HSP72 protects against obesity-induced insulin resistance.
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.
Chung
Jason
J
Cellular and Molecular Metabolism Laboratory, Clinical Physiology, and Human Vascular Biology, Baker Heart Research Institute, Prahran, P.O. Box 6492, Victoria 8008, Australia.
Nguyen
Anh-Khoi
AK
Henstridge
Darren C
DC
Holmes
Anna G
AG
Chan
M H Stanley
MH
Mesa
Jose L
JL
Lancaster
Graeme I
GI
Southgate
Robert J
RJ
Bruce
Clinton R
CR
Duffy
Stephen J
SJ
Horvath
Ibolya
I
Mestril
Ruben
R
Watt
Matthew J
MJ
Hooper
Philip L
PL
Kingwell
Bronwyn A
BA
Vigh
Laszlo
L
Hevener
Andrea
A
Febbraio
Mark A
MA
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
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