量受能量平衡的变化和与肥胖相关的激素的调节，并将阐明这些作用的基础机制。具体目的5研究了LCFACOA在弧中的积累是否模仿瘦素增强对饱腹感信号的反应的作用。这些目标共同有可能从根本上修改我们 了解控制能量稳态和肥胖发病机理的信号网络，从而为持续的努力提供了急需的新方向，以开发更成功的肥胖治疗方法。