Abstract
Reprogramming of adipocyte function in obesity is implicated in metabolic disorders like type 2 diabetes. Here, we used the pig, an animal model sharing many physiological and pathophysiological similarities with humans, to perform in-depth epigenomic and transcriptomic characterization of pure adipocyte fractions. Using a combined DNA methylation capture sequencing and Reduced Representation bisulfite sequencing (RRBS) strategy in 11 lean and 12 obese pigs, we identified in 3529 differentially methylated regions (DMRs) located at close proximity to-, or within genes in the adipocytes. By sequencing of the transcriptome from the same fraction of isolated adipocytes, we identified 276 differentially expressed transcripts with at least one or more DMR. These transcripts were over-represented in gene pathways related to MAPK, metabolic and insulin signaling. Using a candidate gene approach, we further characterized 13 genes potentially regulated by DNA methylation and identified putative transcription factor binding sites that could be affected by the differential methylation in obesity. Our data constitute a valuable resource for further investigations aiming to delineate the epigenetic etiology of metabolic disorders.
Highlights
Obesity is a severe global health concern associated to several metabolic diseases, such as insulin resistance, type 2 diabetes, cardiovascular diseases, and several forms of cancer (Davoodi et al, 2013; Pedersen, 2013)
Compared to the lean group, the obese group is characterized by higher body mass index (BMI), abdomen circumference, visceral fat amounts, and circulating total cholesterol and triglycerides
We found that methylation pattern of adipocytes of obese pigs is altered in 7985 regions, that we assigned to 3529 unique genes
Summary
Obesity is a severe global health concern associated to several metabolic diseases, such as insulin resistance, type 2 diabetes, cardiovascular diseases, and several forms of cancer (Davoodi et al, 2013; Pedersen, 2013). Genetic factors determine approximately 40% to 70% of the phenotypic variation in obesity (Albuquerque et al, 2015); Epigenetic Signatures of Adipocytes in Obesity so far, only a small fraction of this variation has been explained by loci identified by genome wide association studies (GWAS) Epigenetic modifications such as DNA methylation and histone modifications have an important influence on gene regulation and have been acknowledged as additional contributing factors in the development of obesity (Campión et al, 2009; Ronn et al, 2015). Gene expression in adipose tissue changes significantly in the obese state, due to adipocytes expansion and increased exposure of circulating insulin levels (Ahima and Flier, 2000; Reilly and Saltiel, 2017). Long term disturbance of these pathways has considerable consequences for the cells, notably on pathways disrupted in cancer, which may explain why obesity is linked to an increased risk of developing cancer (Hopkins et al, 2016)
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