Global transcript profiles of fat in monozygotic twins discordant for BMI: Pathways behind acquired obesity

K. H. Pietiläinen, J. Naukkarinen, A. Rissanen, J. Saharinen, P. Ellonen, H. Keränen, A. Suomalainen, A. Götz, Tapani Suortti, H. Yki-Järvinen, Matej Orešič, J. Kaprio, L. Peltonen (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

172 Citations (Scopus)

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.

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/m2. 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.

Original languageEnglish
Article numbere51
Pages (from-to)0472-0483
JournalPLoS Medicine
Volume5
Issue number3
DOIs
Publication statusPublished - 2008
MoE publication typeA1 Journal article-refereed

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Monozygotic Twins
Body Mass Index
Obesity
Fats
Mitochondrial DNA
Insulin Resistance
Amino Acids
Branched Chain Amino Acids
Gene-Environment Interaction
Subcutaneous Fat
Hyperinsulinism
Sequence Analysis
Registries
Adipose Tissue
Young Adult
Leukocytes
Down-Regulation
Insulin
Morbidity
Liver

Cite this

Pietiläinen, K. H., Naukkarinen, J., Rissanen, A., Saharinen, J., Ellonen, P., Keränen, H., ... Peltonen, L. (2008). Global transcript profiles of fat in monozygotic twins discordant for BMI: Pathways behind acquired obesity. PLoS Medicine, 5(3), 0472-0483. [e51]. https://doi.org/10.1371/journal.pmed.0050051
Pietiläinen, K. H. ; Naukkarinen, J. ; Rissanen, A. ; Saharinen, J. ; Ellonen, P. ; Keränen, H. ; Suomalainen, A. ; Götz, A. ; Suortti, Tapani ; Yki-Järvinen, H. ; Orešič, Matej ; Kaprio, J. ; Peltonen, L. / Global transcript profiles of fat in monozygotic twins discordant for BMI : Pathways behind acquired obesity. In: PLoS Medicine. 2008 ; Vol. 5, No. 3. pp. 0472-0483.
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title = "Global transcript profiles of fat in monozygotic twins discordant for BMI: Pathways behind acquired obesity",
abstract = "BackgroundThe 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 FindingsWe 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/m2. 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.ConclusionsOur findings emphasize a substantial role of mitochondrial energy- and amino acid metabolism in obesity and development of insulin resistance.",
author = "Pietil{\"a}inen, {K. H.} and J. Naukkarinen and A. Rissanen and J. Saharinen and P. Ellonen and H. Ker{\"a}nen and A. Suomalainen and A. G{\"o}tz and Tapani Suortti and H. Yki-J{\"a}rvinen and Matej Orešič and J. Kaprio and L. Peltonen",
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Pietiläinen, KH, Naukkarinen, J, Rissanen, A, Saharinen, J, Ellonen, P, Keränen, H, Suomalainen, A, Götz, A, Suortti, T, Yki-Järvinen, H, Orešič, M, Kaprio, J & Peltonen, L 2008, 'Global transcript profiles of fat in monozygotic twins discordant for BMI: Pathways behind acquired obesity', PLoS Medicine, vol. 5, no. 3, e51, pp. 0472-0483. https://doi.org/10.1371/journal.pmed.0050051

Global transcript profiles of fat in monozygotic twins discordant for BMI : Pathways behind acquired obesity. / Pietiläinen, K. H.; Naukkarinen, J.; Rissanen, A.; Saharinen, J.; Ellonen, P.; Keränen, H.; Suomalainen, A.; Götz, A.; Suortti, Tapani; Yki-Järvinen, H.; Orešič, Matej; Kaprio, J.; Peltonen, L. (Corresponding Author).

In: PLoS Medicine, Vol. 5, No. 3, e51, 2008, p. 0472-0483.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Global transcript profiles of fat in monozygotic twins discordant for BMI

T2 - Pathways behind acquired obesity

AU - Pietiläinen, K. H.

AU - Naukkarinen, J.

AU - Rissanen, A.

AU - Saharinen, J.

AU - Ellonen, P.

AU - Keränen, H.

AU - Suomalainen, A.

AU - Götz, A.

AU - Suortti, Tapani

AU - Yki-Järvinen, H.

AU - Orešič, Matej

AU - Kaprio, J.

AU - Peltonen, L.

PY - 2008

Y1 - 2008

N2 - BackgroundThe 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 FindingsWe 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/m2. 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.ConclusionsOur findings emphasize a substantial role of mitochondrial energy- and amino acid metabolism in obesity and development of insulin resistance.

AB - BackgroundThe 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 FindingsWe 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/m2. 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.ConclusionsOur findings emphasize a substantial role of mitochondrial energy- and amino acid metabolism in obesity and development of insulin resistance.

U2 - 10.1371/journal.pmed.0050051

DO - 10.1371/journal.pmed.0050051

M3 - Article

VL - 5

SP - 472

EP - 483

JO - PLoS Medicine

JF - PLoS Medicine

SN - 1549-1277

IS - 3

M1 - e51

ER -

Pietiläinen KH, Naukkarinen J, Rissanen A, Saharinen J, Ellonen P, Keränen H et al. Global transcript profiles of fat in monozygotic twins discordant for BMI: Pathways behind acquired obesity. PLoS Medicine. 2008;5(3):0472-0483. e51. https://doi.org/10.1371/journal.pmed.0050051