A Wars2 mutant mouse shows a sex and diet specific change in fat distribution, reduced food intake and depot-specific upregulation of WAT browning

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Mušo, M, Bentley, L, Vizor, L, Yon, M, Burling, K, Barker, P, Zolkiewski, LA, Cox, RD and Dumbell, R ORCID: https://orcid.org/0000-0002-8805-3777, 2022. A Wars2 mutant mouse shows a sex and diet specific change in fat distribution, reduced food intake and depot-specific upregulation of WAT browning. Frontiers in Physiology, 13: 953199. ISSN 1664-042X

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Official URL: https://doi.org/10.3389/fphys.2022.953199

Abstract

Background: Increased waist-to-hip ratio (WHR) is associated with increased mortality and risk of type 2 diabetes and cardiovascular disease. The TBX15-WARS2 locus has consistently been associated with increased WHR. Previous study of the hypomorphic Wars2V117L/V117L mouse model found phenotypes including severely reduced fat mass, and white adipose tissue (WAT) browning, suggesting Wars2 could be a potential modulator of fat distribution and WAT browning.

Methods: To test for differences in browning induction across different adipose depots of Wars2V117L/V117L mice, we measured multiple browning markers of a 4-month old chow-fed cohort in subcutaneous and visceral WAT and brown adipose tissue (BAT). To explain previously observed fat mass loss, we also tested for the upregulation of plasma mitokines FGF21 and GDF15 and for differences in food intake in the same cohort. Finally, to test for diet-associated differences in fat distribution, we placed Wars2V117L/V117L mice on low-fat or high-fat diet (LFD, HFD) and assessed their body composition by Echo-MRI and compared terminal adipose depot weights at 6 months of age.

Results: The chow-fed Wars2V117L/V117L mice showed more changes in WAT browning marker gene expression in the subcutaneous inguinal WAT depot (iWAT) than in the visceral gonadal WAT depot (gWAT). These mice also demonstrated reduced food intake and elevated plasma FGF21 and GDF15, and mRNA from heart and BAT. When exposed to HFD, the Wars2V117L/V117L mice showed resistance to diet-induced obesity and a male and HFD-specific reduction of gWAT: iWAT ratio.

Conclusion: Severe reduction of Wars2 gene function causes a systemic phenotype which leads to upregulation of FGF21 and GDF15, resulting in reduced food intake and depot-specific changes in browning and fat mass.

Item Type:	Journal article
Publication Title:	Frontiers in Physiology
Creators:	Mušo, M., Bentley, L., Vizor, L., Yon, M., Burling, K., Barker, P., Zolkiewski, L.A., Cox, R.D. and Dumbell, R.
Publisher:	Frontiers Media
Date:	25 August 2022
Volume:	13
ISSN:	1664-042X
Identifiers:	Number Type 10.3389/fphys.2022.953199 DOI 1577895 Other
Rights:	© 2022 Mušo, Bentley, Vizor, Yon, Burling, Barker, Zolkiewski, Cox and Dumbell. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Divisions:	Schools > School of Science and Technology
Record created by:	Jonathan Gallacher
Date Added:	02 Aug 2022 08:51
Last Modified:	05 Sep 2022 08:08
URI:	https://irep.ntu.ac.uk/id/eprint/46799