, 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



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.

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


Adipocytes Gene expression Mitochondria Obesity Twins 



Arbitrary Affymetrix units


Branched-chain amino acids


Complementary DNA


Fold change


High-sensitivity C-reactive protein


Ingenuity Pathway Analysis


Magnetic resonance


Mitochondrial ribosomal protein large subunits


Mitochondrial ribosomal protein small subunits


Mitochondrial DNA




Oxidative phosphorylation


Principal components analysis


Quantitative reverse transcription PCR


Subcutaneous adipose tissue


Stromal vascular fraction cell


Tris-buffered saline–Tween


Tricarboxylic acid cycle


Visceral adipose tissue

Supplementary material

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


  1. 1.
    De Pauw A, Tejerina S, Raes M, Keijer J, Arnould T (2009) Mitochondrial (dys)function in adipocyte (de)differentiation and systemic metabolic alterations. Am J Pathol 175:927–939CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Falkenberg M, Larsson NG, Gustafsson CM (2007) DNA replication and transcription in mammalian mitochondria. Annu Rev Biochem 76:679–699CrossRefPubMedGoogle Scholar
  3. 3.
    Pagliarini DJ, Calvo SE, Chang B et al (2008) A mitochondrial protein compendium elucidates complex I disease biology. Cell 134:112–123CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Semple RK, Crowley VC, Sewter CP et al (2004) Expression of the thermogenic nuclear hormone receptor coactivator PGC-1α is reduced in the adipose tissue of morbidly obese subjects. Int J Obes Relat Metab Disord 28:176–179CrossRefPubMedGoogle Scholar
  5. 5.
    Hammarstedt A, Jansson PA, Wesslau C, Yang X, Smith U (2003) Reduced expression of PGC-1 and insulin-signaling molecules in adipose tissue is associated with insulin resistance. Biochem Biophys Res Commun 301:578–582CrossRefPubMedGoogle Scholar
  6. 6.
    Bogacka I, Xie H, Bray GA, Smith SR (2005) Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 54:1392–1399CrossRefPubMedGoogle Scholar
  7. 7.
    Heinonen S, Buzkova J, Muniandy M et al (2015) Impaired mitochondrial biogenesis in adipose tissue in acquired obesity. Diabetes 64:3135–3145CrossRefPubMedGoogle Scholar
  8. 8.
    Kaaman M, Sparks LM, van Harmelen V et al (2007) Strong association between mitochondrial DNA copy number and lipogenesis in human white adipose tissue. Diabetologia 50:2526–2533CrossRefPubMedGoogle Scholar
  9. 9.
    Pietilainen KH, Naukkarinen J, Rissanen A et al (2008) Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity. PLoS Med 5:e51CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Mustelin L, Silventoinen K, Pietilainen K, Rissanen A, Kaprio J (2009) Physical activity reduces the influence of genetic effects on BMI and waist circumference: a study in young adult twins. Int J Obes (Lond) 33:29–36CrossRefGoogle Scholar
  11. 11.
    Hallgren P, Sjostrom L, Hedlund H, Lundell L, Olbe L (1989) Influence of age, fat cell weight, and obesity on O2 consumption of human adipose tissue. Am J Physiol 256:E467–E474PubMedGoogle Scholar
  12. 12.
    Yin X, Lanza IR, Swain JM, Sarr MG, Nair KS, Jensen MD (2014) Adipocyte mitochondrial function is reduced in human obesity independent of fat cell size. J Clin Endocrinol Metab 99:E209–E216CrossRefPubMedGoogle Scholar
  13. 13.
    Fischer B, Schottl T, Schempp C et al (2015) Inverse relationship between body mass index and mitochondrial oxidative phosphorylation capacity in human subcutaneous adipocytes. Am J Physiol Endocrinol Metab 309:E380–E387CrossRefPubMedGoogle Scholar
  14. 14.
    Yehuda-Shnaidman E, Buehrer B, Pi J, Kumar N, Collins S (2010) Acute stimulation of white adipocyte respiration by PKA-induced lipolysis. Diabetes 59:2474–2483CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kaprio J (2006) Twin studies in Finland 2006. Twin Res Hum Genet 9:772–777CrossRefPubMedGoogle Scholar
  16. 16.
    Naukkarinen J, Heinonen S, Hakkarainen A et al (2014) Characterising metabolically healthy obesity in weight-discordant monozygotic twins. Diabetologia 57:167–176CrossRefPubMedGoogle Scholar
  17. 17.
    Pietrobelli A, Formica C, Wang Z, Heymsfield SB (1996) Dual-energy X-ray absorptiometry body composition model: review of physical concepts. Am J Physiol 271:E941–E951PubMedGoogle Scholar
  18. 18.
    Graner M, Seppala-Lindroos A, Rissanen A et al (2012) Epicardial fat, cardiac dimensions, and low-grade inflammation in young adult monozygotic twins discordant for obesity. Am J Cardiol 109:1295–1302CrossRefPubMedGoogle Scholar
  19. 19.
    Heinonen S, Saarinen L, Naukkarinen J et al (2014) Adipocyte morphology and implications for metabolic derangements in acquired obesity. Int J Obes (Lond) 38:1423–1431CrossRefGoogle Scholar
  20. 20.
    Dai M, Wang P, Boyd AD et al (2005) Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data. Nucleic Acids Res 33:e175CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Gentleman RC, Carey VJ, Bates DM et al (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5:R80CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Heinonen S, Muniandy M, Buzkova J et al (2016) Supplementary data for ‘Mitochondria-related transcriptional signature is downregulated in adipocytes in obesity – a study of young healthy MZ twins’. Figshare: https://dx.doi.org/10.6084/m9.figshare.3806286.v1
  23. 23.
    Rao J, Scott A (1984) On chi-squared tests for multiway contingency tables with cell proportions estimated from survey data. Ann Stat 12:46–60CrossRefGoogle Scholar
  24. 24.
    Wilson-Fritch L, Nicoloro S, Chouinard M et al (2004) Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone. J Clin Invest 114:1281–1289CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Choo HJ, Kim JH, Kwon OB et al (2006) Mitochondria are impaired in the adipocytes of type 2 diabetic mice. Diabetologia 49:784–791CrossRefPubMedGoogle Scholar
  26. 26.
    Chattopadhyay M, Guhathakurta I, Behera P et al (2011) Mitochondrial bioenergetics is not impaired in nonobese subjects with type 2 diabetes mellitus. Metabolism 60:1702–1710CrossRefPubMedGoogle Scholar
  27. 27.
    Dahlman I, Forsgren M, Sjogren A et al (2006) Downregulation of electron transport chain genes in visceral adipose tissue in type 2 diabetes independent of obesity and possibly involving tumor necrosis factor-α. Diabetes 55:1792–1799CrossRefPubMedGoogle Scholar
  28. 28.
    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AWJ (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Cildir G, Akincilar SC, Tergaonkar V (2013) Chronic adipose tissue inflammation: all immune cells on the stage. Trends Mol Med 19:487–500CrossRefPubMedGoogle Scholar
  30. 30.
    Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW (2004) Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology 145:2273–2282CrossRefPubMedGoogle Scholar
  31. 31.
    Fain JN (2006) Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm 74:443–477CrossRefPubMedGoogle Scholar
  32. 32.
    Lehr S, Hartwig S, Sell H (2012) Adipokines: a treasure trove for the discovery of biomarkers for metabolic disorders. Proteomics Clin Appl 6:91–101CrossRefPubMedGoogle Scholar
  33. 33.
    Meijer K, de Vries M, Al-Lahham S et al (2011) Human primary adipocytes exhibit immune cell function: adipocytes prime inflammation independent of macrophages. PLoS ONE 6:e17154CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Permana PA, Menge C, Reaven PD (2006) Macrophage-secreted factors induce adipocyte inflammation and insulin resistance. Biochem Biophys Res Commun 341:507–514CrossRefPubMedGoogle Scholar
  35. 35.
    Ruan H, Miles PDG, Ladd CM et al (2002) Profiling gene transcription in vivo reveals adipose tissue as an immediate target of tumor necrosis factor-α: implications for insulin resistance. Diabetes 51:3176–3188CrossRefPubMedGoogle Scholar
  36. 36.
    Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM (1995) Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 95:2409–2415CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB (1995) The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest 95:2111–2119CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Lofgren P, van Harmelen V, Reynisdottir S et al (2000) Secretion of tumor necrosis factor-α shows a strong relationship to insulin-stimulated glucose transport in human adipose tissue. Diabetes 49:688–692CrossRefPubMedGoogle Scholar
  39. 39.
    Mohamed-Ali V, Goodrick S, Rawesh A et al (1997) Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-α, in vivo. J Clin Endocrinol Metab 82:4196–4200PubMedGoogle Scholar
  40. 40.
    Khazen W, M’bika J, Tomkiewicz C et al (2005) Expression of macrophage-selective markers in human and rodent adipocytes. FEBS Lett 579:5631–5634CrossRefPubMedGoogle Scholar
  41. 41.
    Vernochet C, Mourier A, Bezy O et al (2012) Adipose-specific deletion of TFAM increases mitochondrial oxidation and protects mice against obesity and insulin resistance. Cell Metab 16:765–776CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Sutherland LN, Capozzi LC, Turchinsky NJ, Bell RC, Wright DC (2008) Time course of high-fat diet-induced reductions in adipose tissue mitochondrial proteins: potential mechanisms and the relationship to glucose intolerance. Am J Physiol Endocrinol Metab 295:E1076–E1083CrossRefPubMedGoogle Scholar
  43. 43.
    Wang P, Kuo H, Huang H et al (2014) Biphasic response of mitochondrial biogenesis to oxidative stress in visceral fat of diet-induced obesity mice. Antioxid Redox Signal 20:2572–2588CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Schottl T, Kappler L, Fromme T, Klingenspor M (2015) Limited OXPHOS capacity in white adipocytes is a hallmark of obesity in laboratory mice irrespective of the glucose tolerance status. Mol Metab 4:631–642CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Bjorntorp P, Gustafson A, Persson B (1971) Adipose tissue fat cell size and number in relation to metabolism in endogenous hypertriglyceridemia. Acta Med Scand 190:363–367CrossRefPubMedGoogle Scholar
  46. 46.
    van Harmelen V, Skurk T, Rohrig K et al (2003) Effect of BMI and age on adipose tissue cellularity and differentiation capacity in women. Int J Obes Relat Metab Disord 27:889–895CrossRefPubMedGoogle Scholar
  47. 47.
    Virtue S, Vidal-Puig A (2010) Adipose tissue expandability, lipotoxicity and the metabolic syndrome--an allostatic perspective. Biochim Biophys Acta 1801:338–349CrossRefPubMedGoogle Scholar
  48. 48.
    Medina-Gomez G, Virtue S, Lelliott C et al (2005) The link between nutritional status and insulin sensitivity is dependent on the adipocyte-specific peroxisome proliferator-activated receptor-γ2 isoform. Diabetes 54:1706–1716CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Pietilainen KH, Rissanen A, Laamanen M et al (2004) Growth patterns in young adult monozygotic twin pairs discordant and concordant for obesity. Twin Res 7:421–429CrossRefPubMedGoogle Scholar

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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