Orexin agonists as novel obesity therapeutics

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Overweight and obesity are common among Veterans served by the Veterans Health Administration (VHA). Obesity and the chronic diseases associated with obesity place a tremendous burden on our healthcare system and reduce quality of life for the general population as well as for Veterans. As our Veteran population ages over the next decades, this burden will only increase. In addition to few effective pharmacotherapies for obesity prevention, there are no effective therapies for long-term weight maintenance after weight loss in obese subjects. Therapeutically targeting fundamental mechanisms that drive energy expenditure has a larger dividend in terms of improving the health of the overweight Veteran population than would treating individual co-morbidities associated with obesity. One of the possible mechanisms for the development of obesity is decreased availability of the hypothalamic neuropeptide orexin. The orexin neuropeptide, produced in the lateral hypothalamus, are key regulators of physiological functions, including energy homeostasis, sleep/wake stabilization and cognition. A defective orexin system results in weight gain despite reduced food intake, and complete absence of orexin neurons results in the sleep disorder narcolepsy, which is also characterized by weight gain, despite reduced food intake. We and others have consistently demonstrated that orexin enhances physical activity and energy expenditure, and improves sleep/wake patterns. Despite this demonstration that the orexin system can be targeted for weight loss, it’s not feasible to peripherally administer the orexin peptide itself due to its lack of blood- brain barrier permeability. Therefore, to achieve obesity therapies based on orexin, the development and testing of small molecular weight orexin agonists is needed. The overarching hypothesis of this proposal is that small molecular weight agonists for orexin will prevent and reverse diet-induced obesity, through increasing energy expenditure and improving sleep/wake patterns. The goals are to systematically test the efficacy of two small molecule orexin agonists in preventing and reversing high-fat diet-induced obesity by enhancing energy expenditure and improving sleep/wake behavior. To this end, we will expose mice to high-fat diet and use indirect calorimetry in conjunction with wireless radio-telemetric sleep/wake behavioral analyses, to determine if activation of orexin receptors using peripheral novel small molecule orexin agonists prevents and/or reverses obesity, and improves behavioral sleep/wake patterns. The immediate goal is to generate sufficient preclinical data to support use of small molecular-weight orexin agonists to prevent adverse body weight outcomes associated with exposure to obesogenic environments. The long-term goal is to enable research and development of orexin agonists as therapies for obesity and associated comorbidities commonly observed in the Veteran population.