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

Publication date: 6 June 2017
Source:Cell Metabolism, Volume 25, Issue 6
Author(s): Sara Ramírez, Alicia G. Gómez-Valadés, Marc Schneeberger, Luis Varela, Roberta Haddad-Tóvolli, Jordi Altirriba, Eduard Noguera, Anne Drougard, Álvaro Flores-Martínez, Mónica Imbernón, Iñigo Chivite, Macarena Pozo, Andrés Vidal-Itriago, Ainhoa Garcia, Sara Cervantes, Rosa Gasa, Ruben Nogueiras, Pau Gama-Pérez, Pablo M. Garcia-Roves, David A. Cano, Claude Knauf, Joan-Marc Servitja, Tamas L. Horvath, Ramon Gomis, Antonio Zorzano, Marc Claret
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.

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Teaser

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.


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