title: Adiponectin induces A20 expression in adipose tissue to confer metabolic benefit.
abstract: Obesity is a major risk factor for metabolic disease, with white adipose tissue (WAT) inflammation emerging as a key underlying pathology. We detail that mice lacking Reverbα exhibit enhanced fat storage without the predicted increased WAT inflammation or loss of insulin sensitivity. In contrast to most animal models of obesity and obese human patients, Reverbα(-/-) mice exhibit elevated serum adiponectin levels and increased adiponectin secretion from WAT explants in vitro, highlighting a potential anti-inflammatory role of this adipokine in hypertrophic WAT. Indeed, adiponectin was found to suppress primary macrophage responses to lipopolysaccharide and proinflammatory fatty acids, and this suppression depended on glycogen synthase kinase 3β activation and induction of A20. Attenuated inflammatory responses in Reverbα(-/-) WAT depots were associated with tonic elevation of A20 protein and ex vivo shown to depend on A20. We also demonstrate that adipose A20 expression in obese human subjects exhibits a negative correlation with measures of insulin sensitivity. Furthermore, bariatric surgery-induced weight loss was accompanied by enhanced WAT A20 expression, which is positively correlated with increased serum adiponectin and improved metabolic and inflammatory markers, including C-reactive protein. The findings identify A20 as a mediator of adiponectin anti-inflammatory action in WAT and a potential target for mitigating obesity-related pathology.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, U.K.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Hand
authors.affiliation: Faculty of Medical and Health Sciences, University of Manchester, Manchester, U.K.
authors.forename: Paola
authors.initials: P
authors.lastname: Usan
authors.affiliation: Faculty of Medical and Health Sciences, University of Manchester, Manchester, U.K. School of Biological Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Garth J S
authors.initials: GJ
authors.lastname: Cooper
authors.affiliation: School of Biological Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Lance Y
authors.initials: LY
authors.lastname: Xu
authors.affiliation: Centre for Advanced Discovery and Experimental Therapeutics, University of Manchester, Manchester, U.K.
authors.forename: Basil
authors.initials: B
authors.lastname: Ammori
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, U.K.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Cunningham
authors.affiliation: Centre for Advanced Discovery and Experimental Therapeutics, University of Manchester, Manchester, U.K.
authors.forename: Reza
authors.initials: R
authors.lastname: Aghamohammadzadeh
authors.affiliation: Centre for Advanced Discovery and Experimental Therapeutics, University of Manchester, Manchester, U.K.
authors.forename: Handrean
authors.initials: H
authors.lastname: Soran
authors.affiliation: Centre for Advanced Discovery and Experimental Therapeutics, University of Manchester, Manchester, U.K.
authors.forename: Adam
authors.initials: A
authors.lastname: Greenstein
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, U.K.
authors.forename: Andrew S I
authors.initials: AS
authors.lastname: Loudon
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, U.K. david.w.ray@manchester.ac.uk david.bechtold@manchester.ac.uk.
authors.forename: David A
authors.initials: DA
authors.lastname: Bechtold
authors.affiliation: Faculty of Medical and Health Sciences, University of Manchester, Manchester, U.K. david.w.ray@manchester.ac.uk david.bechtold@manchester.ac.uk.
authors.forename: David W
authors.initials: DW
authors.lastname: Ray
mesh_terms: D052242:Adiponectin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000276:immunology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000276:immunology / Q000378:metabolism*; D009765:Obesity / Q000276:immunology / Q000378:metabolism*; D015434:Panniculitis / Q000276:immunology / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; C499919:Adipoq protein, mouse; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse