title: Adipocyte Glucocorticoid Receptor Deficiency Attenuates Aging- and HFD-Induced Obesity and Impairs the Feeding-Fasting Transition.
abstract: Glucocorticoids (GCs) are important regulators of systemic energy metabolism, and aberrant GC action is linked to metabolic dysfunctions. Yet, the extent to which normal and pathophysiological energy metabolism depend on the GC receptor (GR) in adipocytes remains unclear. Here, we demonstrate that adipocyte GR deficiency in mice significantly impacts systemic metabolism in different energetic states. Plasma metabolomics and biochemical analyses revealed a marked global effect of GR deficiency on systemic metabolite abundance and, thus, substrate partitioning in fed and fasted states. This correlated with a decreased lipolytic capacity of GR-deficient adipocytes under postabsorptive and fasting conditions, resulting from impaired signal transduction from β-adrenergic receptors to adenylate cyclase. Upon prolonged fasting, the impaired lipolytic response resulted in abnormal substrate utilization and lean mass wasting. Conversely, GR deficiency attenuated aging-/diet-associated obesity, adipocyte hypertrophy, and liver steatosis. Systemic glucose tolerance was improved in obese GR-deficient mice, which was associated with increased insulin signaling in muscle and adipose tissue. We conclude that the GR in adipocytes exerts central but diverging roles in the regulation of metabolic homeostasis depending on the energetic state. The adipocyte GR is indispensable for the feeding-fasting transition but also promotes adiposity and associated metabolic disorders in fat-fed and aged mice.
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.|Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Mueller
authors.affiliation: Institute for Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hartmann
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: Doris
authors.initials: D
authors.lastname: Kaltenecker
authors.affiliation: Institute for Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Vettorazzi
authors.affiliation: Institute for Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany.
authors.forename: Mandy
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Institute for Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany.
authors.forename: Lea
authors.initials: L
authors.lastname: Mauser
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Amann
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH) and German Center for Diabetes Research (DZD), Neuherberg, Germany.|Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Jall
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH) and German Center for Diabetes Research (DZD), Neuherberg, Germany.|Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Esterbauer
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH) and German Center for Diabetes Research (DZD), Neuherberg, Germany.|Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
authors.forename: Timo D
authors.initials: TD
authors.lastname: Müller
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH) and German Center for Diabetes Research (DZD), Neuherberg, Germany.|Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.affiliation: HEALTH Institute for Biomedicine and Health Sciences, JOANNEUM RESEARCH, Forschungsgesellschaft mbH, Graz, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Magnes
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Haybaeck
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Scherer
authors.affiliation: Center for Biomarker Research in Medicine, CBmed GmbH, Graz, Austria.
authors.forename: Natalie
authors.initials: N
authors.lastname: Bordag
authors.affiliation: Institute for Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany richard.moriggl@lbicr.lbg.ac.at jan.tuckermann@uni-ulm.de.
authors.forename: Jan P
authors.initials: JP
authors.lastname: Tuckermann
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria richard.moriggl@lbicr.lbg.ac.at jan.tuckermann@uni-ulm.de.|Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Medical University of Vienna, Vienna, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D050154:Adiposity / Q000235:genetics; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002853:Chromatography, Liquid; D059305:Diet, High-Fat; D004734:Energy Metabolism; D005215:Fasting; D005234:Fatty Liver / Q000235:genetics; D005247:Feeding Behavior; D006984:Hypertrophy; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D008066:Lipolysis; D008099:Liver / Q000378:metabolism*; D013058:Mass Spectrometry; D055432:Metabolomics; D051379:Mice; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D007328:Insulin; D011943:Receptors, Adrenergic, beta; D011965:Receptors, Glucocorticoid; D000262:Adenylyl Cyclases