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 () and Hoi Leong Xavier Wong ()
Additional contact information
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
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
Hoi Leong Xavier Wong: Hong Kong Baptist University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45452-3

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