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Lymphotoxin regulates commensal responses to enable diet-induced obesity

Nature Immunology volume 13, pages 947–953 (2012)Cite this article

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Abstract

Microbiota are essential for weight gain in mouse models of diet-induced obesity (DIO), but the pathways that cause the microbiota to induce weight gain are unknown. We report that mice deficient in lymphotoxin, a key molecule in gut immunity, were resistant to DIO. Ltbr−/− mice had different microbial community composition compared to their heterozygous littermates, including an overgrowth of segmented filamentous bacteria (SFB). Furthermore, cecal transplantation conferred leanness to germ-free recipients. Housing Ltbr−/− mice with their obese siblings rescued weight gain in Ltbr−/− mice, demonstrating the communicability of the obese phenotype. Ltbr−/− mice lacked interleukin 23 (IL-23) and IL-22, which can regulate SFB. Mice deficient in these pathways also resisted DIO, demonstrating that intact mucosal immunity guides diet-induced changes to the microbiota to enable obesity.

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Figure 1: LTβR is essential for weight gain in response to HFD.
Figure 2: LTβR influences weight gain through changes in the microbiota.
Figure 3: Environmental exposure reveals horizontal transmissibility of the obese phenotype.
Figure 4: LTβR agonizes the innate IL-23–IL-22 axis.
Figure 5: HFD induces LTβR-dependent IL-23, which is essential for DIO.
Figure 6: The transcription factor RORγt is required for weight gain and SFB homeostasis in DIO.
Figure 7: IL-22 restores SFB homeostasis and perigonadal fat pad expansion in Ltbr−/− mice.

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Acknowledgements

This manuscript is dedicated to the memory of Dr. Donald Liu, who provided critical efforts and support. We thank B. Becher (University of Zurich) for IL-23-Ig, C. Dong (MD Anderson Cancer Center) for IL-17, O. Wenjun (Genentech) for IL-22. V.U. was supported by the American Heart Association (AHA Predoctoral 11PRE7320015) and the US National Institutes of Health Medical Scientist Training Program grant GM007281 to the University of Chicago Pritzker School of Medicine. This research was supported by pilot grants from Digestive Diseases Research Core Center (p30 DK42086), the University of Chicago Institutional Translational Medicine (UL1 RR024999), and US National Institutes of Health grants, AI090392, DK080736 and CA134563 to Y.-X.F. T.J.K. was partially funded by the Korea Foundation for International Cooperation of Science & Technology (KICOS) grant (K20702001994-11A0500-03610).

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Authors and Affiliations

  1. Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, Illinois, USA

    Vaibhav Upadhyay, Tae-jin Kim, Sherry Fu, Alexei V Tumanov, Ekaterina P Koroleva, Liufu Deng, Cathryn Nagler & Yang-Xin Fu

  2. Department of Surgery, The University of Chicago, Chicago, Illinois, USA

    Valeriy Poroyko & Donald Liu

  3. Department of Medicine, The University of Chicago, Chicago, Illinois, USA

    Suzanne Devkota & Eugene B Chang

  4. Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    Hong Tang

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  1. Vaibhav Upadhyay
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Contributions

V.U. participated in all experiments. T.K., A.T.V., E.P.K. contributed in the experiments shown in Figures 1, 4 and 5. S.D. and S.F. contributed to the experiments shown in Figure 2. V.U. and V.P. performed bioinformatic analyses. L.D. contributed to the experiments shown in Figure 7. D.L., C.N., H.T. and E.B.C. contributed to experimental design, interpretation of results and critical assessment of the manuscript. V.U. and Y.-X.F. designed all experiments and wrote the manuscript.

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Correspondence to Yang-Xin Fu.

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The authors declare no competing financial interests.

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Upadhyay, V., Poroyko, V., Kim, Tj. et al. Lymphotoxin regulates commensal responses to enable diet-induced obesity. Nat Immunol 13, 947–953 (2012). https://doi.org/10.1038/ni.2403

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