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Artesunate treats obesity in male mice and non-human primates through GDF15/GFRAL signalling axis

Author

Listed:
  • Xuanming Guo

    (Hong Kong Baptist University)

  • Pallavi Asthana

    (Hong Kong Baptist University)

  • Lixiang Zhai

    (Hong Kong Baptist University)

  • Ka Wing Cheng

    (Hong Kong Baptist University
    Hong Kong Baptist University)

  • Susma Gurung

    (Hong Kong Baptist University)

  • Jiangang Huang

    (School of Pharmaceutical Sciences, Xiamen University)

  • Jiayan Wu

    (Hong Kong Baptist University)

  • Yijing Zhang

    (Hong Kong Baptist University)

  • Arun Kumar Mahato

    (University of Helsinki)

  • Mart Saarma

    (University of Helsinki)

  • Mart Ustav

    (Icosagen Ltd.)

  • Hiu Yee Kwan

    (Hong Kong Baptist University)

  • Aiping Lyu

    (Hong Kong Baptist University)

  • Kui Ming Chan

    (City University of Hong Kong)

  • Pingyi Xu

    (the First Affiliated Hospital of Guangzhou Medical University)

  • Zhao-Xiang Bian

    (Hong Kong Baptist University
    Hong Kong Baptist University)

  • Hoi Leong Xavier Wong

    (Hong Kong Baptist University)

Abstract

Obesity, a global health challenge, is a major risk factor for multiple life-threatening diseases, including diabetes, fatty liver, and cancer. There is an ongoing need to identify safe and tolerable therapeutics for obesity management. Herein, we show that treatment with artesunate, an artemisinin derivative approved by the FDA for the treatment of severe malaria, effectively reduces body weight and improves metabolic profiles in preclinical models of obesity, including male mice with overnutrition-induced obesity and male cynomolgus macaques with spontaneous obesity, without inducing nausea and malaise. Artesunate promotes weight loss and reduces food intake in obese mice and cynomolgus macaques by increasing circulating levels of Growth Differentiation Factor 15 (GDF15), an appetite-regulating hormone with a brainstem-restricted receptor, the GDNF family receptor α-like (GFRAL). Mechanistically, artesunate induces the expression of GDF15 in multiple organs, especially the liver, in mice through a C/EBP homologous protein (CHOP)-directed integrated stress response. Inhibition of GDF15/GFRAL signalling by genetic ablation of GFRAL or tissue-specific knockdown of GDF15 abrogates the anti-obesity effect of artesunate in mice with diet-induced obesity, suggesting that artesunate controls bodyweight and appetite in a GDF15/GFRAL signalling-dependent manner. These data highlight the therapeutic benefits of artesunate in the treatment of obesity and related comorbidities.

Suggested Citation

  • Xuanming Guo & Pallavi Asthana & Lixiang Zhai & Ka Wing Cheng & Susma Gurung & Jiangang Huang & Jiayan Wu & Yijing Zhang & Arun Kumar Mahato & Mart Saarma & Mart Ustav & Hiu Yee Kwan & Aiping Lyu & Ku, 2024. "Artesunate treats obesity in male mice and non-human primates through GDF15/GFRAL signalling axis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45452-3
    DOI: 10.1038/s41467-024-45452-3
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