ATM is a first-line malaria medicine. Chemically, it is semi-synthetic derivative of artemisinin (also known as qinghaosu). Artemisinin-based therapy is currently the most effective treatment for uncomplicated Plasmodium falciparum malaria. Common derivatives of artemisinin include dihydroartemisinin (DHA, chemical feature shown in Figure 1E), ATM, artesunate and arteether. Among these, DHA is the metabolite of artemisinin in vivo10. To explore whether other derivatives of artemisinin have similar browning effect as ATM, we exposed C3H10T1/2 cells to different doses of DHA. DHA induced browning-like features in C3H10T1/2 cells as well, as illustrated by the smaller cell size, multiple lipid droplets (Figure 1F) and elevated expression levels of UCP1 and PGC1a (Figure 1G), suggesting that artemisinin and its derivatives share similar browning effect, which is also confirmed by the treatment with artemisinin, artesunate and arteether (data not shown).

To explore whether ATM is able to induce browning in vivo, we subcutaneously injected ATM into the inguinal fat pads of male C57BL6/J mice fed with a high fat diet (HFD). 15 μM of ATM was injected subcutaneously into the inguinal fat pads of mice (100 μl on each side, twice a week). Eight weeks after injection, ATM-treated mice showed lower body weight (Supplementary information, Figure S2A), less adipose tissues (Supplementary information, Figure S2B and S2C), better metabolism (Supplementary information, Figure S2D) and improved fatty liver (Supplementary information, Figure S2E) compared with the control group. Enhanced UCP1 expression in inguinal adipose tissue and better body temperature conservation capability were also observed in ATM-treated mice (Supplementary information, Figure S2F and S2G).

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