Exploring cannabinoid receptor CB1 autophagy and the obesity phenotype of p62-deficient mice.

The endocannabinoid system (ECS) and the autophagy receptor p62 are both implicated in metabolic regulation and obesity, yet the mechanisms linking these pathways remain unclear. Here, we investigated whether p62 modulates CB1 receptor (CB1R) turnover or function and whether CB1R contributes to the metabolic phenotype of p62 knockout (KO) mice. In primary cortical neurons from wild-type mice, inhibition of autophagic flux with Bafilomycin A1 led to substantial CB1R accumulation, demonstrating that CB1R is a subject to autophagy-dependent degradation. CB1R agonist stimulation partially reduced this accumulation, suggesting receptor activation influences turnover. In vivo, p62 deficiency did not significantly alter CB1R protein abundance in the brain or hypothalamus, although hypothalamic ERK1/2 signaling downstream of CB1R was modestly attenuated. P62 KO mice displayed late-onset obesity without hyperphagia, early hypoactivity, and elevated hypothalamic 2-arachidonoylglycerol (2-AG) levels with age. Fasting-refeeding experiments revealed reduced food intake in adult and aged, but not juvenile, p62 KO animals. Pharmacological CB1R antagonism did not uncover a direct receptor-dependent mechanism underlying these phenotypes. Together, these findings indicate that, although CB1R undergoes autophagic degradation in neurons, p62 deficiency does not alter steady-state receptor levels and does not directly account for obesity or hypoactivity in p62 KO mice. Within the scope of the experiments performed, CB1R is therefore unlikely to be a primary driver of the metabolic phenotype associated with p62 deficiency.