The Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, Bronx, NY, USA.
Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
Nat Commun. 2020 Dec 8;11(1):6295. doi: 10.1038/s41467-020-20160-w.
The central melanocortin system plays a fundamental role in the control of feeding and body weight. Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC) also regulate overall glucose homeostasis via insulin-dependent and -independent pathways. Here, we report that a subset of ARC POMC neurons innervate the liver via preganglionic parasympathetic acetylcholine (ACh) neurons in the dorsal motor nucleus of the vagus (DMV). Optogenetic stimulation of this liver-projecting melanocortinergic pathway elevates blood glucose levels that is associated with increased expression of hepatic gluconeogenic enzymes in female and male mice. Pharmacological blockade and knockdown of the melanocortin-4 receptor gene in the DMV abolish this stimulation-induced effect. Activation of melanocortin-4 receptors inhibits DMV cholinergic neurons and optogenetic inhibition of liver-projecting parasympathetic cholinergic fibers increases blood glucose levels. This elevated blood glucose is not due to altered pancreatic hormone release. Interestingly, insulin-induced hypoglycemia increases ARC POMC neuron activity. Hence, this liver-projecting melanocortinergic circuit that we identified may play a critical role in the counterregulatory response to hypoglycemia.
中央黑色素皮质系统在控制摄食和体重方面起着至关重要的作用。下丘脑弓状核（ARC）中的前阿黑皮素原（POMC）神经元也通过胰岛素依赖和非依赖途径调节整体葡萄糖稳态。在这里，我们报告说，ARC 中的一部分 POMC 神经元通过迷走神经背核（DMV）中的节前副交感乙酰胆碱（ACh）神经元支配肝脏。该肝投射黑色素皮质能途径的光遗传学刺激会升高血糖水平，这与雌性和雄性小鼠中肝糖异生酶的表达增加有关。DMV 中黑色素皮质素-4 受体基因的药理学阻断和敲低可消除这种刺激诱导的作用。激活黑色素皮质素-4 受体可抑制 DMV 胆碱能神经元，而光遗传学抑制肝投射副交感胆碱能纤维会增加血糖水平。这种升高的血糖不是由于胰腺激素释放的改变。有趣的是，胰岛素诱导的低血糖会增加 ARC POMC 神经元的活性。因此，我们所鉴定的这个肝投射黑色素皮质能回路可能在低血糖的拮抗反应中起关键作用。
