Abstract
Adipokines secreted by hypertrophic visceral adipose tissue (VAT) instigate low-grade inflammation, followed by hyperglycemia (HG)-related metabolic disorders. The latter may develop with the participation of epigenetic modifications. Our aim was to assess how HG influences selected epigenetic modifications and the expression of interleukin 6 (IL-6) and adiponectin (APN; gene symbol ADIPOQ) during the adipogenesis of human visceral preadipocytes (HPA-v). Adipocytes (Ads) were chronically or transiently HG-treated during three stages of adipogenesis (proliferation, differentiation, maturation). We measured adipokine mRNA, protein, proven or predicted microRNA expression (RT-qPCR and ELISA), and enrichment of H3K9/14ac, H3K4me3, and H3K9me3 at gene promoter regions (chromatin immunoprecipitation). In chronic HG, we detected different expression patterns of the studied adipokines at the mRNA and protein levels. Chronic and transient HG-induced changes in miRNA (miR-26a-5p, miR-26b-5p, let-7d-5p, let-7e-5p, miR-365a-3p, miR-146a-5p) were mostly convergent to altered IL-6 transcription. Alterations in histone marks at the IL6 promoter were also in agreement with IL-6 mRNA. The open chromatin marks at the ADIPOQ promoter mostly reflected the APN transcription during NG adipogenesis, while, in the differentiation stage, HG-induced changes in all studied marks were in line with APN mRNA levels. In summary, HG dysregulated adipokine expression, promoting inflammation. Epigenetic changes coexisted with altered expression of adipokines, especially for IL-6; therefore, epigenetic marks induced by transient HG may act as epi-memory in Ads. Such changes in the epigenome and expression of adipokines could be instrumental in the development of inflammation and metabolic deregulation of VAT.
Highlights
Among the various types of adipose tissue (AT), visceral adipose tissue (VAT) prevails in its contribution to the development and progression of metabolic disorders
Each variant was coded with the letters N or H, reflecting the glycemic conditions, whereas the number of letters denoted the number of completed stages of cell culture (e.g., NNN refers to mature adipocytes that were cultured in NG for all three stages of adipogenesis; HN refers to cells after the differentiation stage that were exposed to HG during the first stage—preadipocyte proliferation)
Expression Profiles of interleukin 6 (IL-6) and APN Are Disrupted with Chronic HG Exposure We observed that, during adipogenesis under NG, the expression of IL-6 mRNA significantly decreased after adipocyte differentiation (NN vs. N, p < 0.001) and was slightly elevated after adipocyte maturation (NNN vs. NN, p = 0.0068; Figure 2A)
Summary
Among the various types of adipose tissue (AT), visceral adipose tissue (VAT) prevails in its contribution to the development and progression of metabolic disorders. Visceral obesity may lead to the development of insulin resistance (IR), prediabetes, and eventually type 2 diabetes mellitus (T2DM). The differentiation of preadipocytes involves a transcriptional cascade including peroxisome proliferator-activated receptor-γ (PPAR-γ) and CCAAT-enhancer-binding proteins (C/EBPs), which manage the process of adipogenesis. Apart from energy storing, AT functions as a complex paracrine and endocrine organ that secretes specific cytokines (i.e., adipokines), e.g., leptin, adiponectin (APN), resistin, visfatin, monocyte chemotactic protein-1, interleukin 6 (IL-6,) and tumor necrosis factor α (TNF-α), and is involved in the energy balance and inflammatory response [4]
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