Abstract
High-fat diet (HFD) is an environmental factor that contributes to the pathogenesis of obesity and type 2 diabetes. A number of genes influencing oxidative phosphorylation (OXPHOS) were found to be downregulated in skeletal muscle of humans and rats treated with HFD and have been implicated in mitochondrial dysfunction, insulin resistance, and consequent type 2 diabetes. In this study, we hypothesized that DNA methylation plays a crucial role in the regulation of OXPHOS genes in skeletal muscle of rats exposed to HFD. Using whole genome promoter methylation analysis of skeletal muscle followed by qPCR and bisulfite sequencing analysis, we identified hypermethylation of Cox5a in HFD rats. Furthermore, we found that Cox5a hypermethylation was associated with downregulation of Cox5a expression at the mRNA and protein level, and a reduction in mitochondrial complex IV activity and ATP content in HFD-induced insulin resistant rats compared to controls. Moreover, we found that while exposure to palmitate resulted in hypermethylation of the Cox5a promoter in rat myotubes, demethylation with 5-aza-2′-deoxycytidine was associated with preserved Cox5a expression, as well as restoration of complex IV activity and cellular ATP content. These novel observations indicate that Cox5a hypermethylation is associated with mitochondrial dysfunction in skeletal muscle of HFD-induced insulin resistant rats.
Highlights
Type 2 diabetes mellitus (T2DM) is a heterogeneous and complex disease characterized by insulin resistance in adipose tissue, liver, and skeletal muscle, as well as impaired pancreatic insulin secretion
We demonstrated that a significant difference of glucose tolerance still existed after 14 h of fasting in high-fat diet (HFD) rats compared with control rats (Figure 1B), a previous study showed that longer fasting could enhance insulin sensitivity in mice [26]
From the skeletal muscle obtained from the control and HFD rats, we identified 500 hypermethylated genes and 284 hypomethylated genes using MeDIP and microarray analysis
Summary
Type 2 diabetes mellitus (T2DM) is a heterogeneous and complex disease characterized by insulin resistance in adipose tissue, liver, and skeletal muscle, as well as impaired pancreatic insulin secretion. There is increasing evidence that DNA methylation is affected by environmental factors and may be a potential molecular mechanism for the interaction between genetic and environmental factors in the development of obesity and T2DM [5,6,7,8]. The present evidence indicates that epigenetic modification by DNA methylation is a potential mechanism by which environmental factors interact with the epigenome, resulting in long-term changes in gene expression. It still remains unclear whether HFD exposure may induce epigenetic modification and how this may lead to certain metabolic disorders such as obesity and T2DM
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