Abstract
We hypothesised that epigenetics may play an important role in mediating fibroblast growth factor 21 (FGF21) resistance in obesity. We aimed to evaluate DNA methylation changes and miRNA pattern in obese subjects associated with high serum FGF21 levels. The study included 136 participants with BMI 27–45 kg/m2. Fasting FGF21, glucose, insulin, GIP, lipids, adipokines, miokines and cytokines were measured and compared in high serum FGF21 (n = 68) group to low FGF21 (n = 68) group. Human DNA Methylation Microarrays were analysed in leukocytes from each group (n = 16). Expression of miRNAs was evaluated using quantitative PCR-TLDA. The study identified differentially methylated genes in pathways related to glucose transport, insulin secretion and signalling, lipid transport and cellular metabolism, response to nutrient levels, thermogenesis, browning of adipose tissue and bone mineralisation. Additionally, it detected transcription factor genes regulating FGF21 and fibroblast growth factor receptor and vascular endothelial growth factor receptor pathways regulation. Increased expression of hsa-miR-875-5p and decreased expression of hsa-miR-133a-3p, hsa-miR-185-5p and hsa-miR-200c-3p were found in the group with high serum FGF21. These changes were associated with high FGF21, VEGF and low adiponectin serum levels. Our results point to a significant role of the epigenetic regulation of genes involved in metabolic pathways related to FGF21 action.
Highlights
Probes differentially methylated (p < 0.01, representing approximately 4.6% of probes located on the array), of which 5425 were significantly hypomethylated and 5774 were significantly hypermethylated in the high fibroblast growth factor 21 (FGF21) group compared to the low FGF21 group
We focused on those genes that were engaged in metabolism of lipids, glucose and adipokines and other pathways known or potentially related to FGF21 activity
Results of microRNA Expression Level in Leukocytes: We demonstrated a statistically significant difference in expression of four miRNAs in peripheral blood leukocytes related to high FGF21 serum levels
Summary
Fibroblast growth factor 21 (FGF21) acts as an endocrine factor that regulates glucose and lipids homeostasis in humans and animals its function is still debated due to its different sites of production and actions [1,2,3]. FGF21 is primarily expressed in the liver and in the skeletal muscles, adipose tissue, gut and pancreas [4]. FGF21 is regulated by nutritional status (fasting state, high carbohydrate and high protein ingestion) as well as physical activity [3,5,6,7]. FGF21 expression in the liver was found to be up-regulated by glucagon and by glucocorticoids, and repressed by insulin [3]. Circulating FGF21 concentrations exhibit a characteristic diurnal rhythm in humans [8].
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