Altered Adipose Tissue DNA Methylation Status in Metabolic Syndrome: Relationships Between Global DNA Methylation and Specific Methylation at Adipogenic, Lipid Metabolism and Inflammatory Candidate Genes and Metabolic Variables

Abstract

Metabolic syndrome (MetS) has been postulated to increase the risk for type 2 diabetes, cardiovascular disease and cancer. Adipose tissue (AT) plays an important role in metabolic homeostasis, and AT dysfunction has an active role in metabolic diseases. MetS is closely related to lifestyle and environmental factors. Epigenetics has emerged as an interesting landscape to evaluate the possible interconnection between AT and metabolic disease, since it can be modulated by environmental factors and metabolic status. The aim of this study was to determine whether MetS has an impact on the global DNA methylation pattern and the DNA methylation of several genes related to adipogenesis (PPARG, PPARA), lipid metabolism (RXRA, SREBF2, SREBF1, SCD, LPL, LXRb), and inflammation (LRP1 C3, LEP and TNF) in visceral adipose tissue. LPL and TNF DNA methylation values were significantly different in the control-case comparisons, with higher and lower methylation respectively in the MetS group. Negative correlations were found between global DNA methylation (measured by LINE-1 methylation levels) and the metabolic deterioration and glucose levels. There were associations among variables of MetS, BMI, and HOMA-IR with DNA methylation at several CpG positions for the studied genes. In particular, there was a strong positive association between serum triglyceride levels (TG) with PPARA and LPL methylation levels. TNF methylation was negatively associated with the metabolic worsening and could be an important factor in preventing MetS occurrence according to logistic regression analysis. Therefore, global DNA methylation and methylation at specific genes related to adipogenesis, lipid metabolism and inflammation are related to the etiology of MetS and might explain in part some of the features associated to metabolic disorders.

Keywords: DNA methylation; adipose tissue; epigenetics; metabolic syndrome.

Figure 1

Diagram presenting the workflow of the study to measure global and specific DNA methylation levels.

Figure 2

Adipogenic factors DNA methylation. DNA methylation profile across the CpG analyzed at the promoters of the adipogenic factors PPARA (A), PPARG (B), and the PPARs partner RXRA (C) in both, Non MetS and MetS groups. Values are given as the mean ± SE. Peroxisome proliferator-activated receptor alpha (PPARA); Peroxisome proliferator-activated receptor gamma (PPARG); Retinoid X receptor alpha (RXRA).

Figure 3

Lipid metabolism DNA methylation. The figure shows the DNA methylation in Non MetS and MetS groups at each CpG for several factors related to lipid metabolism as SREBF1 (A), SREBF2 (B), LRP1 (C), LPL (D), SCD (E), and LXRB (F). Values are given as the mean ± SE. Sterol regulatory element binding transcription factor 1 (SREBF1); Sterol regulatory element binding transcription factor 2 (SREBF2); low density lipoprotein receptor-related protein 1 (LRP1); lipoprotein lipase (LPL); Stearoyl-CoA desaturase (SCD); liver X receptor beta (LXRB). * means p < 0.05 according to a Student’s T-test.

Figure 4

Inflammatory promoters DNA methylation. Comparisons between the Non MetS and the MetS group for DNA methylation at different CpG from genes implied in inflammatory processes as C3 (A), TNF (B) and LEP (C). Values are given as the mean ± SE. Complement factor 3 (C3); tumor necrosis factor (TNF); leptin (LEP). * means p < 0.05 according to a Student’s T-test.