title: Cannabinoid type 1 (CB1) receptors on Sim1-expressing neurons regulate energy expenditure in male mice.
abstract: The paraventricular nucleus of the hypothalamus (PVN) regulates energy balance by modulating not only food intake, but also energy expenditure (EE) and brown adipose tissue thermogenesis. To test the hypothesis that cannabinoid type 1 (CB1) receptor in PVN neurons might control these processes, we used the Cre/loxP system to delete CB1 from single-minded 1 (Sim1) neurons, which account for the majority of PVN neurons. On standard chow, mice lacking CB1 receptor in Sim1 neurons (Sim1-CB1-knockout [KO]) had food intake, body weight, adiposity, glucose metabolism, and EE comparable with wild-type (WT) (Sim1-CB1-WT) littermates. However, maintenance on a high-fat diet revealed a gene-by-diet interaction whereby Sim1-CB1-KO mice had decreased adiposity, improved insulin sensitivity, and increased EE, whereas feeding behavior was similar to Sim1-CB1-WT mice. Additionally, high-fat diet-fed Sim1-CB1-KO mice had increased mRNA expression of the β3-adrenergic receptor, as well as of uncoupling protein-1, cytochrome-c oxidase subunit IV and mitochondrial transcription factor A in the brown adipose tissue, all molecular changes suggestive of increased thermogenesis. Pharmacological studies using β-blockers suggested that modulation of β-adrenergic transmission play an important role in determining EE changes observed in Sim1-CB1-KO. Finally, chemical sympathectomy abolished the obesity-resistant phenotype of Sim1-CB1-KO mice. Altogether, these findings reveal a diet-dependent dissociation in the CB1 receptor control of food intake and EE, likely mediated by the PVN, where CB1 receptors on Sim1-positive neurons do not impact food intake but hinder EE during dietary environmental challenges that promote body weight gain.
authors.affiliation: Inserm (P.C., L.B., O.G.-Q., C.A., S.C., M.E., T.L.-L., D.G., A.C., G.M., D.C.) and Université de Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, unit 862, F-33000 Bordeaux, France; and Department of Biochemistry and Molecular Biology I and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) (L.B.), School of Biology, Complutense University-Instituto Universitario de Investigación Neuroquímica, 28040 Madrid, Spain.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cardinal
authors.forename: Luigi
authors.initials: L
authors.lastname: Bellocchio
authors.forename: Omar
authors.initials: O
authors.lastname: Guzmán-Quevedo
authors.forename: Caroline
authors.initials: C
authors.lastname: André
authors.forename: Samantha
authors.initials: S
authors.lastname: Clark
authors.forename: Melissa
authors.initials: M
authors.lastname: Elie
authors.forename: Thierry
authors.initials: T
authors.lastname: Leste-Lasserre
authors.forename: Delphine
authors.initials: D
authors.lastname: Gonzales
authors.forename: Astrid
authors.initials: A
authors.lastname: Cannich
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marsicano
authors.forename: Daniela
authors.initials: D
authors.lastname: Cota
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D004734:Energy Metabolism; D008297:Male; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D043884:Receptor, Cannabinoid, CB1; D012097:Repressor Proteins; C101750:Sim1 protein, mouse