Hypothalmic Circuits Regulating Energy Balance and Obesity: Synaptic Physiology

调节能量平衡和肥胖的下丘脑回路：突触生理学

• 批准号: 8732623
• 负责人: SHANE T HENTGES
• 金额: $ 31.63万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732623
• 关键词: Acute; Address; Adult; Affect; Amino Acids; Anorexia; Body Weight; Brain; Cells; Cessation of life; Child; Designer Drugs; Diabetes Mellitus; Disease; Eating; Economics; Fluorescent in Situ Hybridization; Genes; Glutamates; Goals; Health Expenditures; Heart Diseases; Homeostasis; Hypothalamic structure; In Situ Hybridization; Knock-out; Label; Life; Maintenance; Malignant Neoplasms; Messenger RNA; Mus; Nature; Neurons; Obesity; Peptides; Phenotype; Physiology; Play; Prevention; Pro-Opiomelanocortin; Proteins; Regulation; Role; Site; Stroke; Synapses; Techniques; Technology; Teenagers; Testing; Therapeutic; United States; Work; base; energy balance; fast food; feeding; gamma-Aminobutyric Acid; insight; mRNA Expression; neuroregulation; obesity treatment; optogenetics; prevent; public health relevance; receptor; therapeutic target

DESCRIPTION (provided by applicant): Obesity is increasingly prevalent and leads to a variety of life-threatening diseases including diabetes, stroke, heart disease and cancers, and has huge economic consequences. Studies on obesity clearly indicate important roles for hypothalamic peptide transmitters in regulating aspects of energy homeostasis. Recently, we have shown that in addition to peptide transmitters, hypothalamic neurons expressing the proopiomelanocortin (POMC) gene, which potently affect energy balance, also release the fast-acting amino acid transmitters GABA and glutamate. The primary goal of this proposal is to test the hypothesis that amino acid transmitters released from POMC neurons play a key role in the regulation of energy balance, and that perturbing GABA and glutamate release from these neurons will affect food intake and body weight. This hypothesis will be tested by 1) determining how GABA and glutamate release from POMC neurons is regulated by fasting and food intake using in situ hybridization and optogenetic stimulation/electrophysiologic techniques. And 2) by determining the result of transiently or persistently disrupting GABA and glutamate release from POMC neurons specifically by using selective knockout approaches, as well as by manipulating POMC neuron activity using designer receptors exclusively activated by designer drugs (DREADD) technology. The consequence of disrupted GABA or glutamate release on energy balance regulation will be determined. Altogether, the results will indicate if POMC neurons affect energy balance circuits via two distinct mechanisms: peptides and amino acid transmitters. It may be that amino acid transmitters in feeding circuits will prove to be viable targets for manipulating energy balance regulation.

描述（由申请人提供）：肥胖日益普遍，导致多种危及生命的疾病，包括糖尿病、中风、心脏病和癌症，并产生巨大的经济后果。对肥胖的研究清楚地表明下丘脑肽递质在调节能量稳态方面的重要作用。最近，我们发现除了肽递质外，表达阿黑皮质素原（POMC）基因的下丘脑神经元（可有效影响能量平衡）也释放快速作用的氨基酸递质 GABA 和谷氨酸。该提案的主要目标是检验以下假设：POMC 神经元释放的氨基酸递质在能量平衡调节中发挥关键作用，并且干扰这些神经元释放的 GABA 和谷氨酸将影响食物摄入和体重。该假设将通过以下方式进行检验：1) 使用原位杂交和光遗传学刺激/电生理技术确定禁食和食物摄入如何调节 POMC 神经元的 GABA 和谷氨酸释放。 2) 通过使用选择性敲除方法，以及通过使用专门由设计药物 (DREADD) 技术激活的设计受体来操纵 POMC 神经元活性，确定短暂或持续破坏 POMC 神经元 GABA 和谷氨酸释放的结果。 GABA 或谷氨酸释放中断对能量平衡调节的影响将被确定。总而言之，结果将表明 POMC 神经元是否通过两种不同的机制影响能量平衡回路：肽和氨基酸递质。喂养回路中的氨基酸递质可能会被证明是操纵能量平衡调节的可行目标。