Universität zu Köln

Timper, Katharina, Paeger, Lars ORCID: 0000-0001-8716-3483, Sanchez-Lasheras, Carmen, Varela, Luis, Jais, Alexander ORCID: 0000-0002-9897-4983, Nolte, Hendrik, Vogt, Merly C., Hausen, A. Christine, Heilinger, Christian, Evers, Nadine, Pospisilik, J. Andrew, Penninger, Josef M., Taylor, Eric B., Horvath, Tamas L., Kloppenburg, Peter and Bruening, Jens Claus (2018). Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity. Cell Reports, 25 (2). S. 383 - 408. CAMBRIDGE: CELL PRESS. ISSN 2211-1247

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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 mitochondria! 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 AIF(Delta POMC) 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Timper, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Paeger, Lars UNSPECIFIED orcid.org/0000-0001-8716-3483 UNSPECIFIED Sanchez-Lasheras, Carmen UNSPECIFIED UNSPECIFIED UNSPECIFIED Varela, Luis UNSPECIFIED UNSPECIFIED UNSPECIFIED Jais, Alexander UNSPECIFIED orcid.org/0000-0002-9897-4983 UNSPECIFIED Nolte, Hendrik UNSPECIFIED UNSPECIFIED UNSPECIFIED Vogt, Merly C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hausen, A. Christine UNSPECIFIED UNSPECIFIED UNSPECIFIED Heilinger, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Evers, Nadine UNSPECIFIED UNSPECIFIED UNSPECIFIED Pospisilik, J. Andrew UNSPECIFIED UNSPECIFIED UNSPECIFIED Penninger, Josef M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Taylor, Eric B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Horvath, Tamas L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kloppenburg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruening, Jens Claus UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-169479
DOI:	10.1016/j.celrep.2018.09.034
Journal or Publication Title:	Cell Reports
Volume:	25
Number:	2
Page Range:	S. 383 - 408
Date:	2018
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	2211-1247
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language APOPTOSIS-INDUCING-FACTOR; ACTIVATED PROTEIN-KINASE; DIET-INDUCED OBESITY; PYRUVATE CARRIER; OXIDATIVE-PHOSPHORYLATION; INSULIN SENSITIVITY; WEIGHT HOMEOSTASIS; LEPTIN RESISTANCE; SKELETAL-MUSCLE; CELL FUNCTION Multiple languages Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16947