title: Insulin resistance is associated with epigenetic and genetic regulation of mitochondrial DNA in obese humans.
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.
authors.affiliation: Department of Human Nutrition, Foods and Exercise, Fralin Translational Obesity Research Center, College of Agriculture and Life Science, Virginia Tech, Blacksburg, Virginia USA.
authors.forename: Louise D
authors.initials: LD
authors.lastname: Zheng
authors.affiliation: Department of Human Nutrition, Foods and Exercise, Fralin Translational Obesity Research Center, College of Agriculture and Life Science, Virginia Tech, Blacksburg, Virginia USA.
authors.forename: Leah E
authors.initials: LE
authors.lastname: Linarelli
authors.affiliation: Department of Human Nutrition, Foods and Exercise, Fralin Translational Obesity Research Center, College of Agriculture and Life Science, Virginia Tech, Blacksburg, Virginia USA.
authors.forename: Longhua
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Human Nutrition, Foods and Exercise, Fralin Translational Obesity Research Center, College of Agriculture and Life Science, Virginia Tech, Blacksburg, Virginia USA.
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Wall
authors.affiliation: Department of Family and Community Medicine, Carilion Clinic, Roanoke, Virginia, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Greenawald
authors.affiliation: Department of Psychiatry, Carilion Clinic, Roanoke, Virginia, USA.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Seidel
authors.affiliation: Department of Human Nutrition, Foods and Exercise, Fralin Translational Obesity Research Center, College of Agriculture and Life Science, Virginia Tech, Blacksburg, Virginia USA ; Department of Family and Community Medicine, Carilion Clinic, Roanoke, Virginia, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Estabrooks
authors.affiliation: Department of Human Nutrition, Foods and Exercise, Fralin Translational Obesity Research Center, College of Agriculture and Life Science, Virginia Tech, Blacksburg, Virginia USA.
authors.forename: Fabio A
authors.initials: FA
authors.lastname: Almeida
authors.affiliation: Department of Human Nutrition, Foods and Exercise, Fralin Translational Obesity Research Center, College of Agriculture and Life Science, Virginia Tech, Blacksburg, Virginia USA.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Cheng
keywords: D-loop; DNA methylation; Epigenetic; Genetic; Insulin resistance; Metabolism; Mitochondrial regulation; Obesity