DNA methylation and gene expression patterns in adipose tissue differ significantly within young adult monozygotic BMI-discordant twin pairs.
BACKGROUND
Little is known about epigenetic alterations associated with subcutaneous adipose tissue (SAT) in obesity. Our aim was to study genome-wide DNA methylation and gene expression differences in SAT in monozygotic (MZ) twin pairs who are discordant for body mass index (BMI). This design completely matches lean and obese groups for genetic background, age, gender and shared environment.


METHODS
14We analyzed DNA methylome and gene expression from SAT, together with body composition (magnetic resonance imaging/spectroscopy) and glucose tolerance test, lipids and C-reactive protein from 26 rare BMI-discordant (intrapair difference in BMI ⩾3 kg m(-2)) MZ twin pairs identified from 10 birth cohorts of young adult Finnish twins.


RESULTS
We found 17 novel obesity-associated genes that were differentially methylated across the genome between heavy and lean co-twins. Nine of them were also differentially expressed. Pathway analyses indicated that dysregulation of SAT in obesity includes a paradoxical downregulation of lipo/adipogenesis and upregulation of inflammation and extracellular matrix remodeling. Furthermore, CpG sites whose methylation correlated with metabolically harmful fat depots (intra-abdominal and liver fat) also correlated with measures of insulin resistance, dyslipidemia and low-grade inflammation, thus suggesting that epigenetic alterations in SAT are associated with the development of unhealthy obesity.


CONCLUSIONS
This is the first study in BMI-discordant MZ twin pairs reporting genome-wide DNA methylation and expression profiles in SAT. We found a number of novel genes and pathways whose methylation and expression patterns differ within the twin pairs, suggesting that the pathological adaptation of SAT to obesity is, at least in part, epigenetically regulated.
Obesity Research Unit, Research Programs Unit, University of Helsinki, Helsinki, Finland.|Endocrinology, Abdominal Center, Helsinki University Central Hospital, and University of Helsinki, Helsinki, Finland.|Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland.
K H
KH
Pietiläinen
Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
K
K
Ismail
Obesity Research Unit, Research Programs Unit, University of Helsinki, Helsinki, Finland.
E
E
Järvinen
Obesity Research Unit, Research Programs Unit, University of Helsinki, Helsinki, Finland.
S
S
Heinonen
Obesity Research Unit, Research Programs Unit, University of Helsinki, Helsinki, Finland.
M
M
Tummers
Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
S
S
Bollepalli
Oslo University Hospital and University of Oslo, Department of Medical Genetics, Oslo, Norway.
R
R
Lyle
Obesity Research Unit, Research Programs Unit, University of Helsinki, Helsinki, Finland.|Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
M
M
Muniandy
The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland.
E
E
Moilanen
HUS Medical Imaging Center, Radiology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
A
A
Hakkarainen
HUS Medical Imaging Center, Radiology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany.|German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany.
J
J
Lundbom
HUS Medical Imaging Center, Radiology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
N
N
Lundbom
Obesity Research Unit, Research Programs Unit, University of Helsinki, Helsinki, Finland.
A
A
Rissanen
Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland.|Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|National Institute for Health and Welfare, Helsinki, Finland.
J
http://orcid.org/0000-0002-3716-2455
J
Kaprio
Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
M
M
Ollikainen
D001823:Body Composition / Q000235:genetics; D015992:Body Mass Index; D019175:DNA Methylation; D005260:Female; D005387:Finland; D020869:Gene Expression Profiling; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050151:Subcutaneous Fat / Q000378:metabolism*; D013851:Thinness / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014430:Twins, Monozygotic; D055815:Young Adult
D019947:Receptors, Interleukin-6; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha