Vagus nerve stimulation (VNS) has been observed to induce a moderate loss of body weight in some individuals. The mechanism by which this particular effect is induced remains as yet unclear, although previous reports, showing that VNS increases the expression of brain-derived neurotrophic factor (BDNF) in the brain of rats, can support the hypothesis of a direct role played by VNS in modulating weight loss. The present study investigates the possible effects of VNS on food intake, body weight, and adipose tissue metabolism in rats. Chronic treatment with VNS in rats, affected food intake and feed efficiency, induced a decrease in body weight and in the amount of perirenal adipose tissue (by ~20 and ~45%, respectively) when compared with sham-operated animals. Moreover, VNS treatment also increased the levels of nonesterified fatty acids (NEFAs) in plasma and visceral adipose tissue by ~50 and 80%, respectively, without affecting the NEFA content of the liver. In addition, VNS treatment decreased endocannabinoids in visceral adipose tissue but not in hypothalamus. These results suggest that body fat reduction following VNS treatment in rats may result from a decreased food intake and increased energy expenditure, a combined imbalance which can be mediated at least in part by a concerted action of a down-regulated endocannabinoid tone in visceral adipose tissue and an increased expression of BDNF in the brain.