Pierre Cardinal 1 , 2 , Caroline André 1 , 2 , Carmelo Quarta 3 , Luigi Bellocchio 1 , 2 , 4 , Samantha Clark 1 , 2 , Melissa Elie 1 , 2 , Thierry Leste-Lasserre 1 , 2 , Marlene Maitre 1 , 2 , Delphine Gonzales 1 , 2 , Astrid Cannich 1 , 2 , Uberto Pagotto 3 , Giovanni Marsicano 1 , 2 , Daniela Cota 1 , 2 , ∗
1 August 2014
CB1 receptor, Endocannabinoid, Ventromedial nucleus, Hypothalamus, Obesity, Leptin, CB1, cannabinoid type-1, FDG, fluorodeoxyglucose, FISH, fluorescent in situ hybridization, PET, positron emission tomography, SF1, steroidogenic factor 1, vGlut2, vesicular transporter of glutamate 2 receptor, VMN, ventromedial nucleus
Metabolic flexibility allows rapid adaptation to dietary change, however, little is known about the CNS mechanisms regulating this process. Neurons in the hypothalamic ventromedial nucleus (VMN) participate in energy balance and are the target of the metabolically relevant hormone leptin. Cannabinoid type-1 (CB 1) receptors are expressed in VMN neurons, but the specific contribution of endocannabinoid signaling in this neuronal population to energy balance regulation is unknown. Here we demonstrate that VMN CB 1 receptors regulate metabolic flexibility and actions of leptin. In chow-fed mice, conditional deletion of CB 1 in VMN neurons (expressing the steroidogenic factor 1, SF1) decreases adiposity by increasing sympathetic activity and lipolysis, and facilitates metabolic effects of leptin. Conversely, under high-fat diet, lack of CB 1 in VMN neurons produces leptin resistance, blunts peripheral use of lipid substrates and increases adiposity. Thus, CB 1 receptors in VMN neurons provide a molecular switch adapting the organism to dietary change.