Heat shock protein 60 as a mediator of adipose tissue inflammation and insulin resistance.
The stress protein heat shock protein 60 (Hsp60) induces secretion of proinflammatory mediators from murine adipocytes. This study aimed to study Hsp60 as a mediator of adipose tissue inflammation and skeletal muscle cell (SkMC) insulin sensitivity and to quantify plasma Hsp60 concentrations in lean and obese individuals. Regulation of Hsp60 release and Hsp60-induced cytokine secretion and signaling was measured in human adipocytes and SkMCs. Adipocytes exhibited higher Hsp60 release than preadipocytes and SkMCs, which was further stimulated by cytokines and Toll-like receptor (TLR)-4 activation. Hsp60 activated extracellular signal-related kinase (ERK)-1/2, Jun NH(2)-terminal kinase (JNK), p38, nuclear factor (NF)-κB, and impaired insulin-stimulated Akt phosphorylation in adipocytes. Furthermore, Hsp60 stimulated adipocytes to secrete tumor necrosis factor-α, interleukin (IL)-6, and IL-8. In SkMCs, Hsp60 activated ERK1/2, JNK, and NF-κB and inhibits insulin signaling and insulin-stimulated glucose uptake. SkMCs released IL-6, IL-8, and monocyte chemoattractant protein-1 on Hsp60 stimulation. Plasma Hsp60 was higher in obese males than in lean males and correlated positively with BMI, blood pressure, leptin, and homeostasis model assessment-insulin resistance. In summary, Hsp60 is released by human adipocytes, increased in plasma of obese humans, and induces insulin resistance. This is accompanied by activation of proinflammatory signaling in human adipocytes and SkMCs. Thus, Hsp60 might be a factor underlying adipose tissue inflammation and obesity-associated metabolic disorders.
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Tina
T
Märker
Henrike
H
Sell
Pia
P
Zillessen
Anja
A
Glöde
Jennifer
J
Kriebel
D Margriet
DM
Ouwens
Piet
P
Pattyn
Johannes
J
Ruige
Susanne
S
Famulla
Michael
M
Roden
Jürgen
J
Eckel
Christiane
C
Habich
D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D002478:Cells, Cultured; D018834:Chaperonin 60 / Q000097:blood / Q000502:physiology*; D018932:Chemokine CCL2 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism
C111835:CCL2 protein, human; D018834:Chaperonin 60; D018932:Chemokine CCL2; D005947:Glucose