title: Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Obesity Research Unit, Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Kirsi H
authors.initials: KH
authors.lastname: Pietiläinen
authors.forename: Jussi
authors.initials: J
authors.lastname: Naukkarinen
authors.forename: Aila
authors.initials: A
authors.lastname: Rissanen
authors.forename: Juha
authors.initials: J
authors.lastname: Saharinen
authors.forename: Pekka
authors.initials: P
authors.lastname: Ellonen
authors.forename: Heli
authors.initials: H
authors.lastname: Keränen
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
authors.forename: Alexandra
authors.initials: A
authors.lastname: Götz
authors.forename: Tapani
authors.initials: T
authors.lastname: Suortti
authors.forename: Hannele
authors.initials: H
authors.lastname: Yki-Järvinen
authors.forename: Matej
authors.initials: M
authors.lastname: Oresic
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kaprio
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D000328:Adult; D000597:Amino Acids, Branched-Chain / Q000097:blood; D015992:Body Mass Index; D002454:Cell Differentiation / Q000502:physiology; D003430:Cross-Sectional Studies; D004272:DNA, Mitochondrial / Q000378:metabolism*; D015536:Down-Regulation; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D006946:Hyperinsulinism / Q000503:physiopathology; D007249:Inflammation / Q000503:physiopathology; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000033:anatomy & histology; D008137:Longitudinal Studies; D008297:Male; D053858:Metabolic Networks and Pathways; D009765:Obesity / Q000209:etiology* / Q000378:metabolism; D014430:Twins, Monozygotic / Q000502:physiology*
chemical_list: D000597:Amino Acids, Branched-Chain; D004272:DNA, Mitochondrial