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Diabetologia

, 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. Wing
Article

Abstract

Aims/hypothesis

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.

Methods

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.

Result

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.

Conclusions/interpretation

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.

Keywords

Adipogenesis Body composition Deubiquitinating enzymes Diabetes Insulin resistance Ubiquitin 

Abbreviations

eWAT

Epididymal white adipose tissue

GTT

Glucose tolerance test

HFD

High-fat diet

ITT

Insulin tolerance test

IUCPQ

Institut universitaire de cardiologie et de pneumologie de Québec

MRI

Magnetic resonance imaging

PPARγ

Peroxisome proliferator-activated receptor γ

PTT

Pyruvate tolerance tests

scWAT

Subcutaneous white adipose tissue

SVF

Stromal vascular fraction

USP19

Ubiquitin-specific peptidase 19

WT

Wild-type

Notes

Acknowledgements

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.

Funding

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)

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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

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