Mitochondrial Dynamics Mediated by Mitofusin 1 Is Required for POMC Neuron Glucose-Sensing and Insulin Release Control

Proopiomelanocortin (POMC) neurons are critical sensors of nutrient availability implicated in energy balance and glucose metabolism control. However, the precise mechanisms underlying nutrient sensing in POMC neurons remain incompletely understood. We show that mitochondrial dynamics mediated by Mitofusin 1 (MFN1) in POMC neurons couple nutrient sensing with systemic glucose metabolism. Mice lacking MFN1 in POMC neurons exhibited defective mitochondrial architecture remodeling and attenuated hypothalamic gene expression programs during the fast-to-fed transition. This loss of mitochondrial flexibility in POMC neurons bidirectionally altered glucose sensing, causing abnormal glucose homeostasis due to defective insulin secretion by pancreatic β cells. Fed mice lacking MFN1 in POMC neurons displayed enhanced hypothalamic mitochondrial oxygen flux and reactive oxygen species generation. Central delivery of antioxidants was able to normalize the phenotype. Collectively, our data posit MFN1-mediated mitochondrial dynamics in POMC neurons as an intrinsic nutrient-sensing mechanism and unveil an unrecognized link between this subset of neurons and insulin release. [Display omitted] •POMC neuron MFN1-dependent mitochondrial dynamics is required for metabolic shifts•Loss of MFN1 in POMC neurons alters central glucose sensing•Mfn1 deletion in POMC neurons causes defective pancreatic insulin release•Impaired insulin secretion is caused by enhanced central ROS production Ramírez et al. report that mitochondrial fusion protein MFN1 in POMC neurons is necessary for adequate mitochondrial dynamism in response to metabolic challenges, central glucose-sensing and pancreatic insulin release. The latter is mechanisticallyassociated with enhanced hypothalamic ROS production. These alterations confer susceptibility to diabetes in a pathophysiological context.