Journal of Physiology and Biochemistry

, Volume 75, Issue 3, pp 253–262 | Cite as

Expression of lipogenic markers is decreased in subcutaneous adipose tissue and adipocytes of older women and is negatively linked to GDF15 expression

  • Veronika Šrámková
  • Michal Koc
  • Eva Krauzová
  • Jana Kračmerová
  • Michaela Šiklová
  • Moustafa Elkalaf
  • Dominique Langin
  • Vladimír Štich
  • Lenka RossmeislováEmail author
Original Article


In aging, the capacity of subcutaneous adipose tissue (SAT) to store lipids decreases and this results in metabolically unfavorable fat redistribution. Triggers of this age-related SAT dysfunction may include cellular senescence or endoplasmic reticulum (ER) stress. Therefore, we compared lipogenic capacity of SAT between young and older women and investigated its relation to senescence and ER stress markers. Samples of SAT and corresponding SAT-derived primary preadipocytes were obtained from two groups of women differing in age (36 vs. 72 years, n = 15 each) but matched for fat mass. mRNA levels of selected genes (lipogenesis: ACACA, FASN, SCD1, DGAT2, ELOVL6; senescence: p16, p21, NOX4, GDF15; ER stress-ATF4, XBP1s, PERK, HSPA5, GADD34, HYOU1, CHOP, EDEM1, DNAJC3) were assessed by qPCR, protein levels of GDF15 by ELISA, and mitochondrial function by the Seahorse Analyzer. Compared to the young, SAT and in vitro differentiated adipocytes from older women exhibited reduced mRNA expression of lipogenic enzymes. Out of analyzed senescence and ER stress markers, the only gene, whose expression correlated negatively with the expression of lipogenic enzymes in both SAT and adipocytes, was GDF15, a marker of not only senescence but also mitochondrial dysfunction. In line with this, inhibition of mitochondrial ATP synthase in adipocytes strongly upregulated GDF15 while reduced expression of lipogenic enzymes. Moreover, adipocytes from older women had a tendency for diminished mitochondrial capacity. Thus, a reduced lipogenic capacity of adipocytes in aged SAT appears to be linked to mitochondrial dysfunction rather than to ER stress or accumulation of senescent cells.


Subcutaneous adipose tissue Lipogenesis Aging Senescence Stress of endoplasmic reticulum Mitochondrial dysfunction 



D.L. is a member of Institut Universitaire de France. We thank Zdenek Hodny, MD, PhD, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, for his help with the selection of senescent markers.

Authors’ contribution

Ve.Š. performed experiments and data analysis and wrote the manuscript; E. K. performed adipose tissue biopsies; M.K, M.E., and J.K. performed experiments; M. Š and D.L. contributed to the discussion and writing of the manuscript; V.Š. performed adipose tissue biopsies and contributed to the discussion and writing of the manuscript; and L.R. designed the study, performed experiments and data analysis, and wrote the manuscript. L.R. is a guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.


The study was supported by grant GAP16-00477S of the Grant Agency of the Czech Republic, AZV 16-29182A of the Czech Health Research Council, and PROGRES Q36 of Charles University.


  1. 1.
    Behnke J, Feige MJ, Hendershot LM (2015) BiP and its nucleotide exchange factors Grp170 and Sil1: mechanisms of action and biological functions. J Mol Biol 427:1589–1608. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Bohnert KR, McMillan JD, Kumar A (2018) Emerging roles of ER stress and unfolded protein response pathways in skeletal muscle health and disease. J Cell Physiol 233:67–78. CrossRefPubMedGoogle Scholar
  3. 3.
    Boulet N, Esteve D, Bouloumie A, Galitzky J (2013) Cellular heterogeneity in superficial and deep subcutaneous adipose tissues in overweight patients. J Physiol Biochem 69:575–583. CrossRefPubMedGoogle Scholar
  4. 4.
    Capel F, Klimcakova E, Viguerie N, Roussel B, Vitkova M, Kovacikova M, Polak J, Kovacova Z, Galitzky J, Maoret JJ, Hanacek J, Pers TH, Bouloumie A, Stich V, Langin D (2009) Macrophages and adipocytes in human obesity: adipose tissue gene expression and insulin sensitivity during calorie restriction and weight stabilization. Diabetes 58:1558–1567. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Collins JM, Neville MJ, Pinnick KE, Hodson L, Ruyter B, van Dijk TH, Reijngoud DJ, Fielding MD, Frayn KN (2011) De novo lipogenesis in the differentiating human adipocyte can provide all fatty acids necessary for maturation. J Lipid Res 52:1683–1692. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Fujita Y, Taniguchi Y, Shinkai S, Tanaka M, Ito M (2016) Secreted growth differentiation factor 15 as a potential biomarker for mitochondrial dysfunctions in aging and age-related disorders. Geriatr Gerontol Int 16(Suppl 1):17–29. CrossRefPubMedGoogle Scholar
  7. 7.
    Ghosh AK, Garg SK, Mau T, O'Brien M, Liu J, Yung R (2015) Elevated endoplasmic reticulum stress response contributes to adipose tissue inflammation in aging. J Gerontol A Biol Sci Med Sci 70:1320–1329. CrossRefPubMedGoogle Scholar
  8. 8.
    Girousse A, Tavernier G, Valle C, Moro C, Mejhert N, Dinel AL, Houssier M, Roussel B, Besse-Patin A, Combes M, Mir L, Monbrun L, Bezaire V, Prunet-Marcassus B, Waget A, Vila I, Caspar-Bauguil S, Louche K, Marques MA, Mairal A, Renoud ML, Galitzky J, Holm C, Mouisel E, Thalamas C, Viguerie N, Sulpice T, Burcelin R, Arner P, Langin D (2013) Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass. PLoS Biol 11:e1001485. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Gregor MF, Hotamisligil GS (2007) Thematic review series: adipocyte biology. Adipocyte stress: the endoplasmic reticulum and metabolic disease. J Lipid Res 48:1905–1914. CrossRefPubMedGoogle Scholar
  10. 10.
    Hasan AU, Ohmori K, Hashimoto T, Kamitori K, Yamaguchi F, Konishi K, Noma T, Igarashi J, Yamashita T, Hirano K, Tokuda M, Minamino T, Nishiyama A, Kohno M (2017) Increase in tumor suppressor Arf compensates gene dysregulation in in vitro aged adipocytes. Biogerontology 18:55–68. CrossRefPubMedGoogle Scholar
  11. 11.
    Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13:89–102. CrossRefGoogle Scholar
  12. 12.
    Hotamisligil GS (2010) Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140:900–917. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hussain SG, Ramaiah KV (2007) Reduced eIF2alpha phosphorylation and increased proapoptotic proteins in aging. Biochem Biophys Res Commun 355:365–370. CrossRefPubMedGoogle Scholar
  14. 14.
    Koc M, Mayerova V, Kracmerova J, Mairal A, Malisova L, Stich V, Langin D, Rossmeislova L (2015) Stress of endoplasmic reticulum modulates differentiation and lipogenesis of human adipocytes. Biochem Biophys Res Commun 460:684–690. CrossRefPubMedGoogle Scholar
  15. 15.
    Lionetti L, Mollica MP, Lombardi A, Cavaliere G, Gifuni G, Barletta A (2009) From chronic overnutrition to insulin resistance: the role of fat-storing capacity and inflammation. Nutr Metab Cardiovasc Dis 19:146–152. CrossRefPubMedGoogle Scholar
  16. 16.
    Martinez G, Duran-Aniotz C, Cabral-Miranda F, Vivar JP, Hetz C (2017) Endoplasmic reticulum proteostasis impairment in aging. Aging Cell 16:615–623. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Mennes E, Dungan CM, Frendo-Cumbo S, Williamson DL, Wright DC (2014) Aging-associated reductions in lipolytic and mitochondrial proteins in mouse adipose tissue are not rescued by metformin treatment. J Gerontol A Biol Sci Med Sci 69:1060–1068. CrossRefPubMedGoogle Scholar
  18. 18.
    Mitterberger MC, Lechner S, Mattesich M, Zwerschke W (2014) Adipogenic differentiation is impaired in replicative senescent human subcutaneous adipose-derived stromal/progenitor cells. J Gerontol A Biol Sci Med Sci 69:13–24. CrossRefPubMedGoogle Scholar
  19. 19.
    Mlinar B, Marc J (2011) New insights into adipose tissue dysfunction in insulin resistance. Clin Chem Lab Med 49:1925–1935. CrossRefPubMedGoogle Scholar
  20. 20.
    Montero R, Yubero D, Villarroya J, Henares D, Jou C, Rodriguez MA, Ramos F, Nascimento A, Ortez CI, Campistol J, Perez-Duenas B, O'Callaghan M, Pineda M, Garcia-Cazorla A, Oferil JC, Montoya J, Ruiz-Pesini E, Emperador S, Meznaric M, Campderros L, Kalko SG, Villarroya F, Artuch R, Jimenez-Mallebrera C (2016) GDF-15 is elevated in children with mitochondrial diseases and is induced by mitochondrial dysfunction. PLoS One 11:e0148709. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Naidoo N (2009) ER and aging-protein folding and the ER stress response. Ageing Res Rev 8:150–159. CrossRefPubMedGoogle Scholar
  22. 22.
    Palmer AK, Tchkonia T, LeBrasseur NK, Chini EN, Xu M, Kirkland JL (2015) Cellular senescence in type 2 diabetes: a therapeutic opportunity. Diabetes 64:2289–2298. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Roberts R, Hodson L, Dennis AL, Neville MJ, Humphreys SM, Harnden KE, Micklem KJ, Frayn KN (2009) Markers of de novo lipogenesis in adipose tissue: associations with small adipocytes and insulin sensitivity in humans. Diabetologia 52:882–890. CrossRefPubMedGoogle Scholar
  24. 24.
    Rosen ED, Spiegelman BM (2006) Adipocytes as regulators of energy balance and glucose homeostasis. Nature 444:847–853. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Rossmeisl M, Syrovy I, Baumruk F, Flachs P, Janovska P, Kopecky J (2000) Decreased fatty acid synthesis due to mitochondrial uncoupling in adipose tissue. FASEB J 14:1793–1800CrossRefPubMedGoogle Scholar
  26. 26.
    Rossmeislova L, Malisova L, Kracmerova J, Tencerova M, Kovacova Z, Koc M, Siklova-Vitkova M, Viquerie N, Langin D, Stich V (2013) Weight loss improves the adipogenic capacity of human preadipocytes and modulates their secretory profile. Diabetes 62:1990–1995. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Skurk T, Ecklebe S, Hauner H (2007) A novel technique to propagate primary human preadipocytes without loss of differentiation capacity. Obesity (Silver Spring) 15:2925–2931. CrossRefGoogle Scholar
  28. 28.
    Smith U, Kahn BB (2016) Adipose tissue regulates insulin sensitivity: role of adipogenesis, de novo lipogenesis and novel lipids. J Intern Med 280:465–475. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Synofzik M, Haack TB, Kopajtich R, Gorza M, Rapaport D, Greiner M, Schonfeld C, Freiberg C, Schorr S, Holl RW, Gonzalez MA, Fritsche A, Fallier-Becker P, Zimmermann R, Strom TM, Meitinger T, Zuchner S, Schule R, Schols L, Prokisch H (2014) Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration. Am J Hum Genet 95:689–697. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Tchkonia T, Morbeck DE, Von Zglinicki T, Van Deursen J, Lustgarten J, Scrable H, Khosla S, Jensen MD, Kirkland JL (2010) Fat tissue, aging, and cellular senescence. Aging Cell 9:667–684. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Wek RC, Jiang HY, Anthony TG (2006) Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans 34:7–11. CrossRefGoogle Scholar
  32. 32.
    Wong H, Riabowol K (1996) Differential CDK-inhibitor gene expression in aging human diploid fibroblasts. Exp Gerontol 31:311–325CrossRefPubMedGoogle Scholar
  33. 33.
    Yore MM, Syed I, Moraes-Vieira PM, Zhang T, Herman MA, Homan EA, Patel RT, Lee J, Chen S, Peroni OD, Dhaneshwar AS, Hammarstedt A, Smith U, McGraw TE, Saghatelian A, Kahn BB (2014) Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159:318–332. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Zheng Z, Zhang C, Zhang K (2010) Role of unfolded protein response in lipogenesis. World J Hepatol 2:203–207. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© University of Navarra 2019

Authors and Affiliations

  • Veronika Šrámková
    • 1
    • 2
  • Michal Koc
    • 1
    • 2
  • Eva Krauzová
    • 1
    • 2
    • 3
  • Jana Kračmerová
    • 1
    • 2
  • Michaela Šiklová
    • 1
    • 2
  • Moustafa Elkalaf
    • 4
  • Dominique Langin
    • 2
    • 5
    • 6
    • 7
  • Vladimír Štich
    • 1
    • 2
    • 3
  • Lenka Rossmeislová
    • 1
    • 2
    Email author
  1. 1.Department of Pathophysiology, Third Faculty of MedicineCharles UniversityPragueCzech Republic
  2. 2.Franco-Czech Laboratory for Clinical Research on ObesityThird Faculty of MedicinePragueCzech Republic
  3. 3.Second Department of Internal MedicineUniversity Hospital Kralovske VinohradyPragueCzech Republic
  4. 4.Department of Biochemistry, Cell and Molecular Biology, Third Faculty of MedicineCharles UniversityPragueCzech Republic
  5. 5.INSERM, UMR1048Institute of Metabolic and Cardiovascular DiseasesToulouseFrance
  6. 6.Paul Sabatier UniversityToulouseFrance
  7. 7.Department of Clinical BiochemistryToulouse University HospitalsToulouseFrance

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