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Peripheral-specific Y1 receptor antagonism increases thermogenesis and protects against diet-induced obesity

Author

Listed:
  • Chenxu Yan

    (St Vincent’s Hospital
    St Vincent’s Hospital)

  • Tianshu Zeng

    (Huazhong University of Science and Technology)

  • Kailun Lee

    (St Vincent’s Hospital)

  • Max Nobis

    (St Vincent’s Hospital
    UNSW Australia)

  • Kim Loh

    (St Vincent’s Hospital
    St. Vincent’s Institute of Medical Research)

  • Luoning Gou

    (Huazhong University of Science and Technology)

  • Zefeng Xia

    (Huazhong University of Science and Technology)

  • Zhongmin Gao

    (St Vincent’s Hospital)

  • Mohammed Bensellam

    (St Vincent’s Hospital
    Université catholique de Louvain)

  • Will Hughes

    (St Vincent’s Hospital
    UNSW Australia)

  • Jackie Lau

    (St Vincent’s Hospital)

  • Lei Zhang

    (St Vincent’s Hospital
    UNSW Australia)

  • Chi Kin Ip

    (St Vincent’s Hospital
    UNSW Australia)

  • Ronaldo Enriquez

    (St Vincent’s Hospital)

  • Hanyu Gao

    (St Vincent’s Hospital)

  • Qiao-Ping Wang

    (Sun Yat-sen University)

  • Qi Wu

    (St Vincent’s Hospital)

  • Jody J. Haigh

    (University of Manitoba)

  • D. Ross Laybutt

    (St Vincent’s Hospital
    UNSW Australia)

  • Paul Timpson

    (St Vincent’s Hospital
    UNSW Australia)

  • Herbert Herzog

    (St Vincent’s Hospital
    UNSW Australia)

  • Yan-Chuan Shi

    (St Vincent’s Hospital
    St Vincent’s Hospital
    UNSW Australia)

Abstract

Obesity is caused by an imbalance between food intake and energy expenditure (EE). Here we identify a conserved pathway that links signalling through peripheral Y1 receptors (Y1R) to the control of EE. Selective antagonism of peripheral Y1R, via the non-brain penetrable antagonist BIBO3304, leads to a significant reduction in body weight gain due to enhanced EE thereby reducing fat mass. Specifically thermogenesis in brown adipose tissue (BAT) due to elevated UCP1 is enhanced accompanied by extensive browning of white adipose tissue both in mice and humans. Importantly, selective ablation of Y1R from adipocytes protects against diet-induced obesity. Furthermore, peripheral specific Y1R antagonism also improves glucose homeostasis mainly driven by dynamic changes in Akt activity in BAT. Together, these data suggest that selective peripheral only Y1R antagonism via BIBO3304, or a functional analogue, could be developed as a safer and more effective treatment option to mitigate diet-induced obesity.

Suggested Citation

  • Chenxu Yan & Tianshu Zeng & Kailun Lee & Max Nobis & Kim Loh & Luoning Gou & Zefeng Xia & Zhongmin Gao & Mohammed Bensellam & Will Hughes & Jackie Lau & Lei Zhang & Chi Kin Ip & Ronaldo Enriquez & Han, 2021. "Peripheral-specific Y1 receptor antagonism increases thermogenesis and protects against diet-induced obesity," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22925-3
    DOI: 10.1038/s41467-021-22925-3
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