Mitochondrial dynamics mediated by Mitofusin 1 is required for POMC neuron glucose-sensing and insulin release control

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. CanoClaude Knauf, Joan Marc Servitja, Tamas L. Horvath, Ramon Gomis, Antonio Zorzano*, Marc Claret

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

61 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1390-1399.e6
Number of pages16
JournalCell Metabolism
Volume25
Issue number6
DOIs
Publication statusPublished - 6 Jun 2017
Externally publishedYes

Keywords

  • diabetes
  • hypothalamus
  • MFN1
  • mitochondria
  • OPA1
  • POMC neurons
  • ROS

Fingerprint

Dive into the research topics of 'Mitochondrial dynamics mediated by Mitofusin 1 is required for POMC neuron glucose-sensing and insulin release control'. Together they form a unique fingerprint.

Cite this