An OGT-STAT5 Axis in Regulatory T Cells Controls Energy and Iron Metabolism

Zengdi Zhang; Oscar C. Salgado; Bing Liu; Zahra Moazzami; Kristin A. Hogquist; Michael A. Farrar; Hai Bin Ruan

doi:10.3389/fimmu.2022.874863

An OGT-STAT5 Axis in Regulatory T Cells Controls Energy and Iron Metabolism

Zengdi Zhang, Oscar C. Salgado, Bing Liu, Zahra Moazzami, Kristin A. Hogquist, Michael A. Farrar, Hai Bin Ruan

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

The immunosuppressive regulatory T (Treg) cells exert emerging effects on adipose tissue homeostasis and systemic metabolism. However, the metabolic regulation and effector mechanisms of Treg cells in coping with obesogenic insults are not fully understood. We have previously established an indispensable role of the O-linked N-Acetylglucosamine (O-GlcNAc) signaling in maintaining Treg cell identity and promoting Treg suppressor function, via STAT5 O-GlcNAcylation and activation. Here, we investigate the O-GlcNAc transferase (OGT)-STAT5 axis in driving the immunomodulatory function of Treg cells for metabolic homeostasis. Treg cell-specific OGT deficiency renders mice more vulnerable to high-fat diet (HFD)-induced adiposity and insulin resistance. Conversely, constitutive STAT5 activation in Treg cells confers protection against adipose tissue expansion and impaired glucose and insulin metabolism upon HFD feeding, in part by suppressing adipose lipid uptake and redistributing systemic iron storage. Treg cell function can be augmented by targeting the OGT-STAT5 axis to combat obesity and related metabolic disorders.

Original language	English (US)
Article number	874863
Journal	Frontiers in immunology
Volume	13
DOIs	https://doi.org/10.3389/fimmu.2022.874863
State	Published - Jul 8 2022

Bibliographical note

Funding Information:
This work was supported by NIH grant R56 AI162791 to H-BR and R01 AI139420 to H-BR and MF.

Publisher Copyright:
Copyright © 2022 Zhang, Salgado, Liu, Moazzami, Hogquist, Farrar and Ruan.

Keywords

O-GlcNAc
Treg - regulatory T cell
adipose tissue
fatty acid uptake
iron

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3389/fimmu.2022.874863

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title = "An OGT-STAT5 Axis in Regulatory T Cells Controls Energy and Iron Metabolism",

abstract = "The immunosuppressive regulatory T (Treg) cells exert emerging effects on adipose tissue homeostasis and systemic metabolism. However, the metabolic regulation and effector mechanisms of Treg cells in coping with obesogenic insults are not fully understood. We have previously established an indispensable role of the O-linked N-Acetylglucosamine (O-GlcNAc) signaling in maintaining Treg cell identity and promoting Treg suppressor function, via STAT5 O-GlcNAcylation and activation. Here, we investigate the O-GlcNAc transferase (OGT)-STAT5 axis in driving the immunomodulatory function of Treg cells for metabolic homeostasis. Treg cell-specific OGT deficiency renders mice more vulnerable to high-fat diet (HFD)-induced adiposity and insulin resistance. Conversely, constitutive STAT5 activation in Treg cells confers protection against adipose tissue expansion and impaired glucose and insulin metabolism upon HFD feeding, in part by suppressing adipose lipid uptake and redistributing systemic iron storage. Treg cell function can be augmented by targeting the OGT-STAT5 axis to combat obesity and related metabolic disorders.",

keywords = "O-GlcNAc, Treg - regulatory T cell, adipose tissue, fatty acid uptake, iron",

author = "Zengdi Zhang and Salgado, {Oscar C.} and Bing Liu and Zahra Moazzami and Hogquist, {Kristin A.} and Farrar, {Michael A.} and Ruan, {Hai Bin}",

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AU - Farrar, Michael A.

AU - Ruan, Hai Bin

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N2 - The immunosuppressive regulatory T (Treg) cells exert emerging effects on adipose tissue homeostasis and systemic metabolism. However, the metabolic regulation and effector mechanisms of Treg cells in coping with obesogenic insults are not fully understood. We have previously established an indispensable role of the O-linked N-Acetylglucosamine (O-GlcNAc) signaling in maintaining Treg cell identity and promoting Treg suppressor function, via STAT5 O-GlcNAcylation and activation. Here, we investigate the O-GlcNAc transferase (OGT)-STAT5 axis in driving the immunomodulatory function of Treg cells for metabolic homeostasis. Treg cell-specific OGT deficiency renders mice more vulnerable to high-fat diet (HFD)-induced adiposity and insulin resistance. Conversely, constitutive STAT5 activation in Treg cells confers protection against adipose tissue expansion and impaired glucose and insulin metabolism upon HFD feeding, in part by suppressing adipose lipid uptake and redistributing systemic iron storage. Treg cell function can be augmented by targeting the OGT-STAT5 axis to combat obesity and related metabolic disorders.

AB - The immunosuppressive regulatory T (Treg) cells exert emerging effects on adipose tissue homeostasis and systemic metabolism. However, the metabolic regulation and effector mechanisms of Treg cells in coping with obesogenic insults are not fully understood. We have previously established an indispensable role of the O-linked N-Acetylglucosamine (O-GlcNAc) signaling in maintaining Treg cell identity and promoting Treg suppressor function, via STAT5 O-GlcNAcylation and activation. Here, we investigate the O-GlcNAc transferase (OGT)-STAT5 axis in driving the immunomodulatory function of Treg cells for metabolic homeostasis. Treg cell-specific OGT deficiency renders mice more vulnerable to high-fat diet (HFD)-induced adiposity and insulin resistance. Conversely, constitutive STAT5 activation in Treg cells confers protection against adipose tissue expansion and impaired glucose and insulin metabolism upon HFD feeding, in part by suppressing adipose lipid uptake and redistributing systemic iron storage. Treg cell function can be augmented by targeting the OGT-STAT5 axis to combat obesity and related metabolic disorders.

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An OGT-STAT5 Axis in Regulatory T Cells Controls Energy and Iron Metabolism

Abstract

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Keywords

UN SDGs

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