The deubiquitinating enzyme USP19 modulates adipogenesis and potentiates high-fat-diet-induced obesity and glucose intolerance in mice
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.
KeywordsAdipogenesis Body composition Deubiquitinating enzymes Diabetes Insulin resistance Ubiquitin
Epididymal white adipose tissue
Glucose tolerance test
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.
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.
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