Differential IL18 signaling via IL18 receptor and Na-Cl co-transporter discriminating thermogenesis and glucose metabolism regulation

Xian Zhang, Songyuan Luo, Minjie Wang, Qiongqiong Cao, Zhixin Zhang, Qin Huang, Jie Li, Zhiyong Deng, Tianxiao Liu, Cong-Lin Liu, Mathilde Meppen, Amelie Vromman, Richard A. Flavell, Gökhan S. Hotamışlıgil, Jian Liu, Peter Libby, Zhangsuo Liu () and Guo-Ping Shi ()
Additional contact information
Xian Zhang: Hefei University of Technology
Songyuan Luo: Brigham and Women’s Hospital and Harvard Medical School
Minjie Wang: Brigham and Women’s Hospital and Harvard Medical School
Qiongqiong Cao: Hefei University of Technology
Zhixin Zhang: Hefei University of Technology
Qin Huang: Brigham and Women’s Hospital and Harvard Medical School
Jie Li: Brigham and Women’s Hospital and Harvard Medical School
Zhiyong Deng: Brigham and Women’s Hospital and Harvard Medical School
Tianxiao Liu: Brigham and Women’s Hospital and Harvard Medical School
Cong-Lin Liu: Brigham and Women’s Hospital and Harvard Medical School
Mathilde Meppen: Brigham and Women’s Hospital and Harvard Medical School
Amelie Vromman: Brigham and Women’s Hospital and Harvard Medical School
Richard A. Flavell: Yale School of Medicine
Gökhan S. Hotamışlıgil: Harvard School of Public Health
Jian Liu: Hefei University of Technology
Peter Libby: Brigham and Women’s Hospital and Harvard Medical School
Zhangsuo Liu: Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province
Guo-Ping Shi: Brigham and Women’s Hospital and Harvard Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract White adipose tissue (WAT) plays a role in storing energy, while brown adipose tissue (BAT) is instrumental in the re-distribution of stored energy when dietary sources are unavailable. Interleukin-18 (IL18) is a cytokine playing a role in T-cell polarization, but also for regulating energy homeostasis via the dimeric IL18 receptor (IL18r) and Na-Cl co-transporter (NCC) on adipocytes. Here we show that IL18 signaling in metabolism is regulated at the level of receptor utilization, with preferential role for NCC in brown adipose tissue (BAT) and dominantly via IL18r in WAT. In Il18r−/−Ncc−/− mice, high-fat diet (HFD) causes more prominent body weight gain and insulin resistance than in wild-type mice. The WAT insulin resistance phenotype of the double-knockout mice is recapitulated in HFD-fed Il18r−/− mice, whereas decreased thermogenesis in BAT upon HFD is dependent on NCC deletion. BAT-selective depletion of either NCC or IL18 reduces thermogenesis and increases BAT and WAT inflammation. IL18r deletion in WAT reduces insulin signaling and increases WAT inflammation. In summary, our study contributes to the mechanistic understanding of IL18 regulation of energy metabolism and shows clearly discernible roles for its two receptors in brown and white adipose tissues.

Date: 2022
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DOI: 10.1038/s41467-022-35256-8

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