The obesity-induced adipokine sST2 exacerbates adipose T(reg) and ILC2 depletion and promotes insulin resistance

Depletion of fat-resident regulatory T cells (T(regs)) 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(regs) 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(reg)/ILC2 homeostasis in adipose tissue, thereby exacerbates obesity-associated insulin resistance in mice. We demonstrated sST2 is a target of TNFα signaling in adipocytes that is countered by Zbtb7b. Fat-specific ablation of Zbtb7b augments adipose sST2 gene expression, leading to diminished fat-resident T(regs)/ILC2s, more pronounced adipose tissue inflammation and fibrosis, and impaired glucose homeostasis in mice. Mechanistically, Zbtb7b suppresses NF-κB activation in response to TNFα through destabilizing IκBα. These findings uncover an adipokine-immune signaling pathway that is engaged in obesity to drive the pathological changes of the immunometabolic landscape.