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The obesity-induced adipokine sST2 exacerbates adipose Treg and ILC2 depletion and promotes insulin resistance.


ABSTRACT: Depletion of fat-resident regulatory T cells (Tregs) and group 2 innate lymphoid cells (ILC2s) has been causally linked to obesity-associated insulin resistance. However, the molecular nature of the pathogenic signals suppress adipose Tregs and ILC2s in obesity remains unknown. Here, we identified the soluble isoform of interleukin (IL)-33 receptor ST2 (sST2) as an obesity-induced adipokine that attenuates IL-33 signaling and disrupts Treg/ILC2 homeostasis in adipose tissue, thereby exacerbates obesity-associated insulin resistance in mice. We demonstrated sST2 is a target of TNF? signaling in adipocytes that is countered by Zbtb7b. Fat-specific ablation of Zbtb7b augments adipose sST2 gene expression, leading to diminished fat-resident Tregs/ILC2s, more pronounced adipose tissue inflammation and fibrosis, and impaired glucose homeostasis in mice. Mechanistically, Zbtb7b suppresses NF-?B activation in response to TNF? through destabilizing I?B?. These findings uncover an adipokine-immune signaling pathway that is engaged in obesity to drive the pathological changes of the immunometabolic landscape.

SUBMITTER: Zhao XY 

PROVIDER: S-EPMC7220368 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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The obesity-induced adipokine sST2 exacerbates adipose T<sub>reg</sub> and ILC2 depletion and promotes insulin resistance.

Zhao Xu-Yun XY   Zhou Linkang L   Chen Zhimin Z   Ji Yewei Y   Peng Xiaoling X   Qi Ling L   Li Siming S   Lin Jiandie D JD  

Science advances 20200513 20


Depletion of fat-resident regulatory T cells (T<sub>regs</sub>) and group 2 innate lymphoid cells (ILC2s) has been causally linked to obesity-associated insulin resistance. However, the molecular nature of the pathogenic signals suppress adipose T<sub>regs</sub> and ILC2s in obesity remains unknown. Here, we identified the soluble isoform of interleukin (IL)-33 receptor ST2 (sST2) as an obesity-induced adipokine that attenuates IL-33 signaling and disrupts T<sub>reg</sub>/ILC2 homeostasis in adi  ...[more]

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