Abstract
Increased adipocyte lipolysis links obesity to insulin resistance. The lipid droplet coating-protein Perilipin participates in regulation of lipolysis and is implicated in obesity. In the present study we investigate epigenetic regulation of the PLIN1 gene by correlating PLIN1 CpG methylation to gene expression and lipolysis, and functionally evaluating PLIN1 promoter methylation. PLIN1 CpG methylation in adipocytes and gene expression in white adipose tissue (WAT) was quantified in two cohorts by array. Basal lipolysis in WAT explants and adipocytes was quantified by measuring glycerol release. CpG-methylation of the PLIN1 promoter in adipocytes from obese women was higher as compared to never-obese women. PLIN1 promoter methylation was inversely correlated with PLIN1 mRNA expression and the lipolytic activity. Human mesenchymal stem cells (hMSCs) differentiated in vitro into adipocytes and harboring methylated PLIN1 promoter displayed decreased reporter gene activity as compared to hMSCs harboring unmethylated promoter. Treatment of hMSCs differentiated in vitro into adipocytes with a DNA methyltransferase inhibitor increased levels of PLIN1 mRNA and protein. In conclusion, the PLIN1 gene is epigenetically regulated and promoter methylation is inversely correlated with basal lipolysis in women suggesting that epigenetic regulation of PLIN1 is important for increased adipocyte lipolysis in insulin resistance states.
Highlights
During lipolysis, intracellular triacylglycerides (TAGs) undergo hydrolysis through the action of lipases
The obese women displayed a higher basal lipolysis in white adipose tissue (WAT) explants and in isolated adipocytes, which was accompanied by higher NEFA in the general circulation as compared to never-obese women
It is demonstrated that CpG methylation of the PLIN1 gene promoter inhibits promoter activity in vitro, and that adipocyte promoter methylation is inversely correlated with PLIN1 mRNA levels in clinical cohorts
Summary
Intracellular triacylglycerides (TAGs) undergo hydrolysis through the action of lipases. We confirmed that obese women displayed lower expression of PLIN1 mRNA in subcutaneous adipose tissue (P = 0.0058) (Fig. 1a), whereas CpG-methylation of the PLIN1 gene in adipocytes was higher (Fig. 1b), as compared to never-obese women. Differential methylation was most pronounced in the promoter and 5′ region of the gene, and CpG-methylation of adipocyte DNA, quantified as beta-value, was higher in obese as compared to never-obese women of both the explorative and validation cohorts (Table 2).
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