Running wheel access and resulting voluntary exercise alter food intake and reduce body weight. The neural mechanisms underlying these effects are unclear. In this study, we first assessed the effects of 7 days of running wheel access on food intake, body weight and hypothalamic gene expression. We demonstrate that running wheel access significantly decreases food intake and body weight and results in a significant elevation of corticotropin-releasing factor (CRF) mRNA expression in the dorsomedial hypothalamus (DMH) but not the paraventricular nucleus. Seven day running wheel access also results in elevated arcuate nucleus and DMH NPY gene expression. To assess a potential role for elevated DMH CRF activity in the activity induced changes in food intake and body weight, we compared changes in food intake, body weight and hypothalamic gene expression in rats receiving intracerebroventricular (ICV) CRF antagonist -helical CRF or vehicle with or without access to running wheels. During a 4-day period of running wheel access, we found that exercise-induced reductions of food intake and body weight were significantly attenuated by ICV injection of the CRF antagonist. The effect on food intake was specific to a blockade of activity-induced changes in meal size. Central CRF antagonist injection further increased DMH CRF mRNA expression in exercised rats. Together, these data suggested that DMH CRF play a critical role in the anorexia resulting from increased voluntary exercise.