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

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Ramirez, Sara ; Gomez-Valades, Alicia G. ; Schneeberger, Marc ; Varela, Luis ; Haddad-Tovolli, Roberta ; Altirriba, Jordi ; Noguera, Eduard ; Drougard, Anne ; Flores-Martinez, Alvaro ; Imbernon, Monica ; Chivite, Inigo ; Pozo, Macarena ; Vidal-Itriago, Andres ; Garcia, Ainhoa ; Cervantes, Sara ; Gasa, Rosa ; Nogueiras, Ruben ; Gama-Perez, Pau ; Garcia-Roves, Pablo M. ; Cano, David A. ; Knauf, Claude ; Servitja, Joan-Marc ; Horvath, Tamas L. ; Gomis, Ramon ; Zorzano, Antonio ; Claret, Marc

• Tipo de documento: Artigo Científico
• Fonte: Cell Metabolism; v. 25, n. 6, p. 1390+, JUN 6 2017.
• Citações Web of Science: 27

Resumo

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 beta 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. (AU)

• Processo FAPESP: 16/01868-2 - Análise transducional de neurônios POMC e análise epigenética de alterações na barreira hematoencefálica na região da eminência média hipotalâmica em camundongos filhos de mães obesas
• Beneficiário: Roberta Haddad Tóvolli
• Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado