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 and brown adipose tissue (BAT) 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-KO) had food intake, body weight, adiposity, glucose metabolism and energy expenditure comparable to wild-type (Sim1-CB₁-WT) littermates. However, maintenance on a high-fat diet (HFD) revealed a gene-by-diet interaction whereby Sim1-CB₁-KO mice had decreased adiposity, improved insulin sensitivity and increased energy expenditure, while feeding behavior was similar to Sim1-CB₁-WT mice. Additionally, HFD-fed Sim1-CB₁-KO mice had increased mRNA expression of the ?3-adrenergic receptor, as well as of UCP-1, Cox-IV and Tfam in the BAT, all molecular changes suggestive of increased thermogenesis. Pharmacological studies using ?-blockers suggested that modulation of ?-adrenergic transmission play an important role in determining energy expenditure 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 energy expenditure, likely mediated by the PVN, where CB₁ receptors on Sim1-positive neurons do not impact food intake, but hinder energy expenditure during dietary environmental challenges that promote body weight gain.

Cardinal P, Bellocchio L, Guzmán-Quevedo O, André C, Clark S, Elie M, Leste-Lasserre T, Gonzales D, Cannich A, Marsicano G, Cota D.

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