PMID- 30528280 OWN - NLM STAT- MEDLINE DCOM- 20191125 LR - 20231213 IS - 2212-8778 (Electronic) IS - 2212-8778 (Linking) VI - 20 DP - 2019 Feb TI - Preadipocytes of obese humans display gender-specific bioenergetic responses to glucose and insulin. PG - 28-37 LID - S2212-8778(18)31046-9 [pii] LID - 10.1016/j.molmet.2018.11.006 [doi] AB - BACKGROUND/OBJECTIVES: Although the prevalence of obesity and its associated metabolic disorders is increasing in both sexes, the clinical phenotype differs between men and women, highlighting the need for individual treatment options. Mitochondrial dysfunction in various tissues, including white adipose tissue (WAT), has been accepted as a key factor for obesity-associated comorbidities such as diabetes. Given higher expression of mitochondria-related genes in the WAT of women, we hypothesized that gender differences in the bioenergetic profile of white (pre-) adipocytes from obese (age- and BMI-matched) donors must exist. SUBJECTS/METHODS: Using Seahorse technology, we measured oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) of (pre-)adipocytes from male (n = 10) and female (n = 10) deeply-phenotyped obese donors under hypo-, normo- and hyperglycemic (0, 5 and 25 mM glucose) and insulin-stimulated conditions. Additionally, expression levels (mRNA/protein) of mitochondria-related genes (e.g. UQCRC2) and glycolytic enzymes (e.g. PKM2) were determined. RESULTS: Dissecting cellular OCR and ECAR into different functional modules revealed that preadipocytes from female donors show significantly higher mitochondrial to glycolytic activity (higher OCR/ECAR ratio, p = 0.036), which is supported by a higher ratio of UQCRC2 to PKM2 mRNA levels (p = 0.021). However, no major gender differences are detectable in in vitro differentiated adipocytes (e.g. OCR/ECAR, p = 0.248). Importantly, glucose and insulin suppress mitochondrial activity (i.e. ATP-linked respiration) significantly only in preadipocytes of female donors, reflecting their trends towards higher insulin sensitivity. CONCLUSIONS: Collectively, we show that preadipocytes, but not in vitro differentiated adipocytes, represent a model system to reveal gender differences with clinical importance for metabolic disease status. In particular preadipocytes of females maintain enhanced mitochondrial flexibility, as demonstrated by pronounced responses of ATP-linked respiration to glucose. CI - Copyright (c) 2018 The Authors. Published by Elsevier GmbH.. All rights reserved. FAU - Keuper, Michaela AU - Keuper M AD - Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tubingen, Tubingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany. Electronic address: michaela.keuper@helmholtz-muenchen.de. FAU - Berti, Lucia AU - Berti L AD - Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tubingen, Tubingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany. FAU - Raedle, Bernhard AU - Raedle B AD - German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute of Experimental Genetics, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany. FAU - Sachs, Stephan AU - Sachs S AD - German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute of Diabetes and Regeneration Research, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany. FAU - Bohm, Anja AU - Bohm A AD - Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tubingen, Tubingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tubingen, Tubingen, Germany. FAU - Fritsche, Louise AU - Fritsche L AD - Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tubingen, Tubingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tubingen, Tubingen, Germany. FAU - Fritsche, Andreas AU - Fritsche A AD - Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tubingen, Tubingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tubingen, Tubingen, Germany. FAU - Haring, Hans-Ulrich AU - Haring HU AD - Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tubingen, Tubingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tubingen, Tubingen, Germany. FAU - Hrabe de Angelis, Martin AU - Hrabe de Angelis M AD - German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute of Experimental Genetics, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany; Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universitat Munchen, Freising, Germany. FAU - Jastroch, Martin AU - Jastroch M AD - German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute for Diabetes and Obesity, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany. FAU - Hofmann, Susanna M AU - Hofmann SM AD - German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute of Diabetes and Regeneration Research, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany; Medizinische Klinik und Poliklinik IV Klinikum der LMU Munchen, Germany. FAU - Staiger, Harald AU - Staiger H AD - Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tubingen, Tubingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tubingen, Tubingen, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181126 PL - Germany TA - Mol Metab JT - Molecular metabolism JID - 101605730 RN - 0 (Carrier Proteins) RN - 0 (Insulin) RN - 0 (Membrane Proteins) RN - 0 (Thyroid Hormones) RN - EC 7.1.1.8 (Electron Transport Complex III) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Adipocytes, White/*metabolism MH - Adult MH - Carrier Proteins/metabolism MH - Cells, Cultured MH - Electron Transport Complex III/metabolism MH - *Energy Metabolism MH - Female MH - Glucose/*metabolism MH - Humans MH - Insulin/*metabolism MH - Male MH - Membrane Proteins/metabolism MH - Middle Aged MH - Obesity/*metabolism MH - Oxygen Consumption MH - Sex Factors MH - Thyroid Hormones/metabolism MH - Thyroid Hormone-Binding Proteins PMC - PMC6358537 OTO - NOTNLM OT - Cellular metabolism OT - Glycolysis OT - Oxidative phosphorylation EDAT- 2018/12/12 06:00 MHDA- 2019/11/26 06:00 PMCR- 2018/11/26 CRDT- 2018/12/12 06:00 PHST- 2018/10/29 00:00 [received] PHST- 2018/11/14 00:00 [revised] PHST- 2018/11/21 00:00 [accepted] PHST- 2018/12/12 06:00 [pubmed] PHST- 2019/11/26 06:00 [medline] PHST- 2018/12/12 06:00 [entrez] PHST- 2018/11/26 00:00 [pmc-release] AID - S2212-8778(18)31046-9 [pii] AID - 10.1016/j.molmet.2018.11.006 [doi] PST - ppublish SO - Mol Metab. 2019 Feb;20:28-37. doi: 10.1016/j.molmet.2018.11.006. Epub 2018 Nov 26.