Reducing the post weight-loss energy expenditure gap with orexin agonists

Project Summary Following weight loss, the new lower body weight is extremely difficult to maintain. Many studies have now shown this is because individuals who lose a significant amount of body weight typically have an “Energy Expenditure Gap” (EEgap) post-weight loss, defined operationally as total energy expenditure (TEE) in the pre-obese state, minus TEE in the post-weight loss state, when at the same body weight. Recent studies suggest that the EEgap may be caused in part by compensatory and enduring reductions in basal energy expenditure (BEE) resulting from increases in activity-induced energy expenditure (AEE). Therefore, someone who has lost significant weight has to consume less and expend more energy to stay weight-stable compared to weight-matched individuals who have never been overweight. Physical activity ranges from a subconscious drive to move (spontaneous physical activity, SPA) to voluntary, structured, goal-oriented and high-intensity physical activity (programmed exercise). Increasing EE through physical activity, in combination with caloric restriction is a common therapeutic approach for weight loss, but most individuals do not adhere to physical exercise programs or maintain sufficient intensity to compensate for reductions in TEE post weight-loss. Our lab is one of few to study CNS regulation of SPA and have focused on the hypothalamic neuropeptide orexin A (OXA), which plays a central role in promoting wakefulness and energy homeostasis. We found that OXA injection and/or orexin neuron activation reverses BEE reductions and increases NEAT and TEE in animal models, without compensatory increases in food intake. Our collaborator Dr. Zhang is on the forefront of developing new small molecular orexin agonists that activate both orexin 1(OX1R) and orexin 2 (OX2R) receptors, and one such OX agonist upon i.p. administration robustly enhances SPA without changing food intake in middle aged mice and 5-mo old obesity prone (OP) rats. In addition, chronic (5wk) administration of the agonist reduced adiposity and weight gain in the New Zealand Obese (NZO) mice, supporting orexin agonists as a potential therapy to prevent weight relapse post weight-loss. The goal of the current project is to test the effects of these orexin agonists in reducing the EEgap, following weight-loss in rodent models of obesity, and to understand if the underlying mechanism involves alterations in mitochondrial respiration. We will also test the effect of these agonists on sleep/wake patterns for side effects. To do this, we will use indirect calorimetry in conjunction with behavioral analyses and peripheral administration of orexin agonist(s), to determine if activation of the orexin system suppresses weight regain. The long-term goal of this project is to enable research and development in using orexin as a therapy for obesity, weight regain and associated comorbidities.