DRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons

Anna Santoro; Michela Campolo; Chen Liu; Hiromi Sesaki; Rosaria Meli; Zhong Wu Liu; Jung Dae Kim; Sabrina Diano

doi:10.1016/j.cmet.2017.01.003

DRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons

Anna Santoro, Michela Campolo, Chen Liu, Hiromi Sesaki, Rosaria Meli, Zhong Wu Liu, Jung Dae Kim, Sabrina Diano

School of Medicine

Research output: Contribution to journal › Article › peer-review

46 Scopus citations

Abstract

Hypothalamic pro-opiomelanocortin (POMC) neurons regulate energy and glucose metabolism. Intracellular mechanisms that enable these neurons to respond to changes in metabolic environment are ill defined. Here we show reduced expression of activated dynamin-related protein (pDRP1), a mitochondrial fission regulator, in POMC neurons of fed mice. These POMC neurons displayed increased mitochondrial size and aspect ratio compared to POMC neurons of fasted animals. Inducible deletion of DRP1 of mature POMC neurons (Drp1^fl/fl-POMC-cre:ER^T2) resulted in improved leptin sensitivity and glucose responsiveness. In Drp1^fl/fl-POMC-cre:ER^T2 mice, POMC neurons showed increased mitochondrial size, ROS production, and neuronal activation with increased expression of Kcnj11 mRNA regulated by peroxisome proliferator-activated receptor (PPAR). Furthermore, deletion of DRP1 enhanced the glucoprivic stimulus in these neurons, causing their stronger inhibition and a greater activation of counter-regulatory responses to hypoglycemia that were PPAR dependent. Together, these data unmasked a role for mitochondrial fission in leptin sensitivity and glucose sensing of POMC neurons.

Original language	English (US)
Pages (from-to)	647-660
Number of pages	14
Journal	Cell Metabolism
Volume	25
Issue number	3
DOIs	https://doi.org/10.1016/j.cmet.2017.01.003
State	Published - Mar 7 2017

Keywords

Drp1
POMC neurons
counter-regulatory responses to hypoglycemia
glucose sensing
leptin
mitochondrial fission

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2017.01.003

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title = "DRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons",

abstract = "Hypothalamic pro-opiomelanocortin (POMC) neurons regulate energy and glucose metabolism. Intracellular mechanisms that enable these neurons to respond to changes in metabolic environment are ill defined. Here we show reduced expression of activated dynamin-related protein (pDRP1), a mitochondrial fission regulator, in POMC neurons of fed mice. These POMC neurons displayed increased mitochondrial size and aspect ratio compared to POMC neurons of fasted animals. Inducible deletion of DRP1 of mature POMC neurons (Drp1fl/fl-POMC-cre:ERT2) resulted in improved leptin sensitivity and glucose responsiveness. In Drp1fl/fl-POMC-cre:ERT2 mice, POMC neurons showed increased mitochondrial size, ROS production, and neuronal activation with increased expression of Kcnj11 mRNA regulated by peroxisome proliferator-activated receptor (PPAR). Furthermore, deletion of DRP1 enhanced the glucoprivic stimulus in these neurons, causing their stronger inhibition and a greater activation of counter-regulatory responses to hypoglycemia that were PPAR dependent. Together, these data unmasked a role for mitochondrial fission in leptin sensitivity and glucose sensing of POMC neurons.",

keywords = "Drp1, POMC neurons, counter-regulatory responses to hypoglycemia, glucose sensing, leptin, mitochondrial fission",

author = "Anna Santoro and Michela Campolo and Chen Liu and Hiromi Sesaki and Rosaria Meli and Liu, {Zhong Wu} and Kim, {Jung Dae} and Sabrina Diano",

note = "Funding Information: The authors thank Ashley Kristant, Arielle Landau, Xiao-Bing Gao, Chitoku Toda, Giuseppe Bruschetta, and Klara Szigeti-Buck for their technical assistance. A.S. and M.C. were partially supported by fellowships from the Italian Society of Pharmacology (SIF). This work was supported by the NIH R01 DK097566, DK105571, and DK107293 (to S.D.). Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

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day = "7",

doi = "10.1016/j.cmet.2017.01.003",

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AU - Santoro, Anna

AU - Campolo, Michela

AU - Liu, Chen

AU - Sesaki, Hiromi

AU - Meli, Rosaria

AU - Liu, Zhong Wu

AU - Kim, Jung Dae

AU - Diano, Sabrina

N1 - Funding Information: The authors thank Ashley Kristant, Arielle Landau, Xiao-Bing Gao, Chitoku Toda, Giuseppe Bruschetta, and Klara Szigeti-Buck for their technical assistance. A.S. and M.C. were partially supported by fellowships from the Italian Society of Pharmacology (SIF). This work was supported by the NIH R01 DK097566, DK105571, and DK107293 (to S.D.). Publisher Copyright: © 2017 Elsevier Inc.

PY - 2017/3/7

Y1 - 2017/3/7

N2 - Hypothalamic pro-opiomelanocortin (POMC) neurons regulate energy and glucose metabolism. Intracellular mechanisms that enable these neurons to respond to changes in metabolic environment are ill defined. Here we show reduced expression of activated dynamin-related protein (pDRP1), a mitochondrial fission regulator, in POMC neurons of fed mice. These POMC neurons displayed increased mitochondrial size and aspect ratio compared to POMC neurons of fasted animals. Inducible deletion of DRP1 of mature POMC neurons (Drp1fl/fl-POMC-cre:ERT2) resulted in improved leptin sensitivity and glucose responsiveness. In Drp1fl/fl-POMC-cre:ERT2 mice, POMC neurons showed increased mitochondrial size, ROS production, and neuronal activation with increased expression of Kcnj11 mRNA regulated by peroxisome proliferator-activated receptor (PPAR). Furthermore, deletion of DRP1 enhanced the glucoprivic stimulus in these neurons, causing their stronger inhibition and a greater activation of counter-regulatory responses to hypoglycemia that were PPAR dependent. Together, these data unmasked a role for mitochondrial fission in leptin sensitivity and glucose sensing of POMC neurons.

AB - Hypothalamic pro-opiomelanocortin (POMC) neurons regulate energy and glucose metabolism. Intracellular mechanisms that enable these neurons to respond to changes in metabolic environment are ill defined. Here we show reduced expression of activated dynamin-related protein (pDRP1), a mitochondrial fission regulator, in POMC neurons of fed mice. These POMC neurons displayed increased mitochondrial size and aspect ratio compared to POMC neurons of fasted animals. Inducible deletion of DRP1 of mature POMC neurons (Drp1fl/fl-POMC-cre:ERT2) resulted in improved leptin sensitivity and glucose responsiveness. In Drp1fl/fl-POMC-cre:ERT2 mice, POMC neurons showed increased mitochondrial size, ROS production, and neuronal activation with increased expression of Kcnj11 mRNA regulated by peroxisome proliferator-activated receptor (PPAR). Furthermore, deletion of DRP1 enhanced the glucoprivic stimulus in these neurons, causing their stronger inhibition and a greater activation of counter-regulatory responses to hypoglycemia that were PPAR dependent. Together, these data unmasked a role for mitochondrial fission in leptin sensitivity and glucose sensing of POMC neurons.

KW - Drp1

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KW - counter-regulatory responses to hypoglycemia

KW - glucose sensing

KW - leptin

KW - mitochondrial fission

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JO - Cell Metabolism

JF - Cell Metabolism

IS - 3

ER -

DRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons

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