title: HSP72 protects against obesity-induced insulin resistance.
abstract: Patients with type 2 diabetes have reduced gene expression of heat shock protein (HSP) 72, which correlates with reduced insulin sensitivity. Heat therapy, which activates HSP72, improves clinical parameters in these patients. Activation of several inflammatory signaling proteins such as c-jun amino terminal kinase (JNK), inhibitor of kappaB kinase, and tumor necrosis factor-alpha, can induce insulin resistance, but HSP 72 can block the induction of these molecules in vitro. Accordingly, we examined whether activation of HSP72 can protect against the development of insulin resistance. First, we show that obese, insulin resistant humans have reduced HSP72 protein expression and increased JNK phosphorylation in skeletal muscle. We next used heat shock therapy, transgenic overexpression, and pharmacologic means to overexpress HSP72 either specifically in skeletal muscle or globally in mice. Herein, we show that regardless of the means used to achieve an elevation in HSP72 protein, protection against diet- or obesity-induced hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance was observed. This protection was tightly associated with the prevention of JNK phosphorylation. These findings identify an essential role for HSP72 in blocking inflammation and preventing insulin resistance in the context of genetic obesity or high-fat feeding.
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Clinical Physiology, and Human Vascular Biology, Baker Heart Research Institute, Prahran, P.O. Box 6492, Victoria 8008, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Chung
authors.forename: Anh-Khoi
authors.initials: AK
authors.lastname: Nguyen
authors.forename: Darren C
authors.initials: DC
authors.lastname: Henstridge
authors.forename: Anna G
authors.initials: AG
authors.lastname: Holmes
authors.forename: M H Stanley
authors.initials: MH
authors.lastname: Chan
authors.forename: Jose L
authors.initials: JL
authors.lastname: Mesa
authors.forename: Graeme I
authors.initials: GI
authors.lastname: Lancaster
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Southgate
authors.forename: Clinton R
authors.initials: CR
authors.lastname: Bruce
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Duffy
authors.forename: Ibolya
authors.initials: I
authors.lastname: Horvath
authors.forename: Ruben
authors.initials: R
authors.lastname: Mestril
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Watt
authors.forename: Philip L
authors.initials: PL
authors.lastname: Hooper
authors.forename: Bronwyn A
authors.initials: BA
authors.lastname: Kingwell
authors.forename: Laszlo
authors.initials: L
authors.lastname: Vigh
authors.forename: Andrea
authors.initials: A
authors.lastname: Hevener
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
mesh_terms: D052242:Adiponectin / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006946:Hyperinsulinism / Q000209:etiology / Q000378:metabolism* / Q000628:therapy*; D006979:Hyperthermia, Induced; D051550:I-kappa B Kinase / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000150:complications*; D010091:Oximes / Q000494:pharmacology; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D050884:HSP72 Heat-Shock Proteins; D007328:Insulin; D010091:Oximes; D010880:Piperidines; D051550:I-kappa B Kinase; D048670:MAP Kinase Kinase 4; C405586:BGP 15