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

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.

Zinc Supplementation Alleviates Lipid and Glucose Metabolic Disorders Induced by a High-Fat Diet

“…After 16 h of fasting, mice were injected with pyruvate (2 g/kg of body weight, Sigma-Aldrich, St. Louis, MO, U.S.A.) intraperitoneally. Blood glucose levels were measured at 15, 30, 60, 90, and 120 min . Blood was collected from the tail vein of mice, and the blood glucose was measured.…”

“…Blood glucose levels were measured at 15, 30, 60, 90, and 120 min. 20 Blood was collected from the tail vein of mice, and the blood glucose was measured. Four mice were randomly selected from each group for testing.…”

USP19 exacerbates lipogenesis and colorectal carcinogenesis by stabilizing ME1

“…USP19 supports normal cell proliferation through stabilizing KPC1, inhibits tumor necrosis factor alpha (TNFa)-induced apoptosis by stabilizing c-inhibitors of apoptosis (IAPs) and regulates Ewing sarcoma growth by deubiquitinating and stabilizing the EWS-FLI1 fusion oncoprotein (Gierisch et al, 2019;Lu et al, 2009;Mei et al, 2011). USP19 is also an important regulator of lipid metabolism because it augments the expression of a number of adipogenic genes (Coyne et al, 2019). Although these studies indicate that USP19 is critical for regulating cell growth and metabolism, the underlying mechanism of how this occurs remains enigmatic in the development of CRC.…”

A big-data approach to understanding metabolic rate and response to obesity in laboratory mice

“…Using body composition data rather than whole body mass as a covariate can help to decrease the variation between groups. It has been proposed that lean mass + 20% fat mass might be used as the covariate for metabolic analysis (Even and Nadkarni, 2012), a calculation which has seen limited adoption (Coyne et al, 2019;Del Moral et al, 2016;Dorfman et al, 2017;Montgomery et al, 2013;Piattini et al, 2019;Schöttl et al, 2015;Seyfarth et al, 2015;Zhao et al, 2016). We find the contribution of fat mass to whole body EE to be highly variable and dependent on the particular features of the study group.…”