Phosphorylation of glycogen synthase kinase-3β in metabolically abnormal obesity affects immune stimulation-induced cytokine production

C. L. Yen, W. C. Chao, Chi-Hsing Wu, Ya-Fang Huang, C. S. Chang, Y. S. Tsai, C. F. Lin, C. C. Shieh

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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. SUBJECTS/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-3 β) 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.

Original languageEnglish
Pages (from-to)270-278
Number of pages9
JournalInternational Journal of Obesity
Volume39
Issue number2
DOIs
Publication statusPublished - Feb 11 2015
Externally publishedYes

Fingerprint

Glycogen Synthase Kinase 3
Obesity
Phosphorylation
Cytokines
Leukocytes
Lipopolysaccharides
Blood Cells
Toll-Like Receptors
CREB-Binding Protein
Insulin
Response Elements
Cyclic AMP
Interleukin-10
Type 2 Diabetes Mellitus
Interferons
Adipose Tissue
Comorbidity
Interleukin-6
Cardiovascular Diseases
Fatty Acids

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Nutrition and Dietetics
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

Phosphorylation of glycogen synthase kinase-3β in metabolically abnormal obesity affects immune stimulation-induced cytokine production. / Yen, C. L.; Chao, W. C.; Wu, Chi-Hsing; Huang, Ya-Fang; Chang, C. S.; Tsai, Y. S.; Lin, C. F.; Shieh, C. C.

In: International Journal of Obesity, Vol. 39, No. 2, 11.02.2015, p. 270-278.

Research output: Contribution to journalArticle

Yen, C. L. ; Chao, W. C. ; Wu, Chi-Hsing ; Huang, Ya-Fang ; Chang, C. S. ; Tsai, Y. S. ; Lin, C. F. ; Shieh, C. C. / Phosphorylation of glycogen synthase kinase-3β in metabolically abnormal obesity affects immune stimulation-induced cytokine production. In: International Journal of Obesity. 2015 ; Vol. 39, No. 2. pp. 270-278.
@article{5e4f5c5e7ae44d29ae912073b35b80bd,
title = "Phosphorylation of glycogen synthase kinase-3β in metabolically abnormal obesity affects immune stimulation-induced cytokine production",
abstract = "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. SUBJECTS/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-3 β) 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.",
author = "Yen, {C. L.} and Chao, {W. C.} and Chi-Hsing Wu and Ya-Fang Huang and Chang, {C. S.} and Tsai, {Y. S.} and Lin, {C. F.} and Shieh, {C. C.}",
year = "2015",
month = "2",
day = "11",
doi = "10.1038/ijo.2014.93",
language = "English",
volume = "39",
pages = "270--278",
journal = "International Journal of Obesity",
issn = "0307-0565",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Phosphorylation of glycogen synthase kinase-3β in metabolically abnormal obesity affects immune stimulation-induced cytokine production

AU - Yen, C. L.

AU - Chao, W. C.

AU - Wu, Chi-Hsing

AU - Huang, Ya-Fang

AU - Chang, C. S.

AU - Tsai, Y. S.

AU - Lin, C. F.

AU - Shieh, C. C.

PY - 2015/2/11

Y1 - 2015/2/11

N2 - 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. SUBJECTS/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-3 β) 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.

AB - 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. SUBJECTS/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-3 β) 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.

UR - http://www.scopus.com/inward/record.url?scp=84922670082&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84922670082&partnerID=8YFLogxK

U2 - 10.1038/ijo.2014.93

DO - 10.1038/ijo.2014.93

M3 - Article

VL - 39

SP - 270

EP - 278

JO - International Journal of Obesity

JF - International Journal of Obesity

SN - 0307-0565

IS - 2

ER -