Obesity poses a threat to people's health. Identification of proper agents to increase or activate thermogenesis in adipose tissues remains a potent therapeutic strategy to combat obesity.  

In a study published in Theranostics, Dr. DING Qiurong's group from Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences identified a rhodanine derivative BML-260 that can activate mitochondrial activity, and in the meantime, promote thermogenesis via upregulating uncoupling protein 1 (UCP1). The finding uncovered the potential medical value of rhodanine derivatives in the prevention and treatment of obesity. 

To identify reagents that can upregulate UCP1 in adipocytes, researchers applied a Ucp1-2A-GFP brown adipocytes screening system to a small molecule library. They then discovered a rhodanine derivative BML-260 that can significantly induce UCP1 upregulation. Characterization demonstrated that BML-260-treated adipocytes have increased mitochondrial activity, enhanced oxidative phosphorylation (OXPHOS) levels, and expression of thermogenesis genes.  

Besides, animals were treated with BML-260 via in situ injection into white adipose tissues (WAT) to assess the in vivo effects. BML-260-treated mice displayed consistent upregulation of UCP1 and the OXPHOS proteins in WAT, and consequently improved cold tolerance in the cold challenge experiment. 

Originally, BML-260 was designed as an inhibitor of JNK Stimulatory Phosphatase-1 (JSP-1), which is a dual-specific phosphatase (DUSP22), also known as JNK pathway-associated phosphatase (JKAP). However, researchers found that the activity of BML-260 in adipocytes was JSP-1 independent. Instead, BML-260 can potently activate multiple pathways including CREB, STAT3, and PPAR pathways that jointly lead to enhanced thermogenesis in adipocytes.   

Rhodanine derivatives, classified as non-mutagenic, can easily undergo different chemical optimizations, and are considered to have overall low mammalian toxicity, presenting a pharmacologically attractive and sufficiently affordable class of small organic molecules.

The discovery that BML-260 can significantly activate UCP1 expression and enhance thermogenesis, provides the possibility that rhodanine derivatives can be applied to combat obesity and offers BML-260 as a starting reagent.  

Rhodanine derivative BML-260 can modulate adipose thermogenesis as revealed in this study. (Image by Dr. Ding's Group)