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.
Non-exercise activity thermogenesis (NEAT) and the spontaneous physical activity that drives it are involved in individual variation in propensity to become obese with overfeeding. Some individuals remain lean in the face of overfeeding, and a high level of NEAT predisposes one to be thin. A discovery made by our lab is the finding that the natural brain chemical called orexin (which occurs in humans) initiates NEAT. Our goal is to understand the parts of the brain in which orexin works so that we can develop therapies for humans based on increasing NEAT. To obtain knowledge needed to do this, we will study mouse brain orexin circuits and possible treatment strategies. This will help determine how best to develop orexin-based treatments for obesity and other brain mechanisms that promote NEAT. We will use a new technology (DREADDS) that allows us to stimulate and monitor the activity of orexin neurons. We will also determine if serotonin affects NEAT. By refining possible drug targets, we will inform individualized treatment for obesity.
|Mavanji, Vijayakumar; Butterick, Tammy A; Duffy, Cayla M et al. (2017) Orexin/hypocretin treatment restores hippocampal-dependent memory in orexin-deficient mice. Neurobiol Learn Mem 146:21-30|