The hypothalamic orexin neuropeptide acutely promotes appetite, yet orexin deficiency in humans and mice is associated with obesity. Prolonged effects of increased orexin signaling upon energy homeostasis have not been fully characterized. Here, we examine the metabolic effects of orexin gain of function utilizing genetic and pharmacologic techniques in mice. Transgenic orexin overexpression confers resistance to high-fat diet-induced obesity and insulin insensitivity by promoting energy expenditure and reducing consumption. Genetic studies indicate that orexin receptor-2 (OX2R), rather than OX1R signaling, predominantly mediates this phenotype. Likewise, prolonged central administration of an OX2R-selective peptide agonist inhibits diet-induced obesity. While orexin overexpression enhances the anorectic-catabolic effects of central leptin administration, obese leptin-deficient mice are completely resistant to the metabolic effects of orexin overexpression or OX2R agonist infusion. We conclude that enhanced orexin-OX2R signaling confers resistance to diet-induced features of the metabolic syndrome through negative energy homeostasis and improved leptin sensitivity.