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

ABSTRACT: 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.

SUBMITTER: Kalin S

PROVIDER: S-EPMC5627977 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Kälin Stefanie S Becker Maike M Ott Verena B VB Serr Isabelle I Hosp Fabian F Mollah Mohammad M H MMH Keipert Susanne S Lamp Daniel D Rohner-Jeanrenaud Francoise F Flynn Victoria K VK Scherm Martin G MG Nascimento Lucas F R LFR Gerlach Katharina K Popp Vanessa V Dietzen Sarah S Bopp Tobias T Krishnamurthy Purna P Kaplan Mark H MH Serrano Manuel M Woods Stephen C SC Tripal Philipp P Palmisano Ralf R Jastroch Martin M Blüher Matthias M Wolfrum Christian C Weigmann Benno B Ziegler Anette-Gabriele AG Mann Matthias M Tschöp Matthias H MH Daniel Carolin C

Cell metabolism 20170901 3

Obesity and type 2 diabetes are associated with metabolic defects and adipose tissue inflammation. Foxp3<sup>+</sup> 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 vi ...[more]

PMID: 28877454

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Project description:OBJECTIVE:Despite the large body of work describing the tumor suppressor functions of Phosphatase and tensin homologue deleted on chromosome ten (PTEN), its roles in adipose homeostasis of adult animals are not yet fully understood. Here, we sought to determine the role of PTEN in whole-body adipose homeostasis. METHODS:We genetically manipulated PTEN in specific fat depots through recombinant adeno-associated viral vector (rAAV)-based gene transfer of Cre recombinase to adult PTENflox mice. Additionally, we used a denervation agent, 6OHDA, to assess the role of sympathetic signaling in PTEN-related adipose remodeling. Furthermore, we chemically manipulated AKT signaling via a pan-AKT inhibitor, MK-2206, to assess the role of AKT in PTEN-related adipose remodeling. Finally, to understand the role of leptin and central signaling on peripheral tissues, we knocked down hypothalamic leptin receptor with a microRNA delivered by a rAAV vector. RESULTS:Knockdown PTEN in individual fat depot resulted in massive expansion of the affected fat depot through activation of AKT signaling associated with suppression of lipolysis and induction of leptin. This hypertrophic expansion of the affected fat depot led to upregulation of PTEN level, higher lipolysis, and induction of white fat browning in other fat depots, and the compensatory reduced fat mass to maintain a set point of whole-body adiposity. Administration of AKT inhibitor MK-2206 prevented the adipose PTEN knockdown-associated effects. 6OHDA-mediated denervation demonstrated that sympathetic innervation was required for the PTEN knockdown-induced adipose redistribution. Knockdown hypothalamic leptin receptor attenuated the adipose redistribution induced by PTEN deficiency in individual fat depot. CONCLUSIONS:Our results demonstrate the essential role of PTEN in adipose homeostasis, including mass and distribution in adulthood, and reveal an "adipose PTEN-leptin-sympathetic nervous system" feedback loop to maintain a set point of adipose PTEN and whole-body adiposity.

Dataset Information

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

Publications

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

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