Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity

Katharina Timper; Lars Paeger; Carmen Sánchez-Lasheras; Luis Varela; Alexander Jais; Hendrik Nolte; Merly C. Vogt; A. Christine Hausen; Christian Heilinger; Nadine Evers; J. Andrew Pospisilik; Josef M. Penninger; Eric B. Taylor; Tamas L. Horvath; Peter Kloppenburg; Jens Claus Brüning

doi:10.1016/j.celrep.2018.09.034

Back

Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity

Journal article

Open access

Peer reviewed

Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity

Katharina Timper, Lars Paeger, Carmen Sánchez-Lasheras, Luis Varela, Alexander Jais, Hendrik Nolte, Merly C. Vogt, A. Christine Hausen, Christian Heilinger, Nadine Evers, …

Cell reports (Cambridge), Vol.25(2), pp.383-397.e10

10/09/2018

DOI: 10.1016/j.celrep.2018.09.034

PMCID: PMC6349418

PMID: 30304679

Files and links (1)

url

https://doi.org/10.1016/j.celrep.2018.09.034View

Published (Version of record) Open Access

Abstract

Mitochondrial oxidative phosphorylation (OXPHOS) and substrate utilization critically regulate the function of hypothalamic proopiomelanocortin (POMC)-expressing neurons. Here, we demonstrate that inactivation of apoptosis-inducing factor (AIF) in POMC neurons mildly impairs mitochondrial respiration and decreases firing of POMC neurons in lean mice. In contrast, under diet-induced obese conditions, POMC-Cre-specific inactivation of AIF prevents obesity-induced silencing of POMC neurons, translating into improved glucose metabolism, improved leptin, and insulin sensitivity, as well as increased energy expenditure in AIFΔPOMC mice. On a cellular level, AIF deficiency improves mitochondrial morphology, facilitates the utilization of fatty acids for mitochondrial respiration, and increases reactive oxygen species (ROS) formation in POMC neurons from obese mice, ultimately leading to restored POMC firing upon HFD feeding. Collectively, partial impairment of mitochondrial function shifts substrate utilization of POMC neurons from glucose to fatty acid metabolism and restores their firing properties, resulting in improved systemic glucose and energy metabolism in obesity. [Display omitted] •AIF deletion in POMC neurons enhances fatty acid oxidation and ROS formation•POMC-specific inactivation of AIF prevents obesity-induced POMC neuron silencing•POMC-specific AIF deletion improves leptin sensitivity and glucose metabolism in obesity•POMC-specific MPC1 deletion improves glucose metabolism in obesity Timper et al. show that mild impairment of mitochondrial OXPHOS upon deletion of AIF or MPC1 in hypothalamic POMC-expressing neurons increases their fatty acid utilization and ROS formation, prevents obesity-induced silencing of these neurons, and improves systemic glucose metabolism in obesity.

AIF

apoptosis-inducing factor

fatty acid

hypothalamic POMC-neurons

mitochondrial

mitochondrial oxidative phosphorylation

MPC-1

obesity

oxidation

pyruvate carrier-1

reactive oxygen species

ROS

Details

Title: Subtitle: Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity
Creators: Katharina Timper - Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
Lars Paeger - Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
Carmen Sánchez-Lasheras - Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
Luis Varela - Fraternal Order of Eagles
Alexander Jais - Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
Hendrik Nolte - Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
Merly C. Vogt - Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
A. Christine Hausen - Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
Christian Heilinger - Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
Nadine Evers - Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
J. Andrew Pospisilik - Max Planck Institute of Immunobiology and Epigenetics
Josef M. Penninger - Austrian Academy of Sciences
Eric B. Taylor - University of Iowa
Tamas L. Horvath - Department of Anatomy and Histology, University of Veterinary Medicine, Budapest, Hungary
Peter Kloppenburg - Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
Jens Claus Brüning - Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
Resource Type: Journal article
Publication Details: Cell reports (Cambridge), Vol.25(2), pp.383-397.e10
Publisher: Elsevier Inc
DOI: 10.1016/j.celrep.2018.09.034
PMID: 30304679
PMCID: PMC6349418
ISSN: 2211-1247
eISSN: 2211-1247
Grant note: DOI: 10.13039/501100001659, name: DFG; name: German Federal and State Governments, award: SFB 1218 TP A08; DOI: 10.13039/501100001711, name: Swiss National Science Foundation; name: University of Basel, Switzerland; DOI: 10.13039/100000002, name: NIH, award: R01-DK-104998; DOI: 10.13039/100000002, name: NIH, award: R01-DK-111178, SFB 1218 TP B07, TR SFB 134 TP A03
Language: English
Date published: 10/09/2018
Academic Unit: Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9984297606402771

Metrics

6 Record Views

29 Times Cited - Web of Science

See more details