Orexin and serotonin interactions to promote physical activity and prevent obesity

这项提案的总体目标是确定针对食欲素大脑网络的策略， 调节自发的身体活动和相关的热量消耗。这种能量 消耗被称为非运动活动产热（NEAT），我们建议， 可以用来开发新的治疗方法，用于预防体重增加和减肥， 锻炼身体具体目标是确定食欲素神经元的哪个亚群是 与对NEAT最稳健的影响相关;治疗时间是否影响 这种有针对性的NEAT疗法;最后，无论是在特定的大脑区域，中缝背核， 核（DRN）调节这种有针对性的NEAT疗法产生的卡路里。和手段改革的重大意义 为需要减肥或预防体重的退伍军人发现新疗法的潜力 增加退伍军人的正式锻炼选择有限，从而减少肥胖的负担， 相关合并症。针对食欲素和血清素受体的药物已经在临床上 提供了概念验证，这些药物可以成功地用于人类 健康新颖之处在于创造一种基于促进NEAT的治疗方法的想法;我们的新 建立了研究大脑网络的方法，使用设计者受体， 设计药物（DREADDs）;我们研究食欲素的动物模型，食欲素是一种神经肽， 增加NEAT;和新获得的设备，允许复杂的量化NEAT。

The overall goal of this proposal is to identify strategies that target the orexin brain network that regulates spontaneous physical activity, and the associated caloric expenditure. This energy expenditure is referred to as non-exercise activity thermogenesis (NEAT), and we propose that this can be exploited to develop new therapies for weight gain prevention and weight loss in those unable to exercise. The specific objectives are to determine which sub-population of orexin neurons are associated with the most robust effect on NEAT; whether therapy length influence the effectiveness of this targeted NEAT therapy; and finally, whether serotonin in a specific brain area, the dorsal raphe nucleus (DRN), modulates the calories produced by this targeted NEAT therapy. The significance is the potential to discover a new therapy for Veterans needing to lose weight or for preventing weight gain in Veterans with limited options for formal exercise, thus reducing the burden of obesity and associated co-morbidities. Drugs targeting orexin and serotonin receptors are already clinically available, providing proof-of-concept that these drugs could be successfully manipulated for human health. The novelty lies in the idea to create a therapy based on promotion of NEAT; our newly established methods to study brain networks using Designer Receptors Exclusively activated by Designer Drugs (DREADDs); our animal models for studying orexin, a neuropeptide that significantly increases NEAT; and newly obtained equipment for allowing sophisticated quantification of NEAT.