title: Mitochondria-related transcriptional signature is downregulated in adipocytes in obesity: a study of young healthy MZ twins.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Subcutaneous abdominal adipocytes in obesity show global expressional downregulation of oxidative pathways, mitochondrial transcripts and OXPHOS protein levels and upregulation of inflammatory pathways.
  
  
  
  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.
authors.affiliation: Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Biomedicum Helsinki, C424b, P.O. Box 63, Haartmaninkatu 8, 00014, Helsinki, Finland.
authors.forename: Sini
authors.identifier: 0000-0002-6342-0577
authors.initials: S
authors.lastname: Heinonen
authors.affiliation: Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Biomedicum Helsinki, C424b, P.O. Box 63, Haartmaninkatu 8, 00014, Helsinki, Finland.
authors.forename: Maheswary
authors.initials: M
authors.lastname: Muniandy
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Jana
authors.initials: J
authors.lastname: Buzkova
authors.affiliation: Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.|Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Adil
authors.initials: A
authors.lastname: Mardinoglu
authors.affiliation: Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain.|CIBEROBN, Instituto de Salud Carlos III, Pamplona, Spain.
authors.forename: Amaia
authors.initials: A
authors.lastname: Rodríguez
authors.affiliation: Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain.|CIBEROBN, Instituto de Salud Carlos III, Pamplona, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Frühbeck
authors.affiliation: HUS Medical Imaging Center, Radiology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Hakkarainen
authors.affiliation: HUS Medical Imaging Center, Radiology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.|Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Jesper
authors.initials: J
authors.lastname: Lundbom
authors.affiliation: HUS Medical Imaging Center, Radiology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Nina
authors.initials: N
authors.lastname: Lundbom
authors.affiliation: FIMM, Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.|Finnish Twin Cohort Study, Department of Public Health, University of Helsinki, Helsinki, Finland.|National Institute for Health and Welfare, Department of Health, Helsinki, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kaprio
authors.affiliation: Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Biomedicum Helsinki, C424b, P.O. Box 63, Haartmaninkatu 8, 00014, Helsinki, Finland.|Department of Psychiatry, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Aila
authors.initials: A
authors.lastname: Rissanen
authors.affiliation: Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Biomedicum Helsinki, C424b, P.O. Box 63, Haartmaninkatu 8, 00014, Helsinki, Finland. kirsi.pietilainen@helsinki.fi.|FIMM, Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland. kirsi.pietilainen@helsinki.fi.|Endocrinology, Abdominal Center, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland. kirsi.pietilainen@helsinki.fi.
authors.forename: Kirsi H
authors.initials: KH
authors.lastname: Pietiläinen
mesh_terms: D050153:Abdominal Fat / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D002097:C-Reactive Protein / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D014430:Twins, Monozygotic; D055815:Young Adult
chemical_list: D002097:C-Reactive Protein
keywords: Adipocytes; Gene expression; Mitochondria; Obesity; Twins