Objective: Humans and rodents show large variability in their individual sensitivity to diet-induced obesity (DIO), which has been associated with differences in intrinsic spontaneous physical activity (SPA). Evidence from genetic and out-bred rat obesity models shows that higher activity of the orexin peptides results in higher intrinsic SPA and protection against DIO. Based on this, we hypothesized that naturally occurring variation in SPA and orexin signaling is sufficient to drive differences in sensitivity to DIO. Design and Methods: Orexin expression, behavioral responses to orexin-A, basal energy expenditure and sensitivity to DIO were measured in in non-manipulated male Sprague-Dawley rats selected for high and low intrinsic SPA. Results: Male Sprague-Dawley rats were classified as high-activity or low-activity based on differences in intrinsic SPA. High-activity rats showed higher expression of prepro-orexin mRNA, higher sensitivity to behavioral effects of orexin injection, higher basal energy expenditure and were more resistant to obesity caused by high-fat diet consumption than low-activity rats. Conclusion: Our results define a new model of differential DIO sensitivity, the high-activity and lowactivity rats, and suggest that naturally occurring variations in intrinsic SPA cause differences in energy expenditure that are mediated by orexin signaling and alter DIO sensitivity.