title: Activation of AMP-activated protein kinase rapidly suppresses multiple pro-inflammatory pathways in adipocytes including IL-1 receptor-associated kinase-4 phosphorylation.
abstract: Inflammation of adipose tissue in obesity is associated with increased IL-1β, IL-6 and TNF-α secretion and proposed to contribute to insulin resistance. AMP-activated protein kinase (AMPK) regulates nutrient metabolism and is reported to have anti-inflammatory actions in adipose tissue, yet the mechanisms underlying this remain poorly characterised. The effect of AMPK activation on cytokine-stimulated proinflammatory signalling was therefore assessed in cultured adipocytes. AMPK activation inhibited IL-1β-stimulated CXCL10 secretion, associated with reduced interleukin-1 receptor associated kinase-4 (IRAK4) phosphorylation and downregulated MKK4/JNK and IKK/IκB/NFκB signalling. AMPK activation inhibited TNF-α-stimulated IKK/IκB/NFκB signalling but had no effect on JNK phosphorylation. The JAK/STAT3 pathway was also suppressed by AMPK after IL-6 stimulation and during adipogenesis. Adipose tissue from AMPKα1-/-mice exhibited increased JNK and STAT3 phosphorylation, supporting suppression of these distinct proinflammatory pathways by AMPK in vivo. The inhibition of multiple pro-inflammatory signalling pathways by AMPK may underlie the reported beneficial effects of AMPK activation in adipose tissue.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, United Kingdom.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Mancini
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, United Kingdom.
authors.forename: Anna D
authors.initials: AD
authors.lastname: White
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, United Kingdom.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bijland
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Rutherford
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, United Kingdom.
authors.forename: Delyth
authors.initials: D
authors.lastname: Graham
authors.affiliation: Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Richter
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, United Kingdom.
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
authors.affiliation: School of Pharmacy, University of Bradford, Bradford, West Yorkshire, BD7 1DP, United Kingdom.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Palmer
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, United Kingdom. Electronic address: Ian.Salt@glasgow.ac.uk.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Salt
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017667:Adipocytes / Q000201:enzymology* / Q000473:pathology*; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D001713:Biphenyl Compounds; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007249:Inflammation / Q000201:enzymology* / Q000473:pathology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011753:Pyrones / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D001713:Biphenyl Compounds; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D011753:Pyrones; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D013876:Thiophenes; D053592:Interleukin-1 Receptor-Associated Kinases; D055372:AMP-Activated Protein Kinases; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile
keywords: AMP-activated protein kinase; Adipocyte; Inflammation; Signalling