Orexin Signaling and the Prevention of Diet-Induced Obesity

The hypothalamic neuropeptide orexin acutely promotes appetite, yet orexin deficiency in humans and mice is associated with obesity. Prolonged effects of orexin signaling upon energy homeostasis have not been fully characterized. In this study, I utilized both genetic and pharmacologic approaches to characterize metabolic effects of orexin gain of function. CAG/orexin transgenic mice confer resistance to high-fat diet-induced obesity and insulin insensitivity by promoting energy expenditure and reducing food consumption. Genetic studies indicated that orexin receptor-2 (OX2R), rather than orexin receptor-1 (OX1R) signaling, predominantly mediates this phenotype. Likewise, prolonged central infusion of an OX2R selective peptide agonist prevents diet-induced obesity. While orexin overexpression enhances the anorectic-catabolic effects of central leptin administration, obese leptin-deficient mice (ob/ob) are completely resistant to the metabolic effects of orexin overexpression or OX2R selective agonist administration. I conclude that enhanced orexin-OX2R signaling confers resistance to diet-induced features of the metabolic syndrome through promoting a negative energy homeostasis and improving leptin sensitivity.