Chronic and Transient Hyperglycemia Induces Changes in the Expression Patterns of IL6 and ADIPOQ Genes and Their Associated Epigenetic Modifications in Differentiating Human Visceral Adipocytes

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.

The Interplay between Insulin Resistance, Inflammation, Oxidative Stress, Base Excision Repair and Metabolic Syndrome in Nonalcoholic Fatty Liver Disease

“…Visceral adipose tissue plays an important role in the development of T2DM, as well as NAFLD, by producing cytokines and activating the NF-κB pathway [226,227]. Increased gluconeogenesis and attenuation of insulin sensitivity are observed due to the activity of protein kinase Cε, fetuin A/B, retinol-binding protein 4, or selenoprotein P. T2DM patients typically demonstrate higher hepatic fat content and inflammation.…”

Epigenetics and Beyond: Targeting Histone Methylation to Treat Type 2 Diabetes Mellitus

“…H3K4me3 enhancement was observed in proinflammatory genes ( MCP-1 and TNF- α), profibrotic genes ( TGF-β1 and collagen III ), and histone-modifying enzyme ( SET1 and BRG1 ) in an ischemia-reperfusion injury animal model ( Naito et al, 2009 ). In IR state, H3K4me3 and H3K9/14ac were reduced in adipose tissue ( Figure 2 ) ( Wróblewski et al, 2021 ). The enhancement of the H3K4me3 level promoted PEPCK expression, which might contribute to hyperglycemia and anorexia in mandarin fish fed on carbohydrate-rich diets ( You et al, 2020 ).…”

Chronic and Intermittent Hyperglycemia Modulates Expression of Key Molecules of PI3K/AKT Pathway in Differentiating Human Visceral Adipocytes

“…IRS binds to the kinase regulatory subunit of PI3K (PI3K-R), the central molecule of the pathway. This, in turn, causes activation of the catalytic PI3K (PI3K-C) subunit that converts phosphatidylinositol (4,5)-biphosphate (PIP2) to phosphatidylinositol (3,4,5)-triphosphate (PIP3) [8]. The main insulin pathway regulator, PTEN, (phosphatase and tensin homolog), inhibits further signal transduction by PIP3 dephosphorylation [10].…”

“…VAT surrounds the abdominal viscera in the mesentery and omentum. It produces and releases a large number of adipocytokines that influence both VAT and other tissues [ 2 , 3 ]. It is suggested that hyperglycemia (HG), a typical marker of diabetes causing nutrient stress, may alter the production of adipocytokines and change biochemical pathways including insulin signaling [ 3 , 4 ].…”

“…It produces and releases a large number of adipocytokines that influence both VAT and other tissues [ 2 , 3 ]. It is suggested that hyperglycemia (HG), a typical marker of diabetes causing nutrient stress, may alter the production of adipocytokines and change biochemical pathways including insulin signaling [ 3 , 4 ]. It was demonstrated that during chronic HG (CHG), adipocytes (Ads) are not capable of storing energy excess and the process of new Ads formation, adipogenesis (ADG), is interrupted [ 5 ].…”