Expression of adipokines and estrogen receptors in adipose tissue and placenta of patients with gestational diabetes mellitus

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Abstract

The purpose of this study was to assess the expression profile of genes with potential role in the development of insulin resistance (adipokines, cytokines/chemokines, estrogen receptors) in subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and placenta of pregnant women with gestational diabetes mellitus (GDM) and age-matched women with physiological pregnancy at the time of Caesarean section. qRT-PCR was used for expression analysis of the studied genes. Leptin gene expression in VAT of GDM group was significantly higher relative to control group. Gene expressions of interleukin-6 and interleukin-8 were significantly increased, whereas the expressions of genes for estrogen receptors α and β were significantly reduced in SAT of GDM group relative to controls, respectively. We found no significant differences in the expression of any genes of interest (LEP, RETN, ADIPOR1, ADIPOR2, TNF-α, CD68, IL-6, IL-8, ERα, ERβ) in placentas of women with GDM relative to controls. We conclude that increased expression of leptin in visceral adipose depot together with increased expressions of proinflammatory cytokines and reduced expressions of estrogen receptors in subcutaneous fat may play a role in the etiopathogenesis of GDM.

Introduction

Gestational diabetes mellitus (GDM) is the most frequent metabolic disorder in pregnancy, affecting 1–10% of all pregnancies (Beischer et al., 1996 and Gabbe, 1986). Although most of the women with GDM return to normal glucose tolerance after delivery, they still have significantly increased risk of developing diabetes later in life (Kim et al., 2002). GDM is considered a prediabetic state, therefore it may display many abnormalities that possibly appear in the very early stages of type 2 diabetes mellitus (T2DM) (Pendegrass et al., 1995). In addition to mechanisms similar to patients with T2DM (Friedman et al., 1999 and Catalano et al., 2002), the etiopathogenesis of GDM includes the combination of the disturbed endocrine function of adipose tissue and placenta (Coughlan et al., 2001, Cseh et al., 2002, Kirwan et al., 2002, Radaelli et al., 2003, Ranheim et al., 2004 and Meller et al., 2006), and the systemic hormonal changes affecting insulin sensitivity in peripheral tissues (Barros et al., 2008).

Adipokines [leptin (LEP; OMIM 164160), resistin (RETN; OMIM 605565), and adiponectin (ADIPOQ; OMIM 605441)], inflammatory cytokines [tumor necrosis factor-α (TNF-α; OMIM 191160), and interleukin-6 (IL-6; OMIM 147620)], and chemokines [interleukin-8 (IL-8; OMIM 146930)] have been implicated in the etiopathogenesis of insulin resistance and in the early defects of T2DM (Bastard et al., 2002, Moller, 2000, Wauters et al., 2000, Coppack, 2001, Kern et al., 2001, Steppan et al., 2001, Weyer et al., 2001, Greenberg and McDaniel, 2002, Havel, 2002, Housa et al., 2006, Kleiblová et al., 2006 and Lamounier-Zepter et al., 2008). Leptin, adiponectin and TNF-α have been suggested as much stronger predictors of pregnancy-associated insulin resistance than gestational hormones, including human placental lactogen and steroids (Lepercq et al., 1998, Kirwan et al., 2002 and Radaelli et al., 2003). In previously published studies, circulating levels of leptin, adiponectin and TNF-α in the early pregnancy closely predicted the development of GDM (Qiu et al., 2004, Hernández Valencia and Zárate, 2005, Maghbooli et al., 2007 and Gao et al., 2008).

To our best knowledge, the contribution of different fat depots (subcutaneous and visceral) to altered levels of adipokines and cytokines in GDM is unknown. Studies of patients with obesity and/or T2DM have shown that metabolic and endocrine characteristics of adipose tissue significantly vary between different locations (Wajchenberg, 2000, Coppack, 2001, Wagenknecht et al., 2003 and Dolinková et al., 2008). Placenta of patients with GDM typically displays structural and functional abnormalities (Alonso et al., 2006) suggesting possible alterations in its endocrine function including disturbed production of adipokines and/or proinflammatory factors (Masuzaki et al., 1997, Radaelli et al., 2003 and Yura et al., 2003). Previous reports confirmed that GDM elicits major changes in the expression profile of placental genes with a prominent increase in markers and mediators of inflammation (Radaelli et al., 2003).

We hypothesized that dysregulated endocrine function of adipose tissue and placenta during pregnancy may contribute to the development of insulin resistance and GDM. The aim of the present study was to characterize the changes in gene expression of adipokines [leptin, resistin, adiponectin and its receptors–adiponectin receptor 1 (ADIPOR1; OMIM 607945), and adiponectin receptor 2 (ADIPOR2; OMIM 607946)], proinflammatory cytokines (IL-6, TNF-α), chemokines (IL-8) and other receptors with potential role in the regulation of glucose and lipid homeostasis [genes for peroxisome proliferator-activated receptor-α (PPAR-α; OMIM 170998), estrogen receptor α (ESR1, ERα; OMIM 133430), and estrogen receptor β (ESR2, ERβ; OMIM 601663)] in subcutaneous and visceral adipose tissue and placenta of patients with gestational diabetes mellitus relative to those in healthy women with physiological pregnancy.

Section snippets

Study subjects

Ten women with GDM (age 34.6 ± 2.50 years) and thirteen healthy age-matched women with physiological pregnancy (age 33.1 ± 1.25 years) were included in the study. Only women with single pregnancy who delivered by planned Cesarean section in the term (40 ± 2 weeks of pregnancy) were enrolled into the study. All GDM were treated by intensive insulin therapy. All women enrolled into the study underwent the 75 g 2 h oral glucose tolerance test (oGTT) between 24th and 28th week of their pregnancy.

Anthropometric characteristic of healthy women with physiological pregnancy and pregnant women with gestational diabetes mellitus (GDM) and their newborns

The study groups were age-matched. Pregnant women with GDM had significantly higher BMI before pregnancy, higher BMI third day after delivery, and higher percentage of body fat third day after delivery relative to control group. Birth weight, birth length and birth weight/length ratio of the newborns did not differ between the groups (Table 1).

Maternal and fetal serum biochemical and hormonal parameters of GDM and control group

Maternal serum levels of adiponectin, resistin, C-peptide, triglycerides, and estradiol did not significantly differ in GDM group as compared with

Discussion

The most important finding of this study is that visceral fat leptin gene expression and subcutaneous fat IL-6 and IL-8 gene expressions were significantly increased, whereas subcutaneous fat ERα and ERβ gene expressions were significantly decreased in women with GDM relative to healthy age-matched women with physiological pregnancy.

Inspite of previously suggested predictive role for leptin in the development of GDM (Qiu et al., 2004, Maghbooli et al., 2007 and Gao et al., 2008), there is still

Acknowledgements

Supported by IGA MHCR no. 8302-5 to MH and PK. We thank to obstetricians and the patients for their collaboration. The special thank belongs to Mrs. Hana Vágnerová for help with the majority of tissue sampling.

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