ILC2s are present in adipose tissue and play a critical role in regulating adipose thermogenesis. However, the mechanisms underlying the activation of adipose-resident ILC2s remain poorly defined. Here, we show that IL-33, a potent ILC2 activator, stimulates phosphorylation of AMPK at Thr172 via TAK1 in primary ILC2s, which provides a feedback mechanism to inhibit IL-33–induced NF-κB activation and IL-13 production. Treating ILC2s with adiponectin or an adiponectin receptor agonist (AdipoRon) activated AMPK and decreased IL-33–NF-κB signaling. AdipoRon also suppressed cold-induced thermogenic gene expression and energy expenditure in vivo. In contrast, adiponectin deficiency increased the ILC2 fraction and activation, leading to up-regulated thermogenic gene expression in adipose tissue of cold-exposed mice. ILC2 deficiency or blocking ILC2 function by neutralization of the IL-33 receptor with anti-ST2 diminished the suppressive effect of adiponectin on cold-induced adipose thermogenesis and energy expenditure. Taken together, our study reveals that adiponectin is a negative regulator of ILC2 function in adipose tissue via AMPK-mediated negative regulation of IL-33 signaling.
Adiponectin restrains ILC2 activation by AMPK-mediated feedback inhibition of IL-33 signaling
Disclosures: The authors declare no competing interests exist.
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Lu Wang, Yan Luo, Liping Luo, Dandan Wu, Xiaofeng Ding, Handong Zheng, Haisha Wu, Bilian Liu, Xin Yang, Floyd Silva, Chunqing Wang, Xing Zhang, Xianyun Zheng, Jindong Chen, Jonathan Brigman, Michael Mandell, Zhiguang Zhou, Feng Liu, Xuexian O. Yang, Meilian Liu; Adiponectin restrains ILC2 activation by AMPK-mediated feedback inhibition of IL-33 signaling. J Exp Med 1 February 2021; 218 (2): e20191054. doi: https://doi.org/10.1084/jem.20191054
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