Anti-Malaria Medicine May Offer Alternative to Common Weight Loss Drugs

In recent years, overweight and obesity are associated with an increased risk for many serious diseases and health conditions. More and more people start to pay attention to weight loss. The herbal medicine Changshan, the root of Dichroa febrifuga Lour, has been used for treating malaria-induced fever for more than 2000 years. Halofuginone (HF) is a quinazoline ketone alkaloid found in the roots and leaves of Changshan, and might be a new option for obesity treatment.

In a study published in Science Advances, a team led by Prof. WENG Jianping from the University of Science and Technology of China of the Chinese Academy of Sciences (CAS), collaborating with a team led by John R. Speakman from the Shenzhen Institutes of Advanced Technology of CAS, discovered that HF can regulate appetite and energy metabolism by increasing the levels of growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21), effectively reducing body weight and improving metabolic health.

The researchers accidentally discovered that HF could safely reduce weight in a preclinical mouse experiment. They then studied its weight reduction effect in a diet-induced obese (DIO) animal model. The researchers found that GDF15, the so called "anorexigenic factor," reduced food intake and realized weight loss by acting on the GDNF family receptor α-like receptor in the brain, and that FGF21, as a core metabolic hormone secreted by the liver, could promote energy consumption, enhance insulin sensitivity, and regulate metabolism in the liver and adipose tissue.

The secret of how HF achieved significant weight management effects lays in its increasing of endogenous GDF15 and FGF21, thereby reducing appetite and increasing energy expenditure in a dual approach. Compared to GDF15 and FGF21 recombinant protein drugs, upregulating GDF15 and FGF21 levels through small molecule drugs are more economical and of patient compliance. The metabolic benefits of HF are maintained regardless of the sex of the mouse, the method of administration, the type of animal model (DIO mice, ob/ob mice, DIO minipigs) and the feeding temperature.

Furthermore, the researchers pointed out that HF up-regulated the expression and secretion of GDF15 and FGF21 through integrating stress response. Knocking down GDF15 and FGF21, respectively, could partially offset the weight loss mediated by HF. HF, as an EPRS1 inhibitor, could exert the effect of reducing weight. However, MAZ-negative compounds, which were unable to inhibit EPRS1, could not reduce weight and did not have the ability to upregulate GDF15 and FGF21, implying that EPRS1 might be the direct molecular target of HF for weight loss.

This study suggests that HF and its chemical derivatives hold promise as potential new drugs for treating the obesity. From antimalarial to anti-obesity, the cross-disciplinary preclinical use of HF, once again, underlines the significance of the traditional Chinese medicine in modern drug research and development.

Reference: Xu S, Liu Z, Tian T, et al. The clinical antiprotozoal drug halofuginone promotes weight loss by elevating GDF15 and FGF21. Sci Adv. 11(13):eadt3142. doi: 10.1126/sciadv.adt3142

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