The Effect of Hindbrain Orexin A Signaling on Brown Adipose Tissue Thermogenesis and Physical Activity

Abstract

Obesity (body mass index (BMI) ≥ 30) and overweight (BMI 25 - 29) are major health concerns in the United States, with the incidence of obesity affecting nearly one third of the US population. Previous work has emphasized the importance of neuropeptides (protein neurotransmitters) in the control of behaviors associated with ingestion and energy expenditure. The orexins (orexin A and orexin B) are a family of neuropeptides important in promoting physical activity, and have also recently been shown to increase energy expenditure through effects on thermogenesis, specifically via the raphe pallidus (RPa) and dorsomedial hypothalamic nucleus. The aim of this project is to explore brain-mediated defense against obesity via control of energy expenditure (EE), specifically focusing on thermogenesis as regulated by hindbrain orexin A (OXA) signaling. While this pathway has been studied in a model using anesthetized rats, similar findings have not yet been duplicated in freely moving animals. Our overall hypothesis is that orexin signaling in the RPa modulates energy balance by increasing brown adipose tissue (BAT) thermogenesis, thereby increasing EE with limited effects on physical activity. Rats received fourth ventricle OXA injections and were monitored for 24 h for food intake, activity, and calorimetry data. Results show that OXA significantly increased heat production (kCal/h) and ambulatory activity in the first two h post-treatment (p = 0.0019, and p = 0.0174, respectively). While ambulatory activity did increase post-treatment, this difference is not believed to be large enough to fully explain the difference in EE during the first 1-2 h. Despite no significant difference in UCP1 expression (a marker of BAT thermogenesis), a lack of difference in food intake suggests that BAT (rather than diet-induced) thermogenesis is contributing to the difference in EE. BAT thermogenesis is an important component of EE in rodents, and has recently been confirmed to increase EE in humans as well. Therefore, data from this and ongoing studies may contribute to the development of orexin-based therapies to increase energy expenditure and reduce body weight in obese humans.