Phosphorylation of glycogen synthase kinase-3β in metabolically abnormal obesity affects immune stimulation-induced cytokine production.
BACKGROUND
Obesity is a severe health problem worldwide, which leads to multiple comorbidities including type 2 diabetes mellitus and cardiovascular diseases. Inflammation has been found to be an important characteristic of adipose tissue in obese subjects. However, obesity is also associated with compromised immune responses to infections and the impact of obesity on immune function has not been fully understood.


METHODS
To clarify the role of obesity in the immune responses, we investigated the Toll-like receptor (TLR)-induced cytokine secretion by leukocytes from obese and lean subjects. We also investigated the relationship between insulin-induced intracellular signaling and cytokine production using peripheral blood mononuclear cells (PBMCs) and a monocytic cell line THP-1.


RESULTS
We found decreased TLR-induced interferon-γ, interleukin-6 (IL-6) and tumor necrosis factor-α secretions and elevated IL-10 secretion by leukocytes from obese subjects when compared with lean controls. PBMCs from obese subjects showed enhanced basal Akt and glycogen synthase kinase-3β (GSK-3β) phosphorylation, which did not further increase with insulin and lipopolysaccharide (LPS) stimulation. We also found that LPS-induced IκBα degradation was inhibited in PBMCs from obese subjects. By using THP-1 cells with GSK-3β knockdown or cells treated with hyperinsulinemic and high-fatty acid conditions, we found that LPS-induced nuclear factor κB (NF-κB) activation was inhibited and cyclic adenosine monophosphate response element-binding protein (CREB) activation was enhanced.


CONCLUSIONS
These findings indicate that GSK-3β is important in the regulation of NF-κB and CREB activation in leukocytes under the metabolic condition of obesity. Our study revealed a key mechanism through which metabolic abnormalities compromise leukocyte functions in people with obesity.
Institute of Basic Medical Science, National Cheng Kung University Medical College, Tainan, Taiwan.
C-L
CL
Yen
1] Institute of Clinical Medicine, National Cheng Kung University Medical College, Tainan, Taiwan [2] Department of Internal Medicine, Taichung Veteran General Hospital, Chiayi Branch, Chiayi, Taiwan.
W-C
WC
Chao
Department of Family Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
C-H
CH
Wu
Institute of Clinical Medicine, National Cheng Kung University Medical College, Tainan, Taiwan.
Y-F
YF
Huang
Department of Family Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
C-S
CS
Chang
Institute of Clinical Medicine, National Cheng Kung University Medical College, Tainan, Taiwan.
Y-S
YS
Tsai
Institute of Clinical Medicine, National Cheng Kung University Medical College, Tainan, Taiwan.
C-F
CF
Lin
1] Institute of Basic Medical Science, National Cheng Kung University Medical College, Tainan, Taiwan [2] Institute of Clinical Medicine, National Cheng Kung University Medical College, Tainan, Taiwan [3] Department of Pediatrics, National Cheng Kung University Hospital, Tainan, Taiwan.
C-C
CC
Shieh
D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006946:Hyperinsulinism / Q000276:immunology / Q000378:metabolism*; D006949:Hyperlipidemias / Q000276:immunology / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000276:immunology; D016753:Interleukin-10 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009765:Obesity / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D020672:I-kappa B Proteins; C508609:IL10 protein, human; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000072000:NF-KappaB Inhibitor alpha; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3