Hypothalmic Circuits Regulating Energy Balance and Obesity: Synaptic Physiology

描述(申请人提供)：肥胖日益普遍，并导致多种危及生命的疾病，包括糖尿病、中风、心脏病和癌症，并具有巨大的经济后果。关于肥胖的研究清楚地表明，下丘脑肽递质在调节能量平衡方面发挥着重要作用。最近，我们发现，除了肽递质，表达前阿片黑素皮质素(POMC)基因的下丘脑神经元也释放快速作用的氨基酸递质GABA和谷氨酸。POMC基因可能影响能量平衡。这一提议的主要目的是检验这样一种假设，即从POMC神经元释放的氨基酸递质在调节能量平衡方面发挥关键作用，并且干扰这些神经元释放的GABA和谷氨酸将影响食物摄入量和体重。这一假说将通过1)利用原位杂交和光遗传刺激/电生理技术来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。以及2)通过使用选择性基因敲除方法，以及通过使用由设计药物(DREADD)专属激活的设计受体(DREADD)技术来操纵POMC神经元的活动，来确定特定地使用选择性敲除方法来瞬时或持续干扰POMC神经元的GABA和谷氨酸释放的结果。扰乱GABA或谷氨酸释放对能量平衡调节的影响将被确定。总之，这些结果将表明POMC神经元是否通过两种不同的机制影响能量平衡电路：多肽和氨基酸递质。也许，馈电回路中的氨基酸发射器将被证明是操纵能量平衡调节的可行目标。

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.