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Endoplasmic reticulum stress is increased in adipose tissue of women with gestational diabetes.

Liong S, Lappas M - PLoS ONE (2015)

Bottom Line: ER stress markers IRE1α, GRP78 and XBP-1s were significantly increased in adipose tissue of obese compared to lean pregnant women.Inhibition of capase-1 with Ac-YVAD-CHO resulted in decreased IL-1α and IL-1β secretion, whereas inhibition of pannexin-1 with carbenoxolone suppressed IL-1β secretion only.In conclusion, this study has demonstrated ER stress to activate the inflammasome in pregnant adipose tissue.

View Article: PubMed Central - PubMed

Affiliation: Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Heidelberg, Victoria, Australia; Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia.

ABSTRACT
Maternal obesity and gestational diabetes mellitus (GDM) are two increasingly common and important obstetric complications that are associated with severe long-term health risks to mothers and babies. IL-1β, which is increased in obese and GDM pregnancies, plays an important role in the pathophysiology of these two pregnancy complications. In non-pregnant tissues, endoplasmic (ER) stress is increased in diabetes and can induce IL-1β via inflammasome activation. The aim of this study was to determine whether ER stress is increased in omental adipose tissue of women with GDM, and if ER stress can also upregulate inflammasome-dependent secretion of IL-1β. ER stress markers IRE1α, GRP78 and XBP-1s were significantly increased in adipose tissue of obese compared to lean pregnant women. ER stress was also increased in adipose tissue of women with GDM compared to BMI-matched normal glucose tolerant (NGT) women. Thapsigargin, an ER stress activator, induced upregulated secretion of mature IL-1α and IL-1β in human omental adipose tissue explants primed with bacterial endotoxin LPS, the viral dsRNA analogue poly(I:C) or the pro-inflammatory cytokine TNF-α. Inhibition of capase-1 with Ac-YVAD-CHO resulted in decreased IL-1α and IL-1β secretion, whereas inhibition of pannexin-1 with carbenoxolone suppressed IL-1β secretion only. Treatment with anti-diabetic drugs metformin and glibenclamide also reduced IL-1α and IL-1β secretion in infection and cytokine-primed adipose tissue. In conclusion, this study has demonstrated ER stress to activate the inflammasome in pregnant adipose tissue. Therefore, increased ER stress may contribute towards the pathophysiology of obesity in pregnancy and GDM.

No MeSH data available.


Related in: MedlinePlus

Anti-diabetic drugs inhibits thapsigargin-induced IL-1α and IL-1β secretion in tissues primed with LPS, poly(I:C) or TNF-α.Adipose tissue was incubated in the absence or presence of 0.5 mM metformin (Metf) or 25 μM glibenclamide (Glib)for 60 min prior to the addition of (A-C) 10 μg/ml LPS, (D-F) 20 μg/ml poly(I:C) or (G-I) 10 ng/ml TNF-α. After 18 h incubation, tissues were incubated with 30 μM thapsigargin (TG) for a further 2 h (n = 6 patients per treatment). The incubation medium was assayed for IL-1α, IL-1β and IL-6 concentration by ELISA. Each bar represents mean concentration ± SEM. *P<0.05 vs. LPS (one way ANOVA); **P<0.05 vs. LPS + TG (one way ANOVA); #P<0.05 vs. poly(I:C) (one-way ANOVA); ##P<0.05 vs. poly(I:C) + TG (one-way ANOVA); †P<0.05 vs. TNF-α (one-way ANOVA); ††P<0.05 vs. TNF-α + TG (one-way ANOVA).
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pone.0122633.g005: Anti-diabetic drugs inhibits thapsigargin-induced IL-1α and IL-1β secretion in tissues primed with LPS, poly(I:C) or TNF-α.Adipose tissue was incubated in the absence or presence of 0.5 mM metformin (Metf) or 25 μM glibenclamide (Glib)for 60 min prior to the addition of (A-C) 10 μg/ml LPS, (D-F) 20 μg/ml poly(I:C) or (G-I) 10 ng/ml TNF-α. After 18 h incubation, tissues were incubated with 30 μM thapsigargin (TG) for a further 2 h (n = 6 patients per treatment). The incubation medium was assayed for IL-1α, IL-1β and IL-6 concentration by ELISA. Each bar represents mean concentration ± SEM. *P<0.05 vs. LPS (one way ANOVA); **P<0.05 vs. LPS + TG (one way ANOVA); #P<0.05 vs. poly(I:C) (one-way ANOVA); ##P<0.05 vs. poly(I:C) + TG (one-way ANOVA); †P<0.05 vs. TNF-α (one-way ANOVA); ††P<0.05 vs. TNF-α + TG (one-way ANOVA).

Mentions: Statistics was performed on the normalised data unless otherwise specified. All statistical analyses were undertaken using GraphPad Prism Version 6 (GraphPad Software, La Jolla, CA). For Fig 1, an unpaired Student’s t-test was used to assess statistical significance between normally distributed data; otherwise, the nonparametric Mann-Whitney U test was used. For Figs 2–5, the homogeneity of data was assessed by the Bartlett test, and when significant, the data were logarithmically transformed before further analysis using a one-way ANOVA (using LSD correction to discriminate among the means). Statistical significance was ascribed to P value <0.05. Data were expressed as mean ± standard error of the mean (SEM).


Endoplasmic reticulum stress is increased in adipose tissue of women with gestational diabetes.

Liong S, Lappas M - PLoS ONE (2015)

Anti-diabetic drugs inhibits thapsigargin-induced IL-1α and IL-1β secretion in tissues primed with LPS, poly(I:C) or TNF-α.Adipose tissue was incubated in the absence or presence of 0.5 mM metformin (Metf) or 25 μM glibenclamide (Glib)for 60 min prior to the addition of (A-C) 10 μg/ml LPS, (D-F) 20 μg/ml poly(I:C) or (G-I) 10 ng/ml TNF-α. After 18 h incubation, tissues were incubated with 30 μM thapsigargin (TG) for a further 2 h (n = 6 patients per treatment). The incubation medium was assayed for IL-1α, IL-1β and IL-6 concentration by ELISA. Each bar represents mean concentration ± SEM. *P<0.05 vs. LPS (one way ANOVA); **P<0.05 vs. LPS + TG (one way ANOVA); #P<0.05 vs. poly(I:C) (one-way ANOVA); ##P<0.05 vs. poly(I:C) + TG (one-way ANOVA); †P<0.05 vs. TNF-α (one-way ANOVA); ††P<0.05 vs. TNF-α + TG (one-way ANOVA).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4388824&req=5

pone.0122633.g005: Anti-diabetic drugs inhibits thapsigargin-induced IL-1α and IL-1β secretion in tissues primed with LPS, poly(I:C) or TNF-α.Adipose tissue was incubated in the absence or presence of 0.5 mM metformin (Metf) or 25 μM glibenclamide (Glib)for 60 min prior to the addition of (A-C) 10 μg/ml LPS, (D-F) 20 μg/ml poly(I:C) or (G-I) 10 ng/ml TNF-α. After 18 h incubation, tissues were incubated with 30 μM thapsigargin (TG) for a further 2 h (n = 6 patients per treatment). The incubation medium was assayed for IL-1α, IL-1β and IL-6 concentration by ELISA. Each bar represents mean concentration ± SEM. *P<0.05 vs. LPS (one way ANOVA); **P<0.05 vs. LPS + TG (one way ANOVA); #P<0.05 vs. poly(I:C) (one-way ANOVA); ##P<0.05 vs. poly(I:C) + TG (one-way ANOVA); †P<0.05 vs. TNF-α (one-way ANOVA); ††P<0.05 vs. TNF-α + TG (one-way ANOVA).
Mentions: Statistics was performed on the normalised data unless otherwise specified. All statistical analyses were undertaken using GraphPad Prism Version 6 (GraphPad Software, La Jolla, CA). For Fig 1, an unpaired Student’s t-test was used to assess statistical significance between normally distributed data; otherwise, the nonparametric Mann-Whitney U test was used. For Figs 2–5, the homogeneity of data was assessed by the Bartlett test, and when significant, the data were logarithmically transformed before further analysis using a one-way ANOVA (using LSD correction to discriminate among the means). Statistical significance was ascribed to P value <0.05. Data were expressed as mean ± standard error of the mean (SEM).

Bottom Line: ER stress markers IRE1α, GRP78 and XBP-1s were significantly increased in adipose tissue of obese compared to lean pregnant women.Inhibition of capase-1 with Ac-YVAD-CHO resulted in decreased IL-1α and IL-1β secretion, whereas inhibition of pannexin-1 with carbenoxolone suppressed IL-1β secretion only.In conclusion, this study has demonstrated ER stress to activate the inflammasome in pregnant adipose tissue.

View Article: PubMed Central - PubMed

Affiliation: Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Heidelberg, Victoria, Australia; Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia.

ABSTRACT
Maternal obesity and gestational diabetes mellitus (GDM) are two increasingly common and important obstetric complications that are associated with severe long-term health risks to mothers and babies. IL-1β, which is increased in obese and GDM pregnancies, plays an important role in the pathophysiology of these two pregnancy complications. In non-pregnant tissues, endoplasmic (ER) stress is increased in diabetes and can induce IL-1β via inflammasome activation. The aim of this study was to determine whether ER stress is increased in omental adipose tissue of women with GDM, and if ER stress can also upregulate inflammasome-dependent secretion of IL-1β. ER stress markers IRE1α, GRP78 and XBP-1s were significantly increased in adipose tissue of obese compared to lean pregnant women. ER stress was also increased in adipose tissue of women with GDM compared to BMI-matched normal glucose tolerant (NGT) women. Thapsigargin, an ER stress activator, induced upregulated secretion of mature IL-1α and IL-1β in human omental adipose tissue explants primed with bacterial endotoxin LPS, the viral dsRNA analogue poly(I:C) or the pro-inflammatory cytokine TNF-α. Inhibition of capase-1 with Ac-YVAD-CHO resulted in decreased IL-1α and IL-1β secretion, whereas inhibition of pannexin-1 with carbenoxolone suppressed IL-1β secretion only. Treatment with anti-diabetic drugs metformin and glibenclamide also reduced IL-1α and IL-1β secretion in infection and cytokine-primed adipose tissue. In conclusion, this study has demonstrated ER stress to activate the inflammasome in pregnant adipose tissue. Therefore, increased ER stress may contribute towards the pathophysiology of obesity in pregnancy and GDM.

No MeSH data available.


Related in: MedlinePlus