Diabetologia

, Volume 60, Issue 1, pp 169–181

Mitochondria-related transcriptional signature is downregulated in adipocytes in obesity: a study of young healthy MZ twins

  • Sini Heinonen
  • Maheswary Muniandy
  • Jana Buzkova
  • Adil Mardinoglu
  • Amaia Rodríguez
  • Gema Frühbeck
  • Antti Hakkarainen
  • Jesper Lundbom
  • Nina Lundbom
  • Jaakko Kaprio
  • Aila Rissanen
  • Kirsi H. Pietiläinen
Article

Abstract

Aims/hypothesis

Low mitochondrial activity in adipose tissue is suggested to be an underlying factor in obesity and its metabolic complications. We aimed to find out whether mitochondrial measures are downregulated in obesity also in isolated adipocytes.

Methods

We studied young adult monozygotic (MZ) twin pairs discordant (n = 14, intrapair difference ΔBMI ≥ 3 kg/m2) and concordant (n = 5, ΔBMI < 3 kg/m2) for BMI, identified from ten birth cohorts of 22- to 36-year-old Finnish twins. Abdominal body fat distribution (MRI), liver fat content (magnetic resonance spectroscopy), insulin sensitivity (OGTT), high-sensitivity C-reactive protein, serum lipids and adipokines were measured. Subcutaneous abdominal adipose tissue biopsies were obtained to analyse the transcriptomics patterns of the isolated adipocytes as well as of the whole adipose tissue. Mitochondrial DNA transcript levels in adipocytes were measured by quantitative real-time PCR. Western blots of oxidative phosphorylation (OXPHOS) protein levels in adipocytes were performed in obese and lean unrelated individuals.

Results

The heavier (BMI 29.9 ± 1.0 kg/m2) co-twins of the discordant twin pairs had more subcutaneous, intra-abdominal and liver fat and were more insulin resistant (p < 0.01 for all measures) than the lighter (24.1 ± 0.9 kg/m2) co-twins. Altogether, 2538 genes in adipocytes and 2135 in adipose tissue were significantly differentially expressed (nominal p < 0.05) between the co-twins. Pathway analysis of these transcripts in both isolated adipocytes and adipose tissue revealed that the heavier co-twins displayed reduced expression of genes relating to mitochondrial pathways, a result that was replicated when analysing the pathways behind the most consistently downregulated genes in the heavier co-twins (in at least 12 out of 14 pairs). Consistently upregulated genes in adipocytes were related to inflammation. We confirmed that mitochondrial DNA transcript levels (12S RNA, 16S RNA, COX1, ND5, CYTB), expression of mitochondrial ribosomal protein transcripts and a major mitochondrial regulator PGC-1α (also known as PPARGC1A) were reduced in the heavier co-twins’ adipocytes (p < 0.05). OXPHOS protein levels of complexes I and III in adipocytes were lower in obese than in lean individuals.

Conclusions/interpretation

Subcutaneous abdominal adipocytes in obesity show global expressional downregulation of oxidative pathways, mitochondrial transcripts and OXPHOS protein levels and upregulation of inflammatory pathways.

Data availability

The datasets analysed and generated during the current study are available in the figshare repository, https://dx.doi.org/10.6084/m9.figshare.3806286.v1

Keywords

Adipocytes Gene expression Mitochondria Obesity Twins 

Abbreviations

AU

Arbitrary Affymetrix units

BCAA

Branched-chain amino acids

cDNA

Complementary DNA

FC

Fold change

hs-CRP

High-sensitivity C-reactive protein

IPA

Ingenuity Pathway Analysis

MR

Magnetic resonance

MRPL

Mitochondrial ribosomal protein large subunits

MRPS

Mitochondrial ribosomal protein small subunits

mtDNA

Mitochondrial DNA

MZ

Monozygotic

OXPHOS

Oxidative phosphorylation

PCA

Principal components analysis

qRT-PCR

Quantitative reverse transcription PCR

SAT

Subcutaneous adipose tissue

SVFC

Stromal vascular fraction cell

TBST

Tris-buffered saline–Tween

TCA

Tricarboxylic acid cycle

VAT

Visceral adipose tissue

Supplementary material

125_2016_4121_MOESM1_ESM.pdf (350 kb)
ESM(PDF 350 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Sini Heinonen
    • 1
  • Maheswary Muniandy
    • 1
  • Jana Buzkova
    • 2
  • Adil Mardinoglu
    • 3
    • 4
  • Amaia Rodríguez
    • 5
    • 6
  • Gema Frühbeck
    • 5
    • 6
  • Antti Hakkarainen
    • 7
  • Jesper Lundbom
    • 7
    • 8
  • Nina Lundbom
    • 7
  • Jaakko Kaprio
    • 9
    • 10
    • 11
  • Aila Rissanen
    • 1
    • 12
  • Kirsi H. Pietiläinen
    • 1
    • 9
    • 13
  1. 1.Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Biomedicum Helsinki, C424bHelsinkiFinland
  2. 2.Research Programs Unit, Molecular Neurology, Biomedicum HelsinkiUniversity of HelsinkiHelsinkiFinland
  3. 3.Department of Biology and Biological EngineeringChalmers University of TechnologyGothenburgSweden
  4. 4.Science for Life LaboratoryKTH – Royal Institute of TechnologyStockholmSweden
  5. 5.Metabolic Research LaboratoryClínica Universidad de NavarraPamplonaSpain
  6. 6.CIBEROBN, Instituto de Salud Carlos III, Pamplona, Spain
  7. 7.HUS Medical Imaging Center, RadiologyHelsinki University Central Hospital and University of HelsinkiHelsinkiFinland
  8. 8.Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes ResearchHeinrich Heine UniversityDüsseldorfGermany
  9. 9.FIMM, Institute for Molecular MedicineUniversity of HelsinkiHelsinkiFinland
  10. 10.Finnish Twin Cohort Study, Department of Public HealthUniversity of HelsinkiHelsinkiFinland
  11. 11.National Institute for Health and Welfare, Department of HealthHelsinkiFinland
  12. 12.Department of PsychiatryHelsinki University Central Hospital and University of HelsinkiHelsinkiFinland
  13. 13.Endocrinology, Abdominal CenterHelsinki University Central Hospital and University of HelsinkiHelsinkiFinland

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