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

Kirsi H. Pietiläinen; Jussi Naukkarinen; Aila Rissanen; Juha Saharinen; Pekka Ellonen; Heli Keränen; Anu Suomalainen; Alexandra Götz; Tapani Suortti; Hannele Yki-Järvinen; Matej Orešič; Jaakko Kaprio; Leena Peltonen

doi:10.1371/journal.pmed.0050051

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

Kirsi H. Pietiläinen
, Jussi Naukkarinen
, Aila Rissanen
, Juha Saharinen
, Pekka Ellonen
, Heli Keränen
, Anu Suomalainen
, Alexandra Götz
, Tapani Suortti
, Hannele Yki-Järvinen
, Matej Orešič
, Jaakko Kaprio
, Leena Peltonen^*

^*Corresponding author for this work

VTT Technical Research Centre of Finland

Wellcome Trust Sanger Institute
MIT Massachusetts Institute of Technology
Broad Institute
Helsinki University Hospital
University of Helsinki
National Public Health Institute of Finland
VTT (former employee or external)

Research output: Contribution to journal › Article › Scientific › peer-review

259 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 language	English
Article number	e51
Pages (from-to)	0472-0483
Journal	PLoS Medicine
Volume	5
Issue number	3
DOIs	https://doi.org/10.1371/journal.pmed.0050051
Publication status	Published - 2008
MoE publication type	A1 Journal article-refereed

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1371/journal.pmed.0050051

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Pietiläinen, K. H., 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, 5(3), 0472-0483. Article e51. https://doi.org/10.1371/journal.pmed.0050051

@article{5f45985d83fa40fa81f48e0377b2f878,

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.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.",

author = "Pietil{\"a}inen, \{Kirsi H.\} and Jussi Naukkarinen and Aila Rissanen and Juha Saharinen and Pekka Ellonen and Heli Ker{\"a}nen and Anu Suomalainen and Alexandra G{\"o}tz and Tapani Suortti and Hannele Yki-J{\"a}rvinen and Matej Ore{\v s}i{\v c} and Jaakko Kaprio and Leena Peltonen",

year = "2008",

doi = "10.1371/journal.pmed.0050051",

language = "English",

volume = "5",

pages = "0472--0483",

journal = "PLoS Medicine",

issn = "1549-1277",

publisher = "Public Library of Science",

number = "3",

}

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

TY - JOUR

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

T2 - Pathways behind acquired obesity

AU - Pietiläinen, Kirsi H.

AU - Naukkarinen, Jussi

AU - Rissanen, Aila

AU - Saharinen, Juha

AU - Ellonen, Pekka

AU - Keränen, Heli

AU - Suomalainen, Anu

AU - Götz, Alexandra

AU - Suortti, Tapani

AU - Yki-Järvinen, Hannele

AU - Orešič, Matej

AU - Kaprio, Jaakko

AU - Peltonen, Leena

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pmed.0050051

DO - 10.1371/journal.pmed.0050051

M3 - Article

SN - 1549-1277

VL - 5

SP - 472

EP - 483

JO - PLoS Medicine

JF - PLoS Medicine

IS - 3

M1 - e51

ER -

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

Abstract

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