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.

中文翻译：

---

MC4R 介导的能量稳态控制需要内源性大麻素

意义 众所周知，大麻可以调节食物摄入量，而大麻素会增加热量和非热量奖励的价值，同时还能调节稳态喂养。在这里，我们表明补品内源性大麻素信号通过以能量状态依赖的方式调节其突触前抑制输入来调节表达脑室旁下丘脑神经元的黑皮质素 4 受体 (MC4R)。具体来说，这种强直 2-AG 信号在禁食期间最大，在饱食时崩溃。削弱 MC4R 神经元的 2-AG 合成能力可减轻体重，并通过增加能量消耗和减少食物摄入来抵抗饮食诱导的肥胖。这种 MC4R 神经元的调节模式可以为调节食物摄入和能量代谢提供新的治疗途径。