Weight Loss after Gastric Bypass Surgery in Human Obesity Remodels Promoter Methylation

• Gastric-bypass-induced weight loss affects expression of metabolic genes in muscle
• Gastric-bypass-induced weight loss normalizes promoter methylation levels
• Methylation at non-CpG sites affects gene expression
• DNA methyltransferase 1 is altered in gastric-bypass-induced weight loss

SummaryDNA methylation provides a mechanism by which environmental factors can control insulin sensitivity in obesity. Here, we assessed DNA methylation in skeletal muscle from obese people before and after Roux-en-Y gastric bypass (RYGB). Obesity was associated with altered expression of a subset of genes enriched in metabolic process and mitochondrial function. After weight loss, the expression of the majority of the identified genes was normalized to levels observed in normal-weight, healthy controls. Among the 14 metabolic genes analyzed, promoter methylation of 11 genes was normalized to levels observed in the normal-weight, healthy subjects. Using bisulfite sequencing, we show that promoter methylation of PGC-1α and PDK4 is altered with obesity and restored to nonobese levels after RYGB-induced weight loss. A genome-wide DNA methylation analysis of skeletal muscle revealed that obesity is associated with hypermethylation at CpG shores and exonic regions close to transcription start sites. Our results provide evidence that obesity and RYGB-induced weight loss have a dynamic effect on the epigenome.

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