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.