Hepatic glycogenolysis and hypometabolism induced by chemogenetic stimulation of C1 neurons.

Abstract

The precise regulation of blood glucose levels is indispensable for maintaining physiological functions. C1 neurons determine the outflow of the autonomic nervous and endocrine systems to maintain blood glucose levels in the body. In contrast, activation of C1 neurons induces a decrease in activity, suggesting that hypoactivity also participates in maintaining blood glucose levels. To examine this, we evaluated both glycogenolysis and hypometabolism induced by the selective activation of C1 neurons. We used DbhCre/0 mice expressing receptors for chemogenetic tools in C1 neurons, owing to microinjection of the viral vector. C1 neurons were activated by intraperitoneal injection of clozapine N-oxide (CNO). The chemogenetic activation of C1 neurons significantly decreased body temperature, oxygen consumption, and carbon dioxide production. On the other hand, the blood glucose level was increased by the activation of C1 neurons 2 h after CNO administration, even in the fasting state. In this situation, an increase in glucagon and corticosterone levels was observed, while hepatic glycogen content decreased significantly. Plasma insulin level was not changed by the activation of C1 neurons despite the blood glucose level increased. Furthermore, adrenal sympathetic nerve activity was significantly increased by the activation of C1 neurons, and plasma catecholamine levels increased significantly. In conclusion, the selective activation of C1 neurons using chemogenetic tools induced an increase in blood glucose level, probably because of hepatic glycogenolysis and hypometabolism. KEY POINTS: Chemogenetic activation of C1 neurons in medulla oblongata decreased body temperature. Oxygen consumption and carbon dioxide production were decreased by chemogenetic activation of C1 neurons in medulla oblongata. Blood glucose level was increased by chemogenetic activation of C1 neurons in medulla oblongata. Chemogenetic activation of C1 neurons in medulla oblongata increased glucagon, corticosterone, and catecholamine levels in plasma. Increase in blood glucose level by activation of C1 neurons occurred due to combined effect of hepatic glycogenolysis and hypometabolism. Abstract figure legend We investigated the effects of selectively activating C1 neurons using chemogenetic tools on blood glucose levels. The activation of C1 neurons resulted in an increase in blood glucose levels. This increase is due to the activation of hepatic glycogenolysis through the release of humoral factors, including adrenaline, glucagon, and corticosterone. Additionally, the decrease in energy expenditure, as evidenced by a reduction in body temperature, oxygen consumption, and carbon dioxide production, suggests that activation of C1 neurons may induce hypometabolism, which could also contribute to an increase in blood glucose levels. These responses indicate that C1 neurons may serve as a switch for energy conservation to maintain blood glucose levels, presumably by being activated in a stressful situation. This article is protected by copyright. All rights reserved.