title: CB1 cannabinoid receptor in SF1-expressing neurons of the ventromedial hypothalamus determines metabolic responses to diet and leptin.
abstract: 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 (CB1) 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 CB1 receptors regulate metabolic flexibility and actions of leptin. In chow-fed mice, conditional deletion of CB1 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 CB1 in VMN neurons produces leptin resistance, blunts peripheral use of lipid substrates and increases adiposity. Thus, CB1 receptors in VMN neurons provide a molecular switch adapting the organism to dietary change.
authors.affiliation: INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France ; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cardinal
authors.affiliation: INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France ; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: André
authors.affiliation: Endocrinology Unit and Centro Unificato di Ricerca BioMedica Applicata, Dept. of Clinical Medicine, University of Bologna, I-40138 Bologna, Italy.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Quarta
authors.affiliation: INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France ; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France.
authors.forename: Luigi
authors.initials: L
authors.lastname: Bellocchio
authors.affiliation: INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France ; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France.
authors.forename: Samantha
authors.initials: S
authors.lastname: Clark
authors.affiliation: INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France ; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France.
authors.forename: Melissa
authors.initials: M
authors.lastname: Elie
authors.affiliation: INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France ; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Leste-Lasserre
authors.affiliation: INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France ; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France.
authors.forename: Marlene
authors.initials: M
authors.lastname: Maitre
authors.affiliation: INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France ; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Gonzales
authors.affiliation: INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France ; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France.
authors.forename: Astrid
authors.initials: A
authors.lastname: Cannich
authors.affiliation: Endocrinology Unit and Centro Unificato di Ricerca BioMedica Applicata, Dept. of Clinical Medicine, University of Bologna, I-40138 Bologna, Italy.
authors.forename: Uberto
authors.initials: U
authors.lastname: Pagotto
authors.affiliation: INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France ; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marsicano
authors.affiliation: INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France ; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cota
keywords: CB1 receptor; CB1, cannabinoid type-1; Endocannabinoid; FDG, fluorodeoxyglucose; FISH, fluorescent in situ hybridization; Hypothalamus; Leptin; Obesity; PET, positron emission tomography; SF1, steroidogenic factor 1; VMN, ventromedial nucleus; Ventromedial nucleus; vGlut2, vesicular transporter of glutamate 2 receptor