Xu Suowen, Liu Zhenghong, Tian Tian, Zhao Wenqi, Wang Zhihua, Liu Monan, Xu Mengyun, Zhang Fanshun, Zhang Zhidan, Chen Meijie, Yin Yanjun, Su Meiming, Fang Wenxiang, Pan Wenhao, Liu Shiyong, Li Min-Dian, Little Peter J, Kamato Danielle, Zhang Songyang, Wang Dongdong, Offermanns Stefan, Speakman John R, Weng Jianping
Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
Anhui Provincial Key Laboratory of Metabolic Health and Panvascular Diseases, Hefei 230001, China.
Sci Adv. 2025 Mar 28;11(13):eadt3142. doi: 10.1126/sciadv.adt3142. Epub 2025 Mar 26.
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 and 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.
肥胖是一种使人虚弱的全球性流行病，由于它是多种疾病的主要潜在危险因素，给医疗保健带来了巨大成本。因此，对于抑制肥胖的药物干预存在未满足的医疗需求。在此，我们报告卤夫酮（一种经美国食品药品监督管理局批准用于治疗硬皮病和抗原生动物的药物）在临床前小鼠和猪模型中是一种有前景的抗肥胖药物。卤夫酮抑制食物摄入，增加能量消耗，并导致饮食诱导的肥胖小鼠体重减轻，同时还减轻胰岛素抵抗和肝脂肪变性。通过使用分子和药理学工具以及转录组学，我们确定卤夫酮通过激活整合应激反应来增加成纤维细胞生长因子21（FGF21）和生长分化因子15（GDF15）的水平。使用FGF21和GDF15基因敲除小鼠，我们表明这两种激素都是引发抗肥胖变化所必需的。总之，我们的研究报告了卤夫酮有益的代谢作用，并强调了其在治疗肥胖及其相关代谢并发症方面的效用，这值得进行临床评估。
