Insulin Resistance is Associated with Epigenetic and Genetic Regulation of Mitochondrial DNA in Obese Humans

Overview

Journal Clin Epigenetics

Publisher Biomed Central

Specialty Genetics

Date 2015 Jun 26

PMID 26110043

Citations 58

Authors

Louise D Zheng

Leah E Linarelli

Longhua Liu

Sarah S Wall

Mark H Greenawald

Richard W Seidel

Paul A Estabrooks

Fabio A Almeida

Zhiyong Cheng

Affiliations

Soon will be listed here.

Abstract

Background: 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. However, the molecular mechanism underlying mitochondrial aberrance remains largely unexplored in human subjects.

Results: Here 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.

Conclusions: The 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.

Citing Articles

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