title: Activating HSP72 in rodent skeletal muscle increases mitochondrial number and oxidative capacity and decreases insulin resistance.
abstract: Induction of heat shock protein (HSP)72 protects against obesity-induced insulin resistance, but the underlying mechanisms are unknown. Here, we show that HSP72 plays a pivotal role in increasing skeletal muscle mitochondrial number and oxidative metabolism. Mice overexpressing HSP72 in skeletal muscle (HSP72Tg) and control wild-type (WT) mice were fed either a chow or high-fat diet (HFD). Despite a similar energy intake when HSP72Tg mice were compared with WT mice, the HFD increased body weight, intramuscular lipid accumulation (triacylglycerol and diacylglycerol but not ceramide), and severe glucose intolerance in WT mice alone. Whole-body VO2, fatty acid oxidation, and endurance running capacity were markedly increased in HSP72Tg mice. Moreover, HSP72Tg mice exhibited an increase in mitochondrial number. In addition, the HSP72 coinducer BGP-15, currently in human clinical trials for type 2 diabetes, also increased mitochondrial number and insulin sensitivity in a rat model of type 2 diabetes. Together, these data identify a novel role for activation of HSP72 in skeletal muscle. Thus, the increased oxidative metabolism associated with activation of HSP72 has potential clinical implications not only for type 2 diabetes but also for other disorders where mitochondrial function is compromised.
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Darren C
authors.initials: DC
authors.lastname: Henstridge
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, AustraliaDepartment of Physiology, Monash University, Clayton, Victoria, Australia.
authors.forename: Clinton R
authors.initials: CR
authors.lastname: Bruce
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Drew
authors.affiliation: N-Gene Research Laboratories, Inc., Budapest, Hungary.
authors.forename: Kálmán
authors.initials: K
authors.lastname: Tory
authors.affiliation: N-Gene Research Laboratories, Inc., Budapest, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Kolonics
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Emma
authors.initials: E
authors.lastname: Estevez
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Chung
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Nadine
authors.initials: N
authors.lastname: Watson
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Timothy
authors.initials: T
authors.lastname: Gardner
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Lee-Young
authors.affiliation: Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Victoria, Australia.
authors.forename: Timothy
authors.initials: T
authors.lastname: Connor
authors.affiliation: Department of Physiology, Monash University, Clayton, Victoria, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Watt
authors.affiliation: Department of Biochemical Genetics, Children's Hospital at Westmead and Disciplines of Genetic Medicine and Paediatrics and Child Health, University of Sydney, New South Wales, Australia.
authors.forename: Kevin
authors.initials: K
authors.lastname: Carpenter
authors.affiliation: Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Hargreaves
authors.affiliation: Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Victoria, Australia.
authors.forename: Sean L
authors.initials: SL
authors.lastname: McGee
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Hevener
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, AustraliaN-Gene Research Laboratories, Inc., Budapest, Hungary mark.febbraio@bakeridi.edu.au.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose; D015153:Blotting, Western; D001835:Body Weight; D019069:Cell Respiration; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D059305:Diet, High-Fat; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism*; D007333:Insulin Resistance; D020738:Leptin / Q000378:metabolism; D008297:Male; D051379:Mice; D008931:Mitochondria, Muscle / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; D050884:HSP72 Heat-Shock Proteins; D020738:Leptin; D047492:Peroxisome Proliferator-Activated Receptors; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1