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: 8629274
• 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/8629274
• 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

7. Project Summary/Abstract 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.

7。项目摘要/摘要 肥胖越来越普遍，导致各种威胁生命的疾病，包括糖尿病，中风， 心脏病和癌症，并产生巨大的经济后果。肥胖的研究清楚地表明 下丘脑肽发射机在调节能量稳态方面的重要作用。最近， 我们已经表明，除了肽发射机外，下丘脑神经元表达 有力影响能量平衡的proOpiomelanocortin（POMC）基因也释放了快速氨基 酸性发射器GABA和谷氨酸。该提议的主要目的是检验氨基的假设 从POMC神经元释放的酸性发射器在能量平衡的调节中起关键作用，并且 从这些神经元中扰动GABA和谷氨酸释放会影响食物摄入和体重。这 假设将通过1）确定如何调节POMC神经元释放GABA和谷氨酸 通过使用原位杂交和光遗传刺激/电生理技术的禁食和食物摄入。 2）通过确定瞬时或持续破坏GABA和谷氨酸释放的结果 POMC神经元专门使用选择性敲除方法以及操纵POMC神经元 使用设计师药物（Dreadd）技术专门激活的设计器受体的活性。这 将确定GABA或谷氨酸释放对能量平衡调节的后果。 总之，结果将指示POMC神经元是否通过两个不同的 机理：肽和氨基酸发射机。可能是喂养电路中的氨基酸发射器 被证明是操纵能源平衡调节的可行目标。