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

Author

Listed:
  • Xian Zhang

    (Hefei University of Technology
    Brigham and Women’s Hospital and Harvard Medical School)

  • Songyuan Luo

    (Brigham and Women’s Hospital and Harvard Medical School
    Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences)

  • 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
    Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province)

  • 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)

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.

Suggested Citation

  • 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 & Gökh, 2022. "Differential IL18 signaling via IL18 receptor and Na-Cl co-transporter discriminating thermogenesis and glucose metabolism regulation," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35256-8
    DOI: 10.1038/s41467-022-35256-8
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    References listed on IDEAS

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    1. Khoa D. Nguyen & Yifu Qiu & Xiaojin Cui & Y. P. Sharon Goh & Julia Mwangi & Tovo David & Lata Mukundan & Frank Brombacher & Richard M. Locksley & Ajay Chawla, 2011. "Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis," Nature, Nature, vol. 480(7375), pages 104-108, December.
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