Hypothalmic Circuits Regulating Energy Balance and Obesity: Synaptic Physiology

描述（由申请人提供）：肥胖症越来越普遍，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，除了肽类递质，下丘脑神经元表达阿黑皮素原（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。该提案的主要目标是验证POMC神经元释放的氨基酸递质在能量平衡调节中起关键作用的假设，以及干扰这些神经元的GABA和谷氨酸释放将影响食物摄入和体重。这一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/电生理学技术确定POMC神经元的GABA和谷氨酸释放如何受禁食和食物摄入的调节。和2）通过使用选择性敲除方法，以及通过使用设计者药物专门激活的设计者受体（DREADD）技术操纵POMC神经元活性，确定特异性地暂时或持续破坏POMC神经元的GABA和谷氨酸释放的结果。将确定GABA或谷氨酸释放中断对能量平衡调节的影响。总之，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。这可能是在喂养电路中的氨基酸递质将被证明是可行的目标操纵能量平衡调节。

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.