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Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity
Obesity Research Unit, Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland; Department of Medicine, Division of Diabetes, Helsinki University Central Hospital, Helsinki, Finland; Finnish Twin Cohort Study, Department of Public Health, University of Helsinki, Helsinki, Finland .
Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland; Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland .
Obesity Research Unit, Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland .
Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland; Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland.
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2008 (English)In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 5, no 3, article id e51Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The acquired component of complex traits is difficult to dissect in humans. Obesity represents such a trait, in which the metabolic and molecular consequences emerge from complex interactions of genes and environment. With the substantial morbidity associated with obesity, a deeper understanding of the concurrent metabolic changes is of considerable importance. The goal of this study was to investigate this important acquired component and expose obesity-induced changes in biological pathways in an identical genetic background.

METHODS AND FINDINGS: We used a special study design of "clonal controls," rare monozygotic twins discordant for obesity identified through a national registry of 2,453 young, healthy twin pairs. A total of 14 pairs were studied (eight male, six female; white), with a mean +/- standard deviation (SD) age 25.8 +/- 1.4 y and a body mass index (BMI) difference 5.2 +/- 1.8 kg/m(2). Sequence analyses of mitochondrial DNA (mtDNA) in subcutaneous fat and peripheral leukocytes revealed no aberrant heteroplasmy between the co-twins. However, mtDNA copy number was reduced by 47% in the obese co-twin's fat. In addition, novel pathway analyses of the adipose tissue transcription profiles exposed significant down-regulation of mitochondrial branched-chain amino acid (BCAA) catabolism (p < 0.0001). In line with this finding, serum levels of insulin secretion-enhancing BCAAs were increased in obese male co-twins (9% increase, p = 0.025). Lending clinical relevance to the findings, in both sexes the observed aberrations in mitochondrial amino acid metabolism pathways in fat correlated closely with liver fat accumulation, insulin resistance, and hyperinsulinemia, early aberrations of acquired obesity in these healthy young adults.

CONCLUSIONS: Our findings emphasize a substantial role of mitochondrial energy- and amino acid metabolism in obesity and development of insulin resistance.

Place, publisher, year, edition, pages
Public Library of Science (PLoS) , 2008. Vol. 5, no 3, article id e51
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URN: urn:nbn:se:oru:diva-70915DOI: 10.1371/journal.pmed.0050051ISI: 000254928900020PubMedID: 18336063Scopus ID: 2-s2.0-41549125912OAI: oai:DiVA.org:oru-70915DiVA, id: diva2:1345870
Available from: 2019-08-26 Created: 2019-08-26 Last updated: 2019-08-28Bibliographically approved

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