Hypothalamic CB1 cannabinoid receptors regulate energy balance in mice.
Cannabinoid type 1 (CB(1)) receptor activation is generally considered a powerful orexigenic signal and inhibition of the endocannabinoid system is beneficial for the treatment of obesity and related metabolic diseases. The hypothalamus plays a critical role in regulating energy balance by modulating both food intake and energy expenditure. Although CB(1) receptor signaling has been implicated in the modulation of both these mechanisms, a complete understanding of its role in the hypothalamus is still lacking. Here we combined a genetic approach with the use of adeno-associated viral vectors to delete the CB(1) receptor gene in the adult mouse hypothalamus and assessed the impact of such manipulation on the regulation of energy balance. Viral-mediated deletion of the CB(1) receptor gene in the hypothalamus led to the generation of Hyp-CB(1)-KO mice, which displayed an approximately 60% decrease in hypothalamic CB(1) receptor mRNA levels. Hyp-CB(1)-KO mice maintained on a normocaloric, standard diet showed decreased body weight gain over time, which was associated with increased energy expenditure and elevated β(3)-adrenergic receptor and uncoupling protein-1 mRNA levels in the brown adipose tissue but, surprisingly, not to changes in food intake. Additionally, Hyp-CB(1)-KO mice were insensitive to the anorectic action of the hormone leptin (5 mg/kg) and displayed a time-dependent hypophagic response to the CB(1) inverse agonist rimonabant (3 mg/kg). Altogether these findings suggest that hypothalamic CB(1) receptor signaling is a key determinant of energy expenditure under basal conditions and reveal its specific role in conveying the effects of leptin and pharmacological CB1 receptor antagonism on food intake.
Group Energy Balance and Obesity, Institut National de la Santé et de la Recherche Médicale, Unité 862, Neurocentre Magendie, 146 Rue Léo Saignat, F-33077 Bordeaux, France.
Pierre
P
Cardinal
Luigi
L
Bellocchio
Samantha
S
Clark
Astrid
A
Cannich
Matthias
M
Klugmann
Beat
B
Lutz
Giovanni
G
Marsicano
Daniela
D
Cota
D000818:Animals; D002153:Calorimetry, Indirect; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology*; D005822:Genetic Vectors / Q000235:genetics; D007031:Hypothalamus / Q000378:metabolism*; D017404:In Situ Hybridization, Fluorescence; D020738:Leptin / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D000077285:Rimonabant
D020738:Leptin; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant