Cannabinoid type 1 (CB1) receptors on Sim1-expressing neurons regulate energy expenditure in male mice.
Endocrinology. 2015-02-01; 156(2): 411-418
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1. Endocrinology. 2015 Feb;156(2):411-8. doi: 10.1210/en.2014-1437. Epub 2014 Dec 2.
Cannabinoid type 1 (CB1) receptors on Sim1-expressing neurons regulate energy
expenditure in male mice.
Cardinal P(1), Bellocchio L, Guzmán-Quevedo O, André C, Clark S, Elie M,
Leste-Lasserre T, Gonzales D, Cannich A, Marsicano G, Cota D.
(1)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.
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.
PMID: 25456065 [Indexed for MEDLINE]