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

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.

Central 5-HTR2C in the Control of Metabolic Homeostasis

“…The improved glucose tolerance in mice by lorcaserin was found to be mediated by reducing the hepatic glucose production and improving glucose disposal, without change of insulin secretion ( 65 ) ( Table 1 and Figure 2 ). Interestingly, a recent study showed that a subset of POMC neurons may have the ability to promote hepatic glucose production, which was speculated to be relevant with the heterogeneity of POMC neurons ( 68 ). Given the complex functions of POMC neurons in the brain, the relationship between this subset of POMC neurons and POMC 5-HTR2C neurons remains to be further elucidated.…”

Suprachiasmatic nucleus-mediated glucose entry into the arcuate nucleus determines the daily rhythm in blood glycemia

“…8,46 Given our findings, both GE and GI should promote a decrease in glycemia. However, recent literature indicated that AgRP neuronal activation or inhibition is not associated with a change in peripheral glucose levels, 47,48 although it may change insulin sensitivity. 49,50 On the other hand, surprisingly, inhibiting and exciting POMC neurons is related to an increase in glucose, 47,48 indicating that POMC neurons are involved in adapting glycemia to the time of the day.…”

“…However, recent literature indicated that AgRP neuronal activation or inhibition is not associated with a change in peripheral glucose levels, 47,48 although it may change insulin sensitivity. 49,50 On the other hand, surprisingly, inhibiting and exciting POMC neurons is related to an increase in glucose, 47,48 indicating that POMC neurons are involved in adapting glycemia to the time of the day. Since there are many different POMC neuronal subpopulations, 51,52 these observations indicate that a specific neuronal POMC population needs to be considered for analyzing neuronal inhibition or excitation by glucose.…”

Arcuate Nucleus-Dependent Regulation of Metabolism—Pathways to Obesity and Diabetes Mellitus

“…In addition, POMC neurons are glucose-excited neurons and play a role in the physiological control of systemic glucose homeostasis as exemplified by chemogenetic inhibition of POMC neurons decreasing glucose levels in normoglycemic animals ( 68 ). However, a more recent study revealed that selective activation of liver-innervating POMC neurons increases glucose concentrations ( 69 ). Thus, the role of POMC neurons in control of glucose homeostasis appears to be more complex and deserves future detailed studies.…”