Abstract
BackgroundMitochondrial alterations have been observed in subjects with metabolic disorders such as obesity and diabetes. Studies on animal models and cell cultures suggest aberrant glucose and lipid levels, and impaired insulin signaling might lead to mitochondrial changes. However, the molecular mechanism underlying mitochondrial aberrance remains largely unexplored in human subjects.ResultsHere we show that the mitochondrial DNA copy number (mtDNAn) was significantly reduced (6.9-fold lower, p < 0.001) in the leukocytes from obese humans (BMI >30). The reduction of mtDNAn was strongly associated with insulin resistance (HOMA-IR: −0.703, p < 0.05; fasting insulin level: −0.015, p < 0.05); by contrast, the correlation between fasting glucose or lipid levels and mtDNAn was not significant. Epigenetic study of the displacement loop (D-loop) region of mitochondrial genome, which controls the replication and transcription of the mitochondrial DNA as well as organization of the mitochondrial nucleoid, revealed a dramatic increase of DNA methylation in obese (5.2-fold higher vs. lean subjects, p < 0.05) and insulin-resistant (4.6-fold higher vs. insulin-sensitive subjects, p < 0.05) individuals.ConclusionsThe reduction of mtDNAn in obese human subjects is associated with insulin resistance and may arise from increased D-loop methylation, suggesting an insulin signaling-epigenetic-genetic axis in mitochondrial regulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0093-1) contains supplementary material, which is available to authorized users.
Highlights
Mitochondrial alterations have been observed in subjects with metabolic disorders such as obesity and diabetes
These findings suggest that changes in mitochondrial DNA copy number (mtDNAn) and mitochondrial DNA (mtDNA) methylation may play an important role in metabolic disorders
We detected a significantly increased DNA methylation in the displacement loop (D-loop) region, which was concomitant with decreased mtDNAn in the obese individuals when they were compared with the lean subjects
Summary
Mitochondrial alterations have been observed in subjects with metabolic disorders such as obesity and diabetes. Studies on animal models and cell cultures suggest aberrant glucose and lipid levels, and impaired insulin signaling might lead to mitochondrial changes. In addition to the changes in glucose and lipid metabolism, obesity is associated with insulin resistance and increased risk of type 2 diabetes (T2D) and cardiovascular diseases (CVD) [1,2,3]. The change in MT-ND6 methylation was significantly associated with nonalcoholic fatty liver-disease activity score [20]. These findings suggest that changes in mtDNAn and mtDNA methylation may play an important role in metabolic disorders
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