In recent years, overweight and obesity have become a serious global health problem, posing significant risk factors for various diseases. Longing for a civilized and healthy lifestyle, more and more people are starting to pay attention to weight loss. Halofuginone (HF), a quinazoline ketone alkaloid found in the roots and leaves of Changshan, might be a new option for obesity treatment.

China has been using the herbal medicine Changshan, the root of Dichroa febrifuga Lour, to treat malaria-induced fever for more than 2,000 years. However, whether HF can be used for treating obesity and its complications remain unclear.

A research team led by Prof. Weng Jianping from the University of Science and Technology of China (USTC) of the Chinese Academy of Sciences (CAS), in collaboration with the team led by Academician 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 study was published in Science Advances.

In a preclinical mouse experiment, researchers accidentally discovered that HF could safely reduce weight, and further studied its weight-reduction effect in a diet-induced obese (DIO) animal model.

The study found that GDF15, the so-called “anorexigenic factor,” reduced food intake and achieved weight loss by acting on the GDNF family receptor α-like (GFRAL) receptor in the brain.

FGF21, as a core metabolic hormone secreted by the liver, can 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 lay in its increase 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. In a DIO mouse model, researchers observed a significant decrease in body weight and enhanced energy metabolism (FGF21 promotes fat burning), as well as improved insulin sensitivity.

These metabolic benefits of HF were 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.

The researchers further point out that HF upregulates the expression and secretion of GDF15 and FGF21 through integrating stress response. Knocking down GDF15 and FGF21, respectively, can partially offset the weight loss mediated by HF. HF, as an EPRS1 inhibitor, can exert the effect of reducing weight.

However, MAZ-negative compounds, which are unable to inhibit EPRS1, could not reduce weight and did not have the ability to upregulate GDF15 and FGF21, implying that EPRS1 may be the direct molecular target of HF for weight loss.

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