Peter Tougaard1,2,3,4, Louise Otterstrøm Martinsen5, Ditte Olsen Lützhøft5, Henrik Elvang Jensen5, Mette Flethøj5, Peter Vandenabeele6,7, Anders Elm Pedersen8,9, Søren Skov5, Axel Kornerup Hansen5, Camilla Hartmann Friis Hansen5. 1. Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, København, Denmark. peter.tougaard@irc.vib-ugent.be. 2. Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, København, Denmark. peter.tougaard@irc.vib-ugent.be. 3. Molecular Signaling and Cell Death Unit, VIB-Ugent Center for Inflammation Research, Flanders Institute for Biotechnology, Ghent, Belgium. peter.tougaard@irc.vib-ugent.be. 4. Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium. peter.tougaard@irc.vib-ugent.be. 5. Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, København, Denmark. 6. Molecular Signaling and Cell Death Unit, VIB-Ugent Center for Inflammation Research, Flanders Institute for Biotechnology, Ghent, Belgium. 7. Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium. 8. Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, København, Denmark. 9. Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, København, Denmark.
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.
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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Authors: Jonathan R Brestoff; Brian S Kim; Steven A Saenz; Rachel R Stine; Laurel A Monticelli; Gregory F Sonnenberg; Joseph J Thome; Donna L Farber; Kabirullah Lutfy; Patrick Seale; David Artis Journal: Nature Date: 2014-12-22 Impact factor: 49.962