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ResearchIn-Press PreviewEndocrinologyImmunology Open Access | 10.1172/jci.insight.140644

Tregs facilitate obesity and insulin resistance via a Blimp-1-IL-10 axis

Lisa Y. Beppu,1 Raja Mooli,2 Xiaoyao Qu,1 Giovanni J. Marrero,1 Christopher A. Finley,1 Allen N. Fooks,1 Zackary P. Mullen,1 Adolfo B. Frias Jr.,1 Ian J. Sipula,2 Bingxian Xie,2 Katherine E. Helfrich,3 Simon C. Watkins,3 Amanda C. Poholek,4 Sadeesh K. Ramakrishnan,2 Michael J. Jurczak,2 and Louise M. D'Cruz1

1Department of Immunology, University of Pittsburgh, Pittsburgh, United States of America

2Division of Endocrinology, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Pediatrics, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Immunology, University of Pittsburgh, Pittsburgh, United States of America

2Division of Endocrinology, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Pediatrics, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Immunology, University of Pittsburgh, Pittsburgh, United States of America

2Division of Endocrinology, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Pediatrics, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Immunology, University of Pittsburgh, Pittsburgh, United States of America

2Division of Endocrinology, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Pediatrics, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Immunology, University of Pittsburgh, Pittsburgh, United States of America

2Division of Endocrinology, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Pediatrics, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Immunology, University of Pittsburgh, Pittsburgh, United States of America

2Division of Endocrinology, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Pediatrics, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Immunology, University of Pittsburgh, Pittsburgh, United States of America

2Division of Endocrinology, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Pediatrics, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Immunology, University of Pittsburgh, Pittsburgh, United States of America

2Division of Endocrinology, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Pediatrics, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Immunology, University of Pittsburgh, Pittsburgh, United States of America

2Division of Endocrinology, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Pediatrics, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Immunology, University of Pittsburgh, Pittsburgh, United States of America

2Division of Endocrinology, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Pediatrics, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Immunology, University of Pittsburgh, Pittsburgh, United States of America

2Division of Endocrinology, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Pediatrics, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Immunology, University of Pittsburgh, Pittsburgh, United States of America

2Division of Endocrinology, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Pediatrics, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Immunology, University of Pittsburgh, Pittsburgh, United States of America

2Division of Endocrinology, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Pediatrics, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Immunology, University of Pittsburgh, Pittsburgh, United States of America

2Division of Endocrinology, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Pediatrics, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Immunology, University of Pittsburgh, Pittsburgh, United States of America

2Division of Endocrinology, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Pediatrics, University of Pittsburgh, Pittsburgh, United States of America

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1Department of Immunology, University of Pittsburgh, Pittsburgh, United States of America

2Division of Endocrinology, University of Pittsburgh, Pittsburgh, United States of America

3Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, United States of America

4Department of Pediatrics, University of Pittsburgh, Pittsburgh, United States of America

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Published December 22, 2020 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.140644.
Copyright © 2020, Beppu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 22, 2020 - Version history
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Abstract

Interleukin-10 (IL-10) is a critical cytokine used by immune cells to suppress inflammation. Paradoxically, immune cell-derived IL-10 can drive insulin resistance in obesity by suppressing adipocyte energy expenditure and thermogenesis. However, the source of IL-10 necessary for the suppression of adipocyte thermogenesis is unknown. We show here that CD4+ Foxp3+ regulatory T cells (Tregs) are a significant source of IL-10, and that Treg-derived IL-10 can suppress adipocyte beiging. Unexpectedly, Treg-specific loss of IL-10 resulted in increased insulin sensitivity and reduced obesity in high fat diet (HFD)-fed male mice. Mechanistically, we determined that Treg-specific loss of the transcription factor Blimp-1, a driver of IL-10 expression by Tregs, phenocopied the Treg-specific IL-10-deficient mice. Loss of Blimp-1 expression in Tregs resulted in reduced ST2+, KLRG1+, IL-10-secreting Tregs, particularly in the white adipose tissue. Blimp-1-deficient mice were protected from glucose intolerance, insulin resistance and diet-induced obesity (DIO), through increased white adipose tissue browning. Taken together, our data show that Blimp-1-regulated IL-10 secretion by Tregs represses white adipose tissue beiging to maintain adipose tissue homeostasis. 

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