Hypothalamic CB1 cannabinoid receptors regulate energy balance in mice.
Endocrinology. 2012-09-01; 153(9): 4136-4143
DOI: 10.1210/en.2012-1405
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1. Endocrinology. 2012 Sep;153(9):4136-43. doi: 10.1210/en.2012-1405. Epub 2012 Jul
9.
Hypothalamic CB1 cannabinoid receptors regulate energy balance in mice.
Cardinal P(1), Bellocchio L, Clark S, Cannich A, Klugmann M, Lutz B, Marsicano G,
Cota D.
Author information:
(1)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.
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.
DOI: 10.1210/en.2012-1405
PMID: 22778221 [Indexed for MEDLINE]