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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

ER stress is increased in adipose tissue from obese pregnant women and with GDM.Adipose tissue was obtained from NGT lean (n = 6 patients) and obese (n = 6 patients) pregnant women at the time of term Caesarean section. The protein abundance of (A) GRP78, (B) IRE1α and (C) XBP-1s was analysed by Western blot. Protein abundance was normalised to Ponceau S staining and the fold change was calculated relative to the lean group. Data is presented as mean ± SEM. *P<0.05 vs. lean (Student’s t-test). Representative Western blot from six patients (3 obese and 3 lean) is also shown. Adipose tissue were also obtained from (D-F) lean and (G-I) obese pregnant women with NGT (n = 6 patients per group), diet-controlled GDM (n = 6 patients per group), insulin-controlled GDM (n = 6 patients) and combined GDM (n = 12 patients per group) at the time of term Caesarean section. The protein abundance of (D-G) GRP78, (E-H) IRE1α and (F-I) XBP-1s was analysed by Western blot. Protein abundance was normalised to Ponceau S staining and the fold change was calculated relative to the NGT group. Data is presented as mean ± SEM. *P<0.05 vs. NGT (Student’s t-test). Representative Western blot from nine patients (3 NGT, 3 GDM diet and 3 GDM insulin) is also shown.
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pone.0122633.g001: ER stress is increased in adipose tissue from obese pregnant women and with GDM.Adipose tissue was obtained from NGT lean (n = 6 patients) and obese (n = 6 patients) pregnant women at the time of term Caesarean section. The protein abundance of (A) GRP78, (B) IRE1α and (C) XBP-1s was analysed by Western blot. Protein abundance was normalised to Ponceau S staining and the fold change was calculated relative to the lean group. Data is presented as mean ± SEM. *P<0.05 vs. lean (Student’s t-test). Representative Western blot from six patients (3 obese and 3 lean) is also shown. Adipose tissue were also obtained from (D-F) lean and (G-I) obese pregnant women with NGT (n = 6 patients per group), diet-controlled GDM (n = 6 patients per group), insulin-controlled GDM (n = 6 patients) and combined GDM (n = 12 patients per group) at the time of term Caesarean section. The protein abundance of (D-G) GRP78, (E-H) IRE1α and (F-I) XBP-1s was analysed by Western blot. Protein abundance was normalised to Ponceau S staining and the fold change was calculated relative to the NGT group. Data is presented as mean ± SEM. *P<0.05 vs. NGT (Student’s t-test). Representative Western blot from nine patients (3 NGT, 3 GDM diet and 3 GDM insulin) is also shown.

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)

ER stress is increased in adipose tissue from obese pregnant women and with GDM.Adipose tissue was obtained from NGT lean (n = 6 patients) and obese (n = 6 patients) pregnant women at the time of term Caesarean section. The protein abundance of (A) GRP78, (B) IRE1α and (C) XBP-1s was analysed by Western blot. Protein abundance was normalised to Ponceau S staining and the fold change was calculated relative to the lean group. Data is presented as mean ± SEM. *P<0.05 vs. lean (Student’s t-test). Representative Western blot from six patients (3 obese and 3 lean) is also shown. Adipose tissue were also obtained from (D-F) lean and (G-I) obese pregnant women with NGT (n = 6 patients per group), diet-controlled GDM (n = 6 patients per group), insulin-controlled GDM (n = 6 patients) and combined GDM (n = 12 patients per group) at the time of term Caesarean section. The protein abundance of (D-G) GRP78, (E-H) IRE1α and (F-I) XBP-1s was analysed by Western blot. Protein abundance was normalised to Ponceau S staining and the fold change was calculated relative to the NGT group. Data is presented as mean ± SEM. *P<0.05 vs. NGT (Student’s t-test). Representative Western blot from nine patients (3 NGT, 3 GDM diet and 3 GDM insulin) is also shown.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4388824&req=5

pone.0122633.g001: ER stress is increased in adipose tissue from obese pregnant women and with GDM.Adipose tissue was obtained from NGT lean (n = 6 patients) and obese (n = 6 patients) pregnant women at the time of term Caesarean section. The protein abundance of (A) GRP78, (B) IRE1α and (C) XBP-1s was analysed by Western blot. Protein abundance was normalised to Ponceau S staining and the fold change was calculated relative to the lean group. Data is presented as mean ± SEM. *P<0.05 vs. lean (Student’s t-test). Representative Western blot from six patients (3 obese and 3 lean) is also shown. Adipose tissue were also obtained from (D-F) lean and (G-I) obese pregnant women with NGT (n = 6 patients per group), diet-controlled GDM (n = 6 patients per group), insulin-controlled GDM (n = 6 patients) and combined GDM (n = 12 patients per group) at the time of term Caesarean section. The protein abundance of (D-G) GRP78, (E-H) IRE1α and (F-I) XBP-1s was analysed by Western blot. Protein abundance was normalised to Ponceau S staining and the fold change was calculated relative to the NGT group. Data is presented as mean ± SEM. *P<0.05 vs. NGT (Student’s t-test). Representative Western blot from nine patients (3 NGT, 3 GDM diet and 3 GDM insulin) is also shown.
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