Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity.
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.
Pietiläinen
Kirsi H
KH
Obesity Research Unit, Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
Naukkarinen
Jussi
J
Rissanen
Aila
A
Saharinen
Juha
J
Ellonen
Pekka
P
Keränen
Heli
H
Suomalainen
Anu
A
Götz
Alexandra
A
Suortti
Tapani
T
Yki-Järvinen
Hannele
H
Oresic
Matej
M
Kaprio
Jaakko
J
Peltonen
Leena
L
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*
D000597:Amino Acids, Branched-Chain; D004272:DNA, Mitochondrial