Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Adipocyte and Cell Biology

Adipose tissue TSH as a new modulator of human adipocyte mitochondrial function

International Journal of Obesity volume 43, pages 1611–1619 (2019)Cite this article

Subjects

Abstract

Background/objectives

Recent studies indicate a possible role of TSH/TSHR signalling axis on adipogenesis and adipose tissue physiology. Here, we aimed to investigate the relationship between adipose tissue TSHB and adipose tissue physiology-related gene expression.

Subjects/methods

Subcutaneous and visceral adipose tissue TSHB gene expression was analysed in two independent cohorts [Cohort1 (N = 96) and Cohort2 (N = 45)] and after bariatric surgery-induced weight loss [Cohort3 (N = 22)]. Adipose tissue TSH protein expression was also analysed in a subgroup of participants from Cohort 1 (N = 16). The effects of recombinant TSH on human subcutaneous preadipocytes and adipocytes were investigated.

Results

In cohort 1, both visceral and subcutaneous adipose tissue TSHB gene expression was positively correlated with the expression of mitochondrial function (PPARGC1A, ISCA2, CISD1, SIRT1, NFE2L2, NRF1) and fatty acid mobilization (CAV1, ENGL1), but not with adipogenic-related genes. Of note, adipose tissue TSH protein levels were also associated with some of these markers of mitochondrial function and fatty acid mobilization. These associations were replicated in cohort 2. Bariatric surgery-induced weight loss resulted in increased subcutaneous adipose tissue TSHB in parallel to increased PPARGC1A. In human subcutaneous adipocytes, rh-TSH administration led to increased mitochondrial respiratory capacity in parallel to increased mitochondrial function- and adipogenic-related gene expression, but no significant effects were observed during differentiation of human preadipocytes.

Conclusion

These data point to a possible role of adipose tissue TSH in the maintenance of adipocyte mitochondrial function.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Pellegrinelli V, Carobbio S, Vidal-Puig A. Adipose tissue plasticity: how fat depots respond differently to pathophysiological cues. Diabetologia. 2016;59:1075–88.

    Article  CAS  Google Scholar 

  2. Klöting N, Blüher M. Adipocyte dysfunction, inflammation and metabolic syndrome. Rev Endocr Metab Disord. 2014;15:277–87.

    Article  Google Scholar 

  3. Heinonen S, Buzkova J, Muniandy M, Kaksonen R, Ollikainen M, Ismail K, et al. Impaired mitochondrial biogenesis in adipose tissue in acquired obesity. Diabetes. 2015;64:3135–45.

    Article  CAS  Google Scholar 

  4. Haraguchi K, Shimura H, Lin L, Endo T, Onaya T. Differentiation of rat preadipocytes is accompanied by expression of thyrotropin receptors. Endocrinology. 1996;137:3200–5.

    Article  CAS  Google Scholar 

  5. Bell A, Gagnon A, Grunder L, Parikh SJ, Smith TJ, Sorisky A. Functional TSH receptor in human abdominal preadipocytes and orbital fibroblasts. Am J Physiol Cell Physiol. 2000;279:C335–40.

    Article  CAS  Google Scholar 

  6. Lu M, Lin RY. TSH stimulates adipogenesis in mouse embryonic stem cells. J Endocrinol. 2008;196:159–69.

    Article  CAS  Google Scholar 

  7. Bell A, Gagnon A, Dods P, Papineau D, Tiberi M, Sorisky A. TSH signaling and cell survival in 3T3-L1 preadipocytes. Am J Physiol Cell Physiol. 2002;283:C1056–64.

    Article  CAS  Google Scholar 

  8. Ma S, Jing F, Xu C, Zhou L, Song Y, Yu C, et al. Thyrotropin and obesity: increased adipose triglyceride content through glycerol-3-phosphate acyltransferase 3. Sci Rep. 2015;5:7633.

    Article  CAS  Google Scholar 

  9. Lu S, Guan Q, Liu Y, Wang H, Xu W, Li X, et al. Role of extrathyroidal TSHR expression in adipocyte differentiation and its association with obesity. Lipids Health Dis. 2012;11:17.

    Article  CAS  Google Scholar 

  10. Nannipieri M, Cecchetti F, Anselmino M, Camastra S, Niccolini P, Lamacchia M, et al. Expression of thyrotropin and thyroid hormone receptors in adipose tissue of patients with morbid obesity and/or type 2 diabetes: effects of weight loss. Int J Obes. 2009;33:1001–6.

    Article  CAS  Google Scholar 

  11. Thrush AB, Gagnon A, Sorisky A. PKC activation is required for TSH-mediated lipolysis via perilipin activation. Horm Metab Res. 2012;44:825–31.

    Article  CAS  Google Scholar 

  12. Gagnon A, Antunes TT, Ly T, Pongsuwan P, Gavin C, Lochnan HA, et al. Thyroid-stimulating hormone stimulates lipolysis in adipocytes in culture and raises serum free fatty acid levels in vivo. Metabolism. 2010;59:547–53.

    Article  CAS  Google Scholar 

  13. Moreno-Navarrete JM, Moreno M, Ortega F, Xifra G, Hong S, Asara JM, et al. TSHB mRNA is linked to cholesterol metabolism in adipose tissue. FASEB J. 2017;31:4482–91.

    Article  CAS  Google Scholar 

  14. American Diabetes Association 2 Classification and diagnosis of diabetes. Diabetes Care. 2015;38:S8–16.

    Article  Google Scholar 

  15. Ortega FJ, Mercader JM, Moreno-Navarrete JM, Nonell L, Puigdecanet E, Rodriquez-Hermosa JI, et al. Surgery-induced weight loss is associated with the downregulation of genes targeted by microRNAs in adipose tissue. J Clin Endocrinol Metab. 2015;100:E1467–76.

    Article  CAS  Google Scholar 

  16. Moreno-Navarrete JM, Ortega F, Rodríguez A, Latorre J, Becerril S, Sabater-Masdeu M, et al. HMOX1 as a marker of iron excess-induced adipose tissue dysfunction, affecting glucose uptake and respiratory capacity in human adipocytes. Diabetologia. 2017;60:915–26.

    Article  CAS  Google Scholar 

  17. Moreno-Navarrete JM, Ortega FJ, Rodríguez-Hermosa JI, Sabater M, Pardo G, Ricart W, et al. OCT1 expression in adipocytes could contribute to increased metformin action in obese subjects. Diabetes. 2011;60:168–76.

    Article  CAS  Google Scholar 

  18. Moreno-Navarrete JM, Ortega F, Sabater M, Ricart W, Fernández-Real JM. Proadipogenic effects of lactoferrin in human subcutaneous and visceral preadipocytes. J Nutr Biochem. 2011;22:1143–9.

    Article  CAS  Google Scholar 

  19. Park JH, Kang HJ, Lee YK, Kang H, Kim J, Chung JH, et al. Inactivation of EWS reduces PGC-1α protein stability and mitochondrial homeostasis. Proc Natl Acad Sci USA. 2015;112:6074–9.

    Article  CAS  Google Scholar 

  20. Stanford KI, Middelbeek RJ, Townsend KL, Lee MY, Takahashi H, So K, et al. A novel role for subcutaneous adipose tissue in exercise-induced improvements in glucose homeostasis. Diabetes. 2015;64:2002–14.

    Article  CAS  Google Scholar 

  21. Jahansouz C, Serrot FJ, Frohnert BI, Foncea RE, Dorman RB, Slusarek B, et al. Roux-en-Y gastric bypass acutely decreases protein carbonylation and increases expression of mitochondrial biogenesis genes in subcutaneous adipose tissue. Obes Surg. 2015;25:2376–85.

    Article  Google Scholar 

  22. Sheftel AD, Wilbrecht C, Stehling O, Niggemeyer B, Elsässer HP, Mühlenhoff U, et al. The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required for [4Fe–4S] protein maturation. Mol Biol Cell. 2012;23:1157–66.

    Article  CAS  Google Scholar 

  23. Wiley SE, Murphy AN, Ross SA, van der Geer P, Dixon JE. MitoNEET is an iron-containing outer mitochondrial membrane protein that regulates oxidative capacity. Proc Natl Acad Sci USA. 2007;104:5318–23.

    Article  CAS  Google Scholar 

  24. Kusminski CM, Holland WL, Sun K, Park J, Spurgin SB, Lin Y, et al. MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nat Med. 2012;18:1539–49.

    Article  CAS  Google Scholar 

  25. Ferecatu I, Gonçalves S, Golinelli-Cohen MP, Clémancey M, Martelli A, Riquier S, et al. The diabetes drug target MitoNEET governs a novel trafficking pathway to rebuild an Fe–S cluster into cytosolic aconitase/iron regulatory protein 1. J Biol Chem. 2014;289:28070–86.

    Article  CAS  Google Scholar 

  26. Zhao Y, Ling F, Griffin TM, He T, Towner R, Ruan H, et al. Up-regulation of the Sirtuin 1 (Sirt1) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) genes in white adipose tissue of Id1 protein-deficient mice: implications in the protection against diet and age-induced glucose intolerance. J Biol Chem. 2014;289:29112–22.

    Article  CAS  Google Scholar 

  27. Jukarainen S, Heinonen S, Rämö JT, Rinnankoski-Tuikka R, Rappou E, Tummers M, et al. Obesity is associated with low NAD(+)/SIRT pathway expression in adipose tissue of BMI-discordant monozygotic twins. J Clin Endocrinol Metab. 2016;101:275–83.

    Article  CAS  Google Scholar 

  28. Rutanen J, Yaluri N, Modi S, Pihlajamäki J, Vänttinen M, Itkonen P, et al. SIRT1 mRNA expression may be associated with energy expenditure and insulin sensitivity. Diabetes. 2010;59:829–35.

    Article  CAS  Google Scholar 

  29. Scarpulla RC. Nuclear control of respiratory gene expression in mammalian cells. J Cell Biochem. 2006;97:673–83.

    Article  CAS  Google Scholar 

  30. Merry TL, Ristow M. Nuclear factor erythroid-derived 2-like 2 (NFE2L2, Nrf2) mediates exercise-induced mitochondrial biogenesis and the anti-oxidant response in mice. J Physiol. 2016;594:5195–207.

    Article  CAS  Google Scholar 

  31. Cohen AW, Razani B, Schubert W, Williams TM, Wang XB, Iyengar P, et al. Role of caveolin-1 in the modulation of lipolysis and lipid droplet formation. Diabetes. 2004;53:1261–70.

    Article  CAS  Google Scholar 

  32. Michailidou Z, Morton NM, Moreno-Navarrete JM, West CC, Stewart KJ, Fernández-Real JM, et al. Adipocyte pseudohypoxia suppresses lipolysis and facilitates benign adipose tissue expansion. Diabetes. 2015;64:733–45.

    Article  CAS  Google Scholar 

  33. Hansen M, Lund MT, Gregers E, Kraunsøe R, Van Hall G, Helge JW, et al. Adipose tissue mitochondrial respiration and lipolysis before and after a weight loss by diet and RYGB. Obesity. 2015;23:2022–9.

    Article  CAS  Google Scholar 

  34. Mardinoglu A, Heiker JT, Gärtner D, Björnson E, Schön MR, Flehmig G, et al. Extensive weight loss reveals distinct gene expression changes in human subcutaneous and visceral adipose tissue. Sci Rep. 2015;5:14841.

    Article  CAS  Google Scholar 

  35. González-Plaza JJ, Gutiérrez-Repiso C, García-Serrano S, Rodriguez-Pacheco F, Garrido-Sánchez L, Santiago-Fernández C, et al. Effect of Roux-en-Y gastric bypass-induced weight loss on the transcriptomic profiling of subcutaneous adipose tissue. Surg Obes Relat Dis. 2016;12:257–63.

    Article  Google Scholar 

  36. Xie X, Sinha S, Yi Z, Langlais PR, Madan M, Bowen BP, et al. Role of adipocyte mitochondria in inflammation, lipemia and insulin sensitivity in humans: effects of pioglitazone treatment. Int J Obes (Lond) 2017; https://doi.org/10.1038/ijo.2017.192.

  37. Bogacka I, Xie H, Bray GA, Smith SR. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes. 2005;54:1392–9.

    Article  CAS  Google Scholar 

  38. Boudina S, Graham TE. Mitochondrial function/dysfunction in white adipose tissue. Exp Physiol. 2014;99:1168–78.

    Article  Google Scholar 

  39. Haraguchi K, Shimura H, Lin L, Saito T, Endo T, Onaya T. Functional expression of thyrotropin receptor in differentiated 3T3-L1 cells: a possible model cell line of extrathyroidal expression of thyrotropin receptor. Biochem Biophys Res Commun. 1996;223:193–8.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was partially supported by research grant PI15/01934 and PI16/01173 from the Instituto de Salud Carlos III from Spain and was also supported by Fondo Europeo de Desarrollo Regional (FEDER). Xunta de Galicia (ML: 2015-CP079), Ministry of Economy and Competitiveness (ML: SAF2015-71026-R) and AtresMedia. CIBEROBN Fisiopatología de la Obesidad y Nutrición is an initiative from the Instituto de Salud Carlos III from Spain. We acknowledge the technical assistance of E. Loshuertos and O. Rovira (both from Endocrinology, IdIBGi, Spain). We want to particularly acknowledge the patients, the FATBANK platform promoted by the CIBEROBN and the IDIBGI Biobank (Biobanc IDIBGI, B.0000872), integrated in the Spanish National Biobanks Network, for their collaboration and coordination.

Author information

Author notes

  1. These authors contributed equally: Ferran Comas, Aina Lluch

Authors and Affiliations

  1. Department of Diabetes, Endocrinology and Nutrition Institut d’Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain

    Ferran Comas, Aina Lluch, Mònica Sabater, Jèssica Latorre, Francisco Ortega, Wifredo Ricart, José Manuel Fernández-Real & José María Moreno-Navarrete

  2. NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain & CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, 15706, Spain

    Miguel López

Authors
  1. Ferran Comas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aina Lluch
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mònica Sabater
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jèssica Latorre
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francisco Ortega
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wifredo Ricart
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Miguel López
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. José Manuel Fernández-Real
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. José María Moreno-Navarrete
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to José Manuel Fernández-Real or José María Moreno-Navarrete.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Comas, F., Lluch, A., Sabater, M. et al. Adipose tissue TSH as a new modulator of human adipocyte mitochondrial function. Int J Obes 43, 1611–1619 (2019). https://doi.org/10.1038/s41366-018-0203-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-018-0203-1

This article is cited by

Search

Advanced search

Quick links