A Stat6/Pten Axis Links Regulatory T Cells with Adipose Tissue Function

Publication date: 5 September 2017
Source:Cell Metabolism, Volume 26, Issue 3
Author(s): Stefanie Kälin, Maike Becker, Verena B. Ott, Isabelle Serr, Fabian Hosp, Mohammad M.H. Mollah, Susanne Keipert, Daniel Lamp, Francoise Rohner-Jeanrenaud, Victoria K. Flynn, Martin G. Scherm, Lucas F.R. Nascimento, Katharina Gerlach, Vanessa Popp, Sarah Dietzen, Tobias Bopp, Purna Krishnamurthy, Mark H. Kaplan, Manuel Serrano, Stephen C. Woods, Philipp Tripal, Ralf Palmisano, Martin Jastroch, Matthias Blüher, Christian Wolfrum, Benno Weigmann, Anette-Gabriele Ziegler, Matthias Mann, Matthias H. Tschöp, Carolin Daniel
Obesity and type 2 diabetes are associated with metabolic defects and adipose tissue inflammation. Foxp3⁺ regulatory T cells (Tregs) control tissue homeostasis by counteracting local inflammation. However, if and how T cells interlink environmental influences with adipocyte function remains unknown. Here, we report that enhancing sympathetic tone by cold exposure, beta3-adrenergic receptor (ADRB3) stimulation or a short-term high-calorie diet enhances Treg induction in vitro and in vivo. CD4⁺ T cell proteomes revealed higher expression of Foxp3 regulatory networks in response to cold or ADRB3 stimulation in vivo reflecting Treg induction. Specifically, Ragulator-interacting protein C17orf59, which limits mTORC1 activity, was upregulated in CD4⁺ T cells by either ADRB3 stimulation or cold exposure, suggesting contribution to Treg induction. By loss- and gain-of-function studies, including Treg depletion and transfers in vivo, we demonstrated that a T cell-specific Stat6/Pten axis links cold exposure or ADRB3 stimulation with Foxp3⁺ Treg induction and adipose tissue function. Our findings offer a new mechanistic model in which tissue-specific Tregs maintain adipose tissue function.

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Teaser

Obesity and type 2 diabetes are associated with metabolic defects and adipose tissue inflammation. Kälin et al. report that a T cell-specific Stat6/Pten signaling axis links cold exposure or adrenergic stimuli with immunosuppressive regulatory T cell activity and adipose tissue function, offering novel molecular targets for improvement of adipose tissue function.


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