Alterations of adiponectin gene expression and DNA methylation in adipose tissues and blood cells are associated with gestational diabetes and neonatal outcome

Abstract

BackgroundAdiponectin critically contributes to metabolic homeostasis, especially by insulin-sensitizing action. Gestational diabetes mellitus (GDM) is characterized by insulin resistance leading to materno-fetal hyperglycemia and detrimental birth outcomes. By investigating paired subcutaneous (SAT) and visceral adipose tissue (VAT) as well as blood (cell) samples of GDM-affected (n = 25) vs. matched control (n = 30) mother-child dyads of the prospective “EaCH” cohort study, we addressed whether alterations of adiponectin plasma, mRNA, and DNA methylation levels are associated with GDM and offspring characteristics.ResultsHypoadiponectinemia was present in women with GDM, even after adjustment for body mass index (BMI). This was accompanied by significantly decreased mRNA levels in both SAT and VAT (P < 0.05), independent of BMI. Maternal plasma adiponectin showed inverse relations with glucose and homeostatic model assessment of insulin resistance (both P < 0.01). In parallel to reduced mRNA expression in GDM, significant (P < 0.05) yet small alterations in locus-specific DNA methylation were observed in maternal fat (~ 2%) and blood cells (~ 1%). While newborn adiponectin levels were similar between groups, DNA methylation in GDM offspring was variously altered (~ 1–4%; P < 0.05).ConclusionsReduced adiponectin seems to be a pathogenic co-factor in GDM, even independent of BMI, affecting materno-fetal metabolism. While altered maternal DNA methylation patterns appear rather marginally involved, functional, diagnostic, and/or predictive implications of cord blood DNA methylation should be further evaluated.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0567-z) contains supplementary material, which is available to authorized users.

Visceral Adipose Tissue Inflammatory Factors (TNF-Alpha, SOCS3) in Gestational Diabetes (GDM): Epigenetics as a Clue in GDM Pathophysiology

“…However, recent data support the suggestion of an explicit part of VAT and visceral adiposity in GDM [18,[36][37][38][39]. Particularly, the expression of insulin receptor and adiponectin were found to be altered in GDM patients, accompanied by altered promoter methylation [16,17]. Importantly, this has been shown to occur even independent of the BMI, which is so far the only adipogenic indicator/marker clinically considered in GDM screening/treatment but, on the other hand, hardly serves as a marker for visceral type of obesity.…”

“…The research presented here is part of the prospective observational 'Early CHARITÉ (EaCH)' cohort study [16,17,19,44]. Genes involved in the inflammatory process were further investigated on the cases in which the optimal material and factors (such as transcription, metabolic and hormonal) could be measured in a complete set so as to avoid a missing data bias.…”

“…No oral antidiabetic drugs were administered in the GDM group, eight were treated by diet and eleven were treated with diet and additional insulin therapy to achieve glycemic control. Further clinical parameters such as plasma insulin, C-peptide, glucose and HOMA-IR were determined for these cases as described elsewhere [16,17,44,47]. The research design and methodology were conducted in accordance with the Declaration of Helsinki, revised in 2004, and approved by the local Ethics Committee (Ethikausschuss 2 am Campus Virchow-Klinikum, Charité Universitätsklinikum Berlin, EA2/026/04).…”

“…As obesity is associated with inflammatory changes [15], we wanted to build on our previous investigations/findings on the 'EaCH' cohort [16][17][18] and now focused on the inflammatory markers, tumor necrosis factor-alpha (TNF-α) and suppressor of cytokine signaling 3 (SOCS3) which have been identified as key candidates of obesity-related insulin resistance [19][20][21]. Through intensified inflammation comes the promotion of cell death/apoptosis critical in restoring tissue homeostasis.…”

“…Epigenetic alterations, especially of promoter methylation patterns, have been proposed as potential causes of insulin resistance, GDM, and obesity in a variety of aspects [2,13,16,17]. Therefore, in order to contribute to a better understanding of GDM pathophysiology, we sought to investigate the potential alterations of both TNF-α and/or SOCS3 mRNA expression and methylation in adipose tissues of women with GDM compared to pregnancies with normal glucose tolerance (NGT).…”