Hypothalmic Circuits Regulating Energy Balance and Obesity: Synaptic Physiology

7.项目摘要/摘要 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，并造成巨大的经济后果。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的重要作用。最近， 我们已经证明，除了肽递质外，下丘脑神经元表达 影响能量平衡的前阿片黑素皮质素(POMC)基因也释放出快速作用的氨基酸。 酸传递体GABA和谷氨酸。这项提议的主要目标是检验氨基转移的假设 POMC神经元释放的酸递质在能量平衡的调节中起着关键作用， 扰乱这些神经元的GABA和谷氨酸的释放将影响食物的摄入量和体重。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来检验 通过原位杂交和光遗传刺激/电生理技术禁食和进食。 以及2)通过确定瞬时或持续干扰GABA和谷氨酸释放的结果 POMC神经元，特别是通过使用选择性基因敲除方法以及通过操纵POMC神经元 使用由设计师药物(DREADD)技术独家激活的设计师受体的活动。这个 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方式影响能量平衡电路 作用机制：多肽和氨基酸递质。可能是馈电回路中的氨基酸递质 将被证明是操纵能源平衡监管的可行目标。

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.