Integration of Long- and Short-Term Control of Feeding

饲喂长短期控制一体化

• 批准号: 7475875
• 负责人: Michael W Schwartz
• 金额: $ 26.17万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475875
• 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.

该提案研究了肥胖相关激素、胰岛素和瘦素之间相互作用的机制，以及控制下丘脑弓状核（ARC）关键神经元亚群的营养相关信号之间的相互作用，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。据推测，瘦素和胰岛素减少食物摄入的一种机制是增强对食物摄入时产生的内源信号的反应，包括缩胆囊素 (CCK)，从而加速饱腹感的发生。具体来说，我们假设下丘脑的下降投射将肥胖相关信号引起的反应与 对饱腹感信号做出反应的后脑回路。通过这种机制，持续减少体内脂肪储存（从而降低血浆胰岛素和瘦素水平）可以减弱对饱腹感信号的反应，从而增加进餐量。具体目标 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 信号传导。一个令人兴奋的新研究领域围绕着这样的假设：胰岛素和瘦素的急性神经元效应集中在细胞内长链脂肪酰辅酶 A (LCFACoA) 分子诱导的神经元效应上。具体目标 2-4 将扩展我们的初步数据，证明 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。具体目标 5 研究 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。总之，这些目标有可能从根本上改变我们的 了解控制能量稳态和肥胖发病机制的信号网络，从而将为持续努力开发更成功的肥胖治疗方法提供急需的新方向。