The endocannabinoid system plays a critical role in the control of energy homeostasis, but the identity and localization of the endocannabinoid signal involved remain unknown. In the present study, we developed transgenic mice that overexpress in forebrain neurons the presynaptic hydrolase, monoacylglycerol lipase (MGL), which deactivates the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). MGL-overexpressing mice show a 50% decrease in forebrain 2-AG levels but no overt compensation in other endocannabinoid components. This biochemical abnormality is accompanied by a series of metabolic changes that include leanness, elevated energy cost of activity, and hypersensitivity to β(3)-adrenergic-stimulated thermogenesis, which is corrected by reinstating 2-AG activity at CB(1)-cannabinoid receptors. Additionally, the mutant mice are resistant to diet-induced obesity and express high levels of thermogenic proteins, such as uncoupling protein 1, in their brown adipose tissue. The results suggest that 2-AG signaling through CB(1) regulates the activity of forebrain neural circuits involved in the control of energy dissipation.