Endogenous cannabinoids are required for MC4R-mediated control of energy homeostasis
Yu Yong, Işın Çakır, Pauline Lining Pan, Jessica E. Biddinger, Rebecca J. Bluett, Ken Mackie, Nathan C. Bingham, Sachin Patel, Masoud Ghamari‐Langroudi
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.