Mc4r-Expressing Neurons In The Pvh Regulate Glycemia Independent Of Insulin

Hypothalamic and extra-hypothalamic neuronal populations play important roles in the regulation of energy balance and glucose homeostasis. However, the underlying mechanisms of this control remain unclear. We have recently reported that inhibition of hypothalamic pro-opiomelanocortin (POMC) neuronal activity leads to a reduction in blood glucose levels of normoglycemic POMC-cre mice. This effect is independent of energy intake. Since hypothalamic POMC neurons project to the paraventricular nucleus of the hypothalamus (PVH) and regulate energy metabolism via melanocortin-4 receptor (MC4R), we hypothesized that changes in the activity of MC4R-expressing neurons in the PVH could alter glycemic levels. To address this, we stereotaxically injected designer receptors exclusively activated by designer drug (DREADD) viruses into the PVH of MC4R-cre mice to chemogenetically and selectively activate or inhibit these neurons. We continuously activated or inhibited these neurons by injecting clozapine-N-oxide (CNO) every 8 hours for 5 days and monitored daily blood glucose levels and energy intake. Interestingly, inhibition of MC4R-expressing neurons in the PVH leads to a significant reduction (∼ 30%) in blood glucose levels despite of increased food intake. On the other hand, blood glucose levels are significantly increased, but food intake is greatly decreased when MC4R-expressing neurons are activated. We further determined the peripheral insulin response via MC4R-expressing neurons in the PVH. We found that CNO-induced inhibition or activation of MC4R-expressing neurons did not affect serum insulin levels. These data suggest that MC4R-expressing neurons in the PVH can regulate blood glucose levels and food intake via divergent cellular mechanisms, which is independent of circulating insulin. Thus, the inhibition of MC4R-expressing neurons may be a promising target for novel antidiabetic medicines. Disclosure A.G. Uner: None. H. Lee: None. J. Han: None. R.M. Pereira: None. X. Sun: None. H. Kim: None. Y. Kim: None.