Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville TN 37232.
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.
Proc Natl Acad Sci U S A. 2021 Oct 19;118(42). doi: 10.1073/pnas.2015990118.
Hypothalamic regulation of feeding and energy expenditure is a fundamental and evolutionarily conserved neurophysiological process critical for survival. Dysregulation of these processes, due to environmental or genetic causes, can lead to a variety of pathological conditions ranging from obesity to anorexia. Melanocortins and endogenous cannabinoids (eCBs) have been implicated in the regulation of feeding and energy homeostasis; however, the interaction between these signaling systems is poorly understood. Here, we show that the eCB 2-arachidonoylglycerol (2-AG) regulates the activity of melanocortin 4 receptor (MC4R) cells in the paraventricular nucleus of the hypothalamus (PVN) via inhibition of afferent GABAergic drive. Furthermore, the tonicity of eCBs signaling is inversely proportional to energy state, and mice with impaired 2-AG synthesis within MC4R neurons weigh less, are hypophagic, exhibit increased energy expenditure, and are resistant to diet-induced obesity. These mice also exhibit MC4R agonist insensitivity, suggesting that the energy state-dependent, 2-AG-mediated suppression of GABA input modulates PVN neuron activity to effectively respond to the MC4R natural ligands to regulate energy homeostasis. Furthermore, post-developmental disruption of PVN 2-AG synthesis results in hypophagia and death. These findings illustrate a functional interaction at the cellular level between two fundamental regulators of energy homeostasis, the melanocortin and eCB signaling pathways in the hypothalamic feeding circuitry.
下丘脑对摄食和能量消耗的调节是一种基本的、进化上保守的神经生理过程，对生存至关重要。由于环境或遗传原因，这些过程的失调会导致从肥胖到厌食等各种病理状况。黑皮质素和内源性大麻素（eCBs）被认为参与了摄食和能量稳态的调节；然而，这些信号系统之间的相互作用还知之甚少。在这里，我们表明，内源性大麻素 2-花生四烯酸甘油（2-AG）通过抑制传入 GABA 能驱动来调节下丘脑室旁核（PVN）中黑皮质素 4 受体（MC4R）细胞的活性。此外，eCB 信号的紧张度与能量状态成反比，并且在 MC4R 神经元中合成 2-AG 受损的小鼠体重减轻、摄食量减少、能量消耗增加且对饮食诱导的肥胖具有抗性。这些小鼠还表现出 MC4R 激动剂不敏感，表明能量状态依赖性、2-AG 介导的 GABA 输入抑制调节 PVN 神经元活性，以有效响应 MC4R 天然配体来调节能量稳态。此外，PVN 2-AG 合成的发育后破坏会导致摄食减少和死亡。这些发现说明了能量平衡的两个基本调节剂——下丘脑摄食回路中的黑皮质素和 eCB 信号通路——在细胞水平上的功能相互作用。
