, Volume 62, Issue 1, pp 136–146 | Cite as

The deubiquitinating enzyme USP19 modulates adipogenesis and potentiates high-fat-diet-induced obesity and glucose intolerance in mice

  • Erin S. Coyne
  • Nathalie Bédard
  • Ying Jia Gong
  • May Faraj
  • André Tchernof
  • Simon S. WingEmail author



Elucidating the molecular mechanisms of fat accumulation and its metabolic consequences is crucial to understanding and treating obesity, an epidemic disease. We have previously observed that Usp19 deubiquitinating enzyme-null mice (Usp19−/−) have significantly lower fat mass than wild-type (WT) mice. Thus, this study aimed to provide further understanding of the role of ubiquitin-specific peptidase 19 (USP19) in fat development, obesity and diabetes.


In this study, the metabolic phenotypes of WT and Usp19−/− mice were compared. The stromal vascular fractions (SVFs) of inguinal fat pads from WT and Usp19−/− mice were isolated and cells were differentiated into adipocytes in culture to assess their adipogenic capacity. Mice were fed a high-fat diet (HFD) for 18 weeks. Body composition, glucose metabolism and metabolic variables were assessed. In addition, following insulin injection, signalling activity was analysed in the muscle, liver and adipose tissue. Finally, the correlation between the expression of Usp19 mRNA and adipocyte function genes in human adipose tissue was analysed.


Upon adipogenic differentiation, SVF cells from Usp19−/− failed to accumulate lipid and upregulate adipogenic genes, unlike cells from WT mice. Usp19−/− mice were also found to have smaller fat pads throughout the lifespan and a higher percentage of lean mass, compared with WT mice. When fed an HFD, Usp19−/− mice were more glucose tolerant, pyruvate tolerant and insulin sensitive than WT mice. Moreover, HFD-fed Usp19−/− mice had enhanced insulin signalling in the muscle and the liver, but not in adipose tissue. Finally, USP19 mRNA expression in human adipose tissue was positively correlated with the expression of important adipocyte genes in abdominal fat depots, but not subcutaneous fat depots.


USP19 is an important regulator of fat development. Its inactivation in mice exerts effects on multiple tissues, which may protect against the negative metabolic effects of high-fat feeding. These findings suggest that inhibition of USP19 could have therapeutic potential to protect from the deleterious consequences of obesity and diabetes.


Adipogenesis Body composition Deubiquitinating enzymes Diabetes Insulin resistance Ubiquitin 



Epididymal white adipose tissue


Glucose tolerance test


High-fat diet


Insulin tolerance test


Institut universitaire de cardiologie et de pneumologie de Québec


Magnetic resonance imaging


Peroxisome proliferator-activated receptor γ


Pyruvate tolerance tests


Subcutaneous white adipose tissue


Stromal vascular fraction


Ubiquitin-specific peptidase 19





The authors thank the team at the IUPCQ tissue bank for providing the human adipose tissue samples and M. Kokoeva (Department of Medicine, McGill University Health Centre, Montréal, QC, Canada) for the metabolic studies. The authors also thank M. Plourde (Department of Medicine, McGill University, Montréal, QC, Canada) for excellent technical assistance.

Contributions statement

ESC, MF, AT and SSW conceptualised and designed the studies. ESC, NB, YJG and SSW executed the experiments and analysed the data. ESC and SSW wrote the original draft. ESC, NB, YJG, MF, AT, SSW edited and revised the manuscript. ESC, NB, YJG, MF, AT, SSW approved the final version of this manuscript. SSW is the guarantor of this work.


This work was supported by grants from the Canadian Institutes of Health Research (SSW, MOP 82734) and from the Canadian Cancer Society Research Institute Innovation Grant (SSW no. 703394).

Duality of interest

SSW receives funding from ALMAC Discovery for work on USP19 that is not related to the studies presented in this manuscript. AT receives research funding from Johnson & Johnson and Medtronic for studies unrelated to this manuscript.

Supplementary material

125_2018_4754_MOESM1_ESM.pdf (1.1 mb)
ESM (PDF 1114 kb)


  1. 1.
    Malik VS, Willett WC, Hu FB (2013) Global obesity: trends, risk factors and policy implications. Nat Rev Endocrinol 9(1):13–27. CrossRefPubMedGoogle Scholar
  2. 2.
    Varshavsky A (2012) The ubiquitin system, an immense realm. Annu Rev Biochem 81(1):167–176. CrossRefPubMedGoogle Scholar
  3. 3.
    Coyne ES, Wing SS (2016) The business of deubiquitination - location, location, location. F1000Res 5:163CrossRefGoogle Scholar
  4. 4.
    Clague MJ, Barsukov I, Coulson JM, Liu H, Rigden DJ, Urbe S (2013) Deubiquitylases from genes to organism. Physiol Rev 93(3):1289–1315. CrossRefPubMedGoogle Scholar
  5. 5.
    Jin S, Tian S, Chen Y et al (2016) USP19 modulates autophagy and antiviral immune responses by deubiquitinating Beclin-1. EMBO J 35(8):866–880. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Cui J, Jin S, Wang RF (2016) The BECN1-USP19 axis plays a role in the crosstalk between autophagy and antiviral immune responses. Autophagy 12(7):1210–1211. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Hassink GC, Zhao B, Sompallae R et al (2009) The ER-resident ubiquitin-specific protease 19 participates in the UPR and rescues ERAD substrates. EMBO Rep 10(7):755–761. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Lee JG, Takahama S, Zhang G, Tomarev SI, Ye Y (2016) Unconventional secretion of misfolded proteins promotes adaptation to proteasome dysfunction in mammalian cells. Nat Cell Biol 18(7):765–776. CrossRefPubMedGoogle Scholar
  9. 9.
    Lu Y, Bedard N, Chevalier S, Wing SS (2011) Identification of distinctive patterns of USP19-mediated growth regulation in normal and malignant cells. PLoS One 6(1):e15936. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Altun M, Zhao B, Velasco K et al (2012) Ubiquitin-specific protease 19 (USP19) regulates hypoxia-inducible factor 1alpha (HIF-1alpha) during hypoxia. J Biol Chem 287(3):1962–1969. CrossRefPubMedGoogle Scholar
  11. 11.
    Wiles B, Miao M, Coyne E, Larose L, Cybulsky AV, Wing SS (2015) USP19 deubiquitinating enzyme inhibits muscle cell differentiation by suppressing unfolded-protein response signaling. Mol Biol Cell 26(5):913–923. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Ogawa M, Kitakaze T, Harada N, Yamaji R (2015) Female-specific regulation of skeletal muscle mass by USP19 in young mice. J Endocrinol 225(3):135–145. CrossRefPubMedGoogle Scholar
  13. 13.
    Combaret L, Adegoke OA, Bedard N, Baracos V, Attaix D, Wing SS (2005) USP19 is a ubiquitin-specific protease regulated in rat skeletal muscle during catabolic states. Am J Physiol Endocrinol Metab 288(4):E693–E700. CrossRefPubMedGoogle Scholar
  14. 14.
    Bedard N, Jammoul S, Moore T et al (2015) Inactivation of the ubiquitin-specific protease 19 deubiquitinating enzyme protects against muscle wasting. FASEB J 29(9):3889–3898. CrossRefPubMedGoogle Scholar
  15. 15.
    Coyne ES, Bedard N, Wykes L et al (2018) Knockout of USP19 deubiquitinating enzyme prevents muscle wasting by modulating insulin and glucocorticoid signaling. Endocrinology 159(8):2966–2977. CrossRefPubMedGoogle Scholar
  16. 16.
    Galarraga M, Campion J, Munoz-Barrutia A et al (2012) Adiposoft: automated software for the analysis of white adipose tissue cellularity in histological sections. J Lipid Res 53(12):2791–2796. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Rosen ED, Walkey CJ, Puigserver P, Spiegelman BM (2000) Transcriptional regulation of adipogenesis. Genes Dev 14(11):1293–1307PubMedGoogle Scholar
  18. 18.
    Tschop MH, Speakman JR, Arch JR et al (2011) A guide to analysis of mouse energy metabolism. Nat Methods 9(1):57–63. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Lim KH, Choi JH, Park JH et al (2016) Ubiquitin specific protease 19 involved in transcriptional repression of retinoic acid receptor by stabilizing CORO2A. Oncotarget 7(23):34759–34772. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Faraj M, Lu HL, Cianflone K (2004) Diabetes, lipids, and adipocyte secretagogues. Biochem Cell Biol 82(1):170–190. CrossRefPubMedGoogle Scholar
  21. 21.
    Galic S, Oakhill JS, Steinberg GR (2010) Adipose tissue as an endocrine organ. Mol Cell Endocrinol 316(2):129–139. CrossRefPubMedGoogle Scholar
  22. 22.
    Balkau B, Mhamdi L, Oppert JM et al (2008) Physical activity and insulin sensitivity: the RISC study. Diabetes 57(10):2613–2618. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Richter EA, Garetto LP, Goodman MN, Ruderman NB (1982) Muscle glucose metabolism following exercise in the rat: increased sensitivity to insulin. J Clin Invest 69(4):785–793. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Preis SR, Massaro JM, Robins SJ et al (2010) Abdominal subcutaneous and visceral adipose tissue and insulin resistance in the Framingham heart study. Obesity (Silver Spring) 18(11):2191–2198. CrossRefGoogle Scholar
  25. 25.
    Wajchenberg BL, Giannella-Neto D, da Silva ME, Santos RF (2002) Depot-specific hormonal characteristics of subcutaneous and visceral adipose tissue and their relation to the metabolic syndrome. Horm Metab Res 34(11/12):616–621. CrossRefPubMedGoogle Scholar
  26. 26.
    Tchernof A, Despres JP (2013) Pathophysiology of human visceral obesity: an update. Physiol Rev 93(1):359–404. CrossRefPubMedGoogle Scholar
  27. 27.
    Gao Y, Koppen A, Rakhshandehroo M et al (2013) Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60. Nat Commun 4(1):2656. CrossRefPubMedGoogle Scholar
  28. 28.
    Suzuki M, Setsuie R, Wada K (2009) Ubiquitin carboxyl-terminal hydrolase l3 promotes insulin signaling and adipogenesis. Endocrinology 150(12):5230–5239. CrossRefPubMedGoogle Scholar
  29. 29.
    Setsuie R, Suzuki M, Kabuta T et al (2009) Ubiquitin C-terminal hydrolase-L3-knockout mice are resistant to diet-induced obesity and show increased activation of AMP-activated protein kinase in skeletal muscle. FASEB J 23(12):4148–4157. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of BiochemistryMcGill UniversityMontréalCanada
  2. 2.Department of MedicineMcGill University and Research Institute of the McGill University Health CentreMontréalCanada
  3. 3.Institut de recherches cliniques de MontréalMontréalCanada
  4. 4.Faculty of MedicineUniversité de MontréalMontréalCanada
  5. 5.Montréal Diabetes Research CenterMontréalCanada
  6. 6.Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ)Université LavalQuébecCanada

Personalised recommendations