Hypothalmic Circuits Regulating Energy Balance and Obesity: Synaptic Physiology

7.项目概要/摘要 肥胖症越来越普遍，并导致各种危及生命的疾病，包括糖尿病，中风， 心脏病和癌症，并产生巨大的经济后果。对肥胖症的研究清楚地表明 下丘脑肽递质在调节能量稳态方面的重要作用。最近， 我们已经表明，除了肽递质，下丘脑神经元表达 前阿黑皮素（POMC）基因，这有力地影响能量平衡，也释放快速作用的氨基 酸递质GABA和谷氨酸。这个提议的主要目的是检验氨基 POMC神经元释放的酸性递质在能量平衡的调节中起关键作用， 干扰这些神经元的GABA和谷氨酸释放将影响食物摄入和体重。这 假设将通过1）确定POMC神经元的GABA和谷氨酸释放是如何调节的 采用原位杂交和光遗传学刺激/电生理学技术，通过禁食和食物摄入。 和2）通过测定短暂或持续地干扰GABA和谷氨酸从 通过使用选择性敲除方法，以及通过操纵POMC神经元， 活性使用设计师受体专门激活的设计师药物（DREADD）技术。的 将确定GABA或谷氨酸释放中断对能量平衡调节的后果。 总之，结果将表明POMC神经元是否通过两种不同的方式影响能量平衡回路。 机制：肽和氨基酸递质。可能是进食回路中的氨基酸递质 将被证明是操纵能量平衡调节的可行目标。

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.