Optogenetic stimulation of the liver-projecting melanocortinergic pathway promotes hepatic glucose production

Eunjin Kwon, Hye-Young Joung, Shun-Mei Liu, Streamson C. Chua, Gary J. Schwartz and Young-Hwan Jo ()
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Eunjin Kwon: Albert Einstein College of Medicine
Hye-Young Joung: Albert Einstein College of Medicine
Shun-Mei Liu: Albert Einstein College of Medicine
Streamson C. Chua: Albert Einstein College of Medicine
Gary J. Schwartz: Albert Einstein College of Medicine
Young-Hwan Jo: Albert Einstein College of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-20160-w

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