Hypothalamic CB1 Cannabinoid Receptors Regulate Energy Balance in Mice

Cannabinoid type 1 (CB1) 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 CB1 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 CB1 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 CB1 receptor gene in the hypothalamus led to the generation of Hyp-CB1-KO mice, which displayed an approximately 60% decrease in hypothalamic CB1 receptor mRNA levels. Hyp-CB1-KO mice maintained on a normocaloric, standard diet showed decreased body weight gain over time, which was associated with increased energy expenditure and elevated beta(3)-adrenergic receptor and uncoupling protein-1 mRNA levels in the brown adipose tissue but, surprisingly, not to changes in food intake. Additionally, Hyp-CB1-KO mice were insensitive to the anorectic action of the hormone leptin (5 mg/kg) and displayed a time-dependent hypophagic response to the CB1 inverse agonist rimonabant (3 mg/kg). Altogether these findings suggest that hypothalamic CB1 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. (Endocrinology 153: 4136-4143, 2012)