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

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, Kui Ming Chan, Pingyi Xu, Zhao Xiang Bian*, Hoi Leong Xavier Wong*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

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.

Original languageEnglish
Article number1034
Number of pages14
JournalNature Communications
Volume15
Issue number1
DOIs
Publication statusPublished - 3 Feb 2024

Scopus Subject Areas

  • Physics and Astronomy(all)
  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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