Insulin resistance is associated with epigenetic and genetic regulation of mitochondrial DNA in obese humans

dc.contributor.authorZheng, Louise D.en
dc.contributor.authorLinarelli, Leah E.en
dc.contributor.authorLiu, Longhuaen
dc.contributor.authorWall, Sarah S.en
dc.contributor.authorGreenawald, Mark H.en
dc.contributor.authorSeidel, Richard W.en
dc.contributor.authorEstabrooks, Paul A.en
dc.contributor.authorAlmeida, Fabio A.en
dc.contributor.authorCheng, Zhiyongen
dc.contributor.departmentHuman Nutrition, Foods, and Exerciseen
dc.date.accessioned2015-07-31T16:40:48Zen
dc.date.available2015-07-31T16:40:48Zen
dc.date.issued2015-06-10en
dc.date.updated2015-07-31T16:40:48Zen
dc.description.abstractBackground 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.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationClinical Epigenetics. 2015 Jun 10;7(1):60en
dc.identifier.doihttps://doi.org/10.1186/s13148-015-0093-1en
dc.identifier.urihttp://hdl.handle.net/10919/55024en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.holderZheng et al.en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleInsulin resistance is associated with epigenetic and genetic regulation of mitochondrial DNA in obese humansen
dc.title.serialClinical Epigeneticsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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