title: Lack of Adipocyte AMPK Exacerbates Insulin Resistance and Hepatic Steatosis through Brown and Beige Adipose Tissue Function.
abstract: Brown (BAT) and white (WAT) adipose tissues play distinct roles in maintaining whole-body energy homeostasis, and their dysfunction can contribute to non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. The AMP-activated protein kinase (AMPK) is a cellular energy sensor, but its role in regulating BAT and WAT metabolism is unclear. We generated an inducible model for deletion of the two AMPK β subunits in adipocytes (iβ1β2AKO) and found that iβ1β2AKO mice were cold intolerant and resistant to β-adrenergic activation of BAT and beiging of WAT. BAT from iβ1β2AKO mice had impairments in mitochondrial structure, function, and markers of mitophagy. In response to a high-fat diet, iβ1β2AKO mice more rapidly developed liver steatosis as well as glucose and insulin intolerance. Thus, AMPK in adipocytes is vital for maintaining mitochondrial integrity, responding to pharmacological agents and thermal stress, and protecting against nutrient-overload-induced NAFLD and insulin resistance.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Emilio P
authors.initials: EP
authors.lastname: Mottillo
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Desjardins
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Crane
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Brennan K
authors.initials: BK
authors.lastname: Smith
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Alex E
authors.initials: AE
authors.lastname: Green
authors.affiliation: Nestlé Institute of Health Sciences SA, EPFL Innovation Park, Lausanne, Switzerland.
authors.forename: Serge
authors.initials: S
authors.lastname: Ducommun
authors.affiliation: The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Tora I
authors.initials: TI
authors.lastname: Henriksen
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Irena A
authors.initials: IA
authors.lastname: Rebalka
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Aida
authors.initials: A
authors.lastname: Razi
authors.affiliation: Nestlé Institute of Health Sciences SA, EPFL Innovation Park, Lausanne, Switzerland.
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Camilla
authors.initials: C
authors.lastname: Scheele
authors.affiliation: St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Victoria 3065, Australia; Mary MacKillop Institute for Health Research Australian Catholic University, Victoria Parade, Fitzroy, Victoria 3065, Australia.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kemp
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hawke
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Ortega
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit 48201, MI, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Granneman
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada. Electronic address: gsteinberg@mcmaster.ca.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology*; D000069796:Adipose Tissue, Beige / Q000187:drug effects / Q000201:enzymology*; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000201:enzymology*; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat; D004789:Enzyme Activation / Q000187:drug effects; D005234:Fatty Liver / Q000201:enzymology* / Q000473:pathology; D017353:Gene Deletion; D006706:Homeostasis / Q000187:drug effects; D007333:Insulin Resistance; D008066:Lipolysis / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009638:Norepinephrine / Q000494:pharmacology; D022722:Thermogenesis / Q000187:drug effects
chemical_list: D055372:AMP-Activated Protein Kinases; D009638:Norepinephrine