The clinical antiprotozoal drug halofuginone promotes weight loss by elevating GDF15 and FGF21
Obesity is a debilitating global pandemic with a huge cost on health care due to it being a major underlying risk factor for several diseases. Therefore, there is an unmet medical need for pharmacological interventions to curb obesity. Here, we report that halofuginone, a Food and Drug Administration-approved anti-scleroderma and antiprotozoal drug, is a promising anti-obesity agent in preclinical mouse and pig models. Halofuginone suppressed food intake, increased energy expenditure, and resulted in weight loss in diet-induced obese mice while also alleviating insulin resistance and hepatic steatosis. Using molecular and pharmacological tools with transcriptomics, we identified that halofuginone increases fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) levels via activating integrated stress response. Using <i>Gdf15</i> and <i>Fgf21</i> knockout mice, we show that both hormones are necessary to elicit anti-obesity changes. Together, our study reports the beneficial metabolic effects of halofuginone and underscores its utility in treating obesity and its associated metabolic complications, which merits clinical assessment.
Authors
- Meijie Chen (ORCID: https://orcid.org/0000-0001-5742-4160)
- Suowen Xu (ORCID: https://orcid.org/0000-0002-5488-5217)
- Wenhao Pan (ORCID: https://orcid.org/0000-0002-5732-0748)
- John R. Speakman (ORCID: https://orcid.org/0000-0002-2457-1823)
- Peter J. Little (ORCID: https://orcid.org/0000-0003-3726-9153)
- Wenqi Zhao
- Meiming Su (ORCID: https://orcid.org/0009-0008-8183-896X)
- Shiyong Liu (ORCID: https://orcid.org/0000-0002-9789-6282)
- Dongdong Wang (ORCID: https://orcid.org/0000-0002-6195-4428)
- Stefan Offermanns (ORCID: https://orcid.org/0000-0001-8676-6805)
- Weng Jingqing
- Ze Liu (ORCID: https://orcid.org/0009-0002-5208-8908)
- Danielle Kamato (ORCID: https://orcid.org/0000-0002-1089-2829)
- Fanshun Zhang (ORCID: https://orcid.org/0000-0003-3726-6067)
- Zhihua Wang (ORCID: https://orcid.org/0000-0002-0967-287X)
- Min‐Dian Li (ORCID: https://orcid.org/0000-0002-3650-1507)
- Tian Tian (ORCID: https://orcid.org/0000-0002-4137-5015)
- Song‐Yang Zhang (ORCID: https://orcid.org/0000-0002-4356-897X)
- Zhidan Zhang
- Mengyun Xu (ORCID: https://orcid.org/0000-0001-6544-0777)
- Monan Liu
- W. X. Fang (ORCID: https://orcid.org/0000-0002-7782-5874)
- Yanjun Yin
Institutions
- Griffith University (AU)
- University of Science and Technology of China (CN)
- University Health Network (CA)
- Army Medical University (CN)
- University of Aberdeen (GB)
- Anhui Medical University (CN)
- Chinese Academy of Sciences (CN)
- Toronto General Hospital (CA)
- Guangzhou University (CN)
- Max Planck Institute for Heart and Lung Research (DE)
- Anhui Provincial Hospital (CN)
- Southwest Hospital (CN)
- First Affiliated Hospital of Anhui Medical University (CN)
- Shenzhen Institutes of Advanced Technology (CN)
- McMaster University (CA)
Publication Details
- Journal
- Science Advances
- Published
- 2025-03-26
- DOI
- https://doi.org/10.1126/sciadv.adt3142
- Citations
- 12
- Primary Topic
- GDF15 and Related Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 20.02