Obesity alone or with type 2 diabetes is associated with tissue specific alterations in DNA methylation and gene expression of PPARGC1A and IGF2

Abstract

BACKGROUND: Epigenetic modifications of key genes have been linked to the development of aging related diseases, such as type 2 diabetes, with increased DNA methylation of the transcriptional co-activator, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) in islets and skeletal muscle of patients with type 2 diabetes. Here, we examined DNA methylation and gene expression of PPARGC1A and insulin like growth factor-2 (IGF2) in adipose tissue and skeletal muscle of lean and morbidly obese individuals with or without type 2 diabetes. METHODS: Adipose tissue and skeletal muscle biopsies were collected from 24 lean, obese, and obese patients with type 2 diabetes (n=8/group). DNA methylation and gene expression of PPARGC1A and IGF2 were measured using pyrosequencing and quantitative real-time PCR respectively. RESULTS: DNA methylation and expression of both genes varied in a tissue specific manner (P<0.05). The highest levels of PPARGC1A methylation were observed in subcutaneous adipose tissue and lowest in muscle (P≤0.001), whereas IGF2 methylation was lowest in subcutaneous adipose tissue as compared with visceral adipose tissue and muscle (P≤0.04). Expression of PPARGC1A and IGF2 was highest in muscle and lowest in subcutaneous adipose tissue (P≤0.001) and PPARGC1A expression was conversely correlated with DNA methylation in skeletal muscle (r=-0.54, P=0.008). Obese patients with type 2 diabetes had higher PPARGC1A methylation in subcutaneous adipose tissue (P=0.01) and lower IGF2 DNA methylation in muscle (P=0.01) as compared with lean individuals. Obese patients with and without type 2 diabetes had reduced expression of both genes in subcutaneous adipose tissue (P≤0.04) as compared to lean individuals. CONCLUSIONS: This study showed tissue specific DNA methylation and gene expression of PPARGC1A and IGF2, which may also be associated with obesity and type 2 diabetes. Further study of the effects of tissue specific DNA methylation on risk of obesity and type 2 diabetes in a larger cohort is now warranted.