FGF19 in the Hindbrain Lowers Blood Glucose and Alters Excitability of Vagal Motor Neurons in Hyperglycemic Mice

Abstract

Abstract Fibroblast growth factor 19 (FGF19) is a protein hormone that produces antidiabetic effects when administered intracerebroventricularly in the forebrain. However, no studies have examined how FGF19 affects hindbrain neurons that participate directly in autonomic control of systemic glucose regulation. Within the dorsal hindbrain, parasympathetic motor neurons of the dorsal motor nucleus of the vagus (DMV) express fibroblast growth factor receptors and their activity regulates visceral homeostatic processes, including energy balance. This study tested the hypothesis that FGF19 acts in the hindbrain to alter DMV neuron excitability and lower blood glucose concentration. Fourth ventricle administration of FGF19 produced no effect on blood glucose concentration in control mice, but induced a significant, peripheral muscarinic receptor-dependent decrease in systemic hyperglycemia for up to 12 h in streptozotocin-treated mice, a model of type 1 diabetes. Patch-clamp recordings from DMV neurons in vitro revealed that FGF19 application altered synaptic and intrinsic membrane properties of DMV neurons, with the balance of FGF19 effects being significantly modified by a recent history of systemic hyperglycemia. These findings identify central parasympathetic circuitry as a novel target for FGF19 and suggest that FGF19 acting in the dorsal hindbrain can alter vagal output to produce its beneficial metabolic effects.