Orexin and serotonin interactions to promote physical activity and prevent obesity

这项提案的总体目标是确定以食欲素大脑网络为目标的策略 调节自发的身体活动，以及相关的卡路里消耗。这股能量 支出被称为非运动活动生热(NEAT)，我们建议这 可以被用来开发预防体重增加和减肥的新疗法 锻炼身体。具体目标是确定食欲素神经元的哪些亚群 与对NEAT的最强有力的效果相关；治疗时间长短是否影响 这种有针对性的整洁疗法；最后，是否特定大脑区域中的5-羟色胺，背中缝 核(DRN)，调节这种有针对性的整形疗法产生的卡路里。重要的是 为需要减肥或预防体重的退伍军人发现新疗法的可能性 在正式锻炼选择有限的退伍军人中获益，从而减轻肥胖和 相关的共病。针对食欲素和5-羟色胺受体的药物已经在临床上使用 提供概念证据，证明这些药物可以成功地用于人类 健康。新奇之处在于创造了一种基于促进Neat的治疗；我们的新 已建立的研究大脑网络的方法，使用专门激活的设计者受体 特制药物(DREADDS)；我们研究食欲素的动物模型，一种神经肽，显著 增加整齐；以及新获得的设备，允许复杂的量化整齐。

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.