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. Cano; Claude Knauf; Joan Marc Servitja; Tamas L. Horvath; Ramon Gomis; Antonio Zorzano; Marc Claret

doi:10.1016/j.cmet.2017.05.010

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 journal › Article › peer-review

103 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 language	English
Pages (from-to)	1390-1399.e6
Number of pages	16
Journal	Cell Metabolism
Volume	25
Issue number	6
DOIs	https://doi.org/10.1016/j.cmet.2017.05.010
Publication status	Published - 6 Jun 2017
Externally published	Yes

Keywords

diabetes
hypothalamus
MFN1
mitochondria
OPA1
POMC neurons
ROS

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10.1016/j.cmet.2017.05.010

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Ramírez, S., Gómez-Valadés, A. G., Schneeberger, M., Varela, L., Haddad-Tóvolli, R., Altirriba, J., Noguera, E., Drougard, A., Flores-Martínez, Á., Imbernón, M., Chivite, I., Pozo, M., Vidal-Itriago, A., Garcia, A., Cervantes, S., Gasa, R., Nogueiras, R., Gama-Pérez, P., Garcia-Roves, P. M., ... Claret, M. (2017). Mitochondrial dynamics mediated by Mitofusin 1 is required for POMC neuron glucose-sensing and insulin release control. Cell Metabolism, 25(6), 1390-1399.e6. https://doi.org/10.1016/j.cmet.2017.05.010

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

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.",

keywords = "diabetes, hypothalamus, MFN1, mitochondria, OPA1, POMC neurons, ROS",

author = "Sara Ram{\'i}rez and G{\'o}mez-Valad{\'e}s, {Alicia G.} and Marc Schneeberger and Luis Varela and Roberta Haddad-T{\'o}volli and Jordi Altirriba and Eduard Noguera and Anne Drougard and {\'A}lvaro Flores-Mart{\'i}nez and M{\'o}nica Imbern{\'o}n and I{\~n}igo Chivite and Macarena Pozo and Andr{\'e}s Vidal-Itriago and Ainhoa Garcia and Sara Cervantes and Rosa Gasa and Ruben Nogueiras and Pau Gama-P{\'e}rez and Garcia-Roves, {Pablo M.} and Cano, {David A.} and Claude Knauf and Servitja, {Joan Marc} and Horvath, {Tamas L.} and Ramon Gomis and Antonio Zorzano and Marc Claret",

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month = jun,

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Ramírez, S, Gómez-Valadés, AG, Schneeberger, M, Varela, L, Haddad-Tóvolli, R, Altirriba, J, Noguera, E, Drougard, A, Flores-Martínez, Á, Imbernón, M, Chivite, I, Pozo, M, Vidal-Itriago, A, Garcia, A, Cervantes, S, Gasa, R, Nogueiras, R, Gama-Pérez, P, Garcia-Roves, PM, Cano, DA, Knauf, C, Servitja, JM, Horvath, TL, Gomis, R, Zorzano, A & Claret, M 2017, 'Mitochondrial dynamics mediated by Mitofusin 1 is required for POMC neuron glucose-sensing and insulin release control', Cell Metabolism, vol. 25, no. 6, pp. 1390-1399.e6. https://doi.org/10.1016/j.cmet.2017.05.010

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T1 - Mitochondrial dynamics mediated by Mitofusin 1 is required for POMC neuron glucose-sensing and insulin release control

AU - Ramírez, Sara

AU - Gómez-Valadés, Alicia G.

AU - Schneeberger, Marc

AU - Varela, Luis

AU - Haddad-Tóvolli, Roberta

AU - Altirriba, Jordi

AU - Noguera, Eduard

AU - Drougard, Anne

AU - Flores-Martínez, Álvaro

AU - Imbernón, Mónica

AU - Chivite, Iñigo

AU - Pozo, Macarena

AU - Vidal-Itriago, Andrés

AU - Garcia, Ainhoa

AU - Cervantes, Sara

AU - Gasa, Rosa

AU - Nogueiras, Ruben

AU - Gama-Pérez, Pau

AU - Garcia-Roves, Pablo M.

AU - Cano, David A.

AU - Knauf, Claude

AU - Servitja, Joan Marc

AU - Horvath, Tamas L.

AU - Gomis, Ramon

AU - Zorzano, Antonio

AU - Claret, Marc

PY - 2017/6/6

Y1 - 2017/6/6

N2 - 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.

AB - 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.

KW - diabetes

KW - hypothalamus

KW - MFN1

KW - mitochondria

KW - OPA1

KW - POMC neurons

KW - ROS

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DO - 10.1016/j.cmet.2017.05.010

M3 - Article

C2 - 28591639

AN - SCOPUS:85020183352

SN - 1550-4131

VL - 25

SP - 1390-1399.e6

JO - Cell Metabolism

JF - Cell Metabolism

IS - 6

ER -

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

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