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Animal Models

TL1A regulates adipose-resident innate lymphoid immune responses and enables diet-induced obesity in mice

Abstract

Background/objectives

TL1A is a pro-inflammatory cytokine that is homologous to TNFα and connected with the development of several chronic inflammatory disorders. The preliminary results of this study indicated reduced fat accumulation in 9-month-old TL1A-deficient mice at steady state. Thus, the objective was to investigate whether TL1A-deficient mice are resistant to the development of high-fat (HF) diet-induced obesity and to investigate the impact on lymphocyte infiltration in adipose tissue.

Methods

TL1A-deficient and TL1A-sufficient male BALB/cJ littermate mice were fed a 60% HF diet or a 10% low-fat control diet for 22 weeks. Mouse body composition and weight were monitored, and tissues were processed and evaluated by flow cytometry, qPCR, and histology.

Results

In this study, the TL1A-deficient HF-diet-fed mice had reduced whole-body weight gain, which was directly explained by a corresponding fat mass reduction (average 37.2%), compared with that of their TL1A-sufficient littermates. Despite previous data showing marked changes in the gut microbial community, TL1A-deficient GF mice also displayed reduced adiposity. Furthermore, the TL1A-deficient mice were resistant to hepatic steatosis and were shown to have improved glucose tolerance, as determined by oral glucose tolerance test (OGTT), and greater insulin sensitivity. In the epididymal white adipose tissue (eWAT), TL1A deficiency in HF-diet-fed mice resulted in a reduced abundance of IL-18Ra+ type-1 ILCs and γδT cells as well as markedly reduced expression of the mitochondria-regulating genes Ucp1, Ucp2, Ucp3, and Prdm16. Finally, to investigate the link of TL1A to obesity in humans, we identified a noncoding polymorphism (rs4979453) close to the TL1A locus that is associated with waist circumference in men (p = 0.00096, n = 60586).

Conclusions

These findings indicate that TL1A plays an important role in regulating adipose tissue mass and that this role is independent of the gut microbiota. Furthermore, we show that TL1A regulates adipose-resident innate lymphocytes and mitochondria-mediated oxidative stress in eWAT.

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Fig. 1: TL1A-deficient mice challenged with a high-fat diet have reduced body weight gains because of lower adiposity.
Fig. 2: TL1A-deficient germ-free mice fed a low-fat diet have a reduced amount of eWAT.
Fig. 3: TL1A-deficient mice fed a high-fat diet are more glucose tolerant and insulin sensitive than TL1A-sufficient mice.
Fig. 4: TL1A-deficient mice fed a high-fat diet have an increased proportion of ST2+ ILC2s and fewer IL-18Ra+ ILC1s and TCRγδ+ T cells in the eWAT.
Fig. 5: TL1A-deficient mice fed a high-fat diet showed less hepatic steatosis and fewer ballooning cells than TL1A-sufficient mice.
Fig. 6: TL1A deficiency results in decreased expression of Tnf, Ripk3 and the mitochondrial uncoupling genes Ucp1, Ucp2, and Ucp3 in the eWAT.

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Acknowledgements

The study was funded by a Sapere Aude Research Talent grant from The Danish Council for Independent Research (Grant no. 5053–00073B) and the “Gut, Grain & Greens (3G) Center” supported by Innovation Fund Denmark (Grant no. 11–116163). Taconic Biosciences, which is part of the 3G Center, kindly handled the breeding and provided the mice used in this study. Biogen kindly provided the TL1A-deficient mice. The research was also supported a by Methusalem grant (BO16/MET_V/007, Ghent University). Furthermore, the authors thank Elisabeth V. Andersen, Helene B. Riemann, Simon P.N. Larsen, Frederikke Lindenberg, Katja Bendtsen, Mohammad T. Yassin, Hannah Zakariassen, Ann Laigaard, Line F. Zachariassen, and Randi Lundberg for helping during the OGTT procedure, euthanasia, and flow cytometry preparations. Moreover, the authors would thank Torben Hansen and Christian T. for their contribution and guidance concerning the identification of the obesity-associated TL1A SNP.

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Contributions

PT was involved in all in vivo procedures and LOM. assisted with most termination procedures. PT and CHFH formulated the study design. AKH, SS, AEP, PV, and CHFH supervised the project. HEJ and MF performed all the histological evaluations. PT designed the flow cytometry panel and conducted the flow cytometry analyses. DOL and PT performed the qPCR analyses. LOM and PT made the mesoscale measurements. PT analyzed the data and wrote the manuscript. All authors contributed to the manuscript with comments and corrections.

Corresponding author

Correspondence to Peter Tougaard.

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AEP is employed by Merck A/S. However, the present study is unrelated to this employment, as it was mainly completed before his employment. He is still affiliated with the University of Copenhagen. Otherwise, the authors declare no conflicts of interest.

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Tougaard, P., Martinsen, L.O., Lützhøft, D.O. et al. TL1A regulates adipose-resident innate lymphoid immune responses and enables diet-induced obesity in mice. Int J Obes 44, 1062–1074 (2020). https://doi.org/10.1038/s41366-020-0539-1

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