CB1 cannabinoid receptor in SF1-expressing neurons of the ventromedial hypothalamus determines metabolic responses to diet and leptin

Pierre Cardinal; Caroline André; Carmelo Quarta; Luigi Bellocchio; Samantha Clark; Melissa Elie; Thierry Leste-Lasserre; Marlene Maitre; Delphine Gonzales; Astrid Cannich; Uberto Pagotto; Giovanni Marsicano; Daniela Cota

doi:10.1016/j.molmet.2014.07.004

CB1 cannabinoid receptor in SF1-expressing neurons of the ventromedial hypothalamus determines metabolic responses to diet and leptin

Mol Metab. 2014 Aug 1;3(7):705-16. doi: 10.1016/j.molmet.2014.07.004. eCollection 2014 Oct.

Affiliations

¹ 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.
² Endocrinology Unit and Centro Unificato di Ricerca BioMedica Applicata, Dept. of Clinical Medicine, University of Bologna, I-40138 Bologna, Italy.

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.

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.