Endogenous cannabinoids are required for MC4R-mediated control of energy homeostasis

Abstract

Significance Cannabis is well known to regulate food intake, and cannabinoids increase the value of caloric and non-caloric rewards, while also regulating homeostatic feeding. Here, we show that tonic endogenous cannabinoid signaling regulates the melanocortin 4 receptor (MC4R) expressing paraventricular hypothalamic neurons through modulation of their presynaptic inhibitory inputs in an energy state–dependent manner. Specifically, this tonic 2-AG signal is maximal during fasting and collapses in satiation. Impairing 2-AG synthetic capacity from MC4R neurons reduces body weight and confers resistance to diet-induced obesity via increased energy expenditure and reduced food intake. This mode of regulation of MC4R neurons could offer a new therapeutic avenue to modulate food intake and energy metabolism.