The clinical antiprotozoal drug halofuginone promotes weight loss by elevating GDF15 and FGF21

Obesity is a debilitating disease with increasing worldwide prevalence. Despite its high prevalence, specific pharmacologic intervention for obesity is challenging. Here, we report that halofuginone, an FDA-approved anti-scleroderma and anti-protozoal drug, is a promising anti-obesity agent in rodent models. Halofuginone suppressed food intake, increased energy expenditure, and resulted in weight loss in preclinical diet-induced obese mouse models, while also decreasing insulin resistance and hepatic steatosis. By combining genetic and pharmacological tools with transcriptomics, we identified that halofuginone increases FGF21 and GDF15 levels via ATF4. Using knockout mice, we show these hormones are both necessary for its anti-obesity effects. Thus, our study first reports the beneficial metabolic effects of halofuginone and underscores its utility to treat obesity and its associated metabolic complications.