Leptin and Insulin Responses in Hypothalamic NPY Neurons

下丘脑 NPY 神经元中的瘦素和胰岛素反应

• 批准号: 8313577
• 负责人: Christopher Javadi
• 金额: $ 2.94万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313577
• 关键词: ART protein; Ablation; Acute; Adult; Automobile Driving; Binding; Blood Glucose; Body Weight; Brain; Brain region; Catalytic Domain; Child; Cranial Nerves; Diet; Disease; Eating; Endogenous Factors; Energy Intake; Energy Metabolism; Equilibrium; Event; Fasting; Fatty acid glycerol esters; Feedback; Feeding behaviors; Food Energy; Frequencies; Genes; Genetic; Glucose; Homeostasis; Hormonal; Hormones; Human; Hypertension; Hypothalamic structure; Insulin; Insulin Receptor; Leptin; Ligands; Liver diseases; Mammals; Measures; Mediating; Melanocortin 4 Receptor; Modeling; Mus; Neuraxis; Neurons; Neuropeptides; Neurotransmitters; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Pathway interactions; Peptides; Peripheral; Peripheral Nerves; Preparation; Prevalence; Pro-Opiomelanocortin; Production; Reporter; Resistance; Rodent; Role; Signal Transduction; Slice; Structure of nucleus infundibularis hypothalami; Synapses; System; Techniques; Testing; Wood material; agouti protein; alpha-Melanocyte stimulating hormone; blood glucose regulation; energy balance; feeding; gamma-Aminobutyric Acid; glucose tolerance; insight; insulin tolerance; leptin receptor; neural circuit; neuropeptide Y; neurotransmitter release; optogenetics; overexpression; relating to nervous system; research study; response; transmission process; vesicular GABA transporter

DESCRIPTION (provided by applicant): Obesity is fundamentally a disorder of energy balance. Adult body weight is normally maintained within a narrow range by neural and hormonal circuits which act to balance energy intake and expenditure. To accomplish this balancing act, the central nervous system senses and responds to changes in circulating metabolites, such as glucose and free fatty acids, and hormones, such as insulin and leptin. In humans and other mammals, these peripheral signals are integrated by neural circuits in the hypothalamus, which then coordinate responses via projections to other brain regions. One such feedback circuit, the melanocortin circuit in the arcuate nucleus of the hypothalamus, consists of neuropeptide Y (NPY)-expressing neurons, which promote feeding and decrease energy expenditure, and pro-opiomelanocortin (POMC)-expressing neurons, which inhibit feeding and increase energy expenditure. However, the downstream events of hormone sensing in NPY neurons are presently unclear. This project will investigate the acute changes in electrical activity of NPY neurons in response to leptin and insulin and the intracellular signalin pathway that may mediate these effects. Determining these pathways may reveal insights into how resistance to these signals occurs in obesity and type 2 diabetes. PUBLIC HEALTH RELEVANCE: The number of obese adults and children is increasing dramatically worldwide, driving parallel increases in the prevalence of type 2 diabetes mellitus, hypertension, liver disease, and other associated conditions. Fundamentally, obesity is a disorder of the neural and hormonal mechanisms that sense the quantity of stored energy and appropriately modify food intake and energy expenditure; a better understanding these mechanisms is required to develop new treatments that safely lower body weight and blood glucose. This project aims to reveal how the circulating hormones leptin and insulin regulate a component of the hypothalamic melanocortin system, a key neural circuit that controls body weight and energy expenditure.

描述（由申请人提供）：肥胖从根本上来说是一种能量平衡紊乱。成人体重通常通过神经和激素回路维持在一个狭窄的范围内，这些回路起到平衡能量摄入和消耗的作用。为了实现这种平衡作用，中枢神经系统感知循环代谢物（例如葡萄糖和游离脂肪酸）以及激素（例如胰岛素和瘦素）的变化并做出反应。在人类和其他哺乳动物中，这些外周信号由下丘脑的神经回路整合，然后通过投射到其他大脑区域来协调反应。其中一种反馈回路是下丘脑弓状核中的黑皮质素回路，由表达神经肽 Y (NPY) 的神经元和表达阿片黑皮质素原 (POMC) 的神经元组成，前者促进进食并减少能量消耗，后者抑制进食和减少能量消耗。增加能量消耗。然而，NPY 神经元激素感应的下游事件目前尚不清楚。该项目将研究 NPY 神经元响应瘦素和胰岛素的电活动的急性变化，以及可能介导这些效应的细胞内信号通路。确定这些途径可能会揭示肥胖和 2 型糖尿病中对这些信号的抵抗如何发生的见解。 公共卫生相关性：全球肥胖成人和儿童的数量急剧增加，导致 2 型糖尿病、高血压、肝病和其他相关疾病的患病率同步增加。从根本上说，肥胖是一种神经和激素机制的紊乱，这些机制感知储存的能量数量并适当地调整食物摄入和能量消耗；需要更好地了解这些机制来开发安全降低体重和血糖的新疗法。该项目旨在揭示循环激素瘦素和胰岛素如何调节下丘脑黑皮质素系统的一个组成部分，下丘脑黑皮质素系统是控制体重和能量消耗的关键神经回路。