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Scientists Identify a Rhodanine Derivative That Can Regulate Adipose Thermogenesis

2019-05-30

Obesity poses a tremendous burden for patients and the public healthcare system. Identification of proper agents to increase or activate thermogenesis in adipose tissues remains a potent therapeutic strategy to combat obesity.  

A recent study led by Dr. DING Qiurong from Shanghai Institute of Nutrition and Health, 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), uncovering the potential medical value of rhodanine derivatives in the prevention and treatment of obesity. 

In the study, researchers applied a Ucp1-2A-GFP brown adipocytes screening system to a small molecule library, with the aim to identify reagents that can upregulate UCP1 in adipocytes. A rhodanine derivative BML-260 was later discovered that can significantly induce UCP1 upregulation. Further characterization demonstrated that BML-260-treated adipocytes have increased mitochondrial activity, enhanced oxidative phosphorylation (OXPHOS) levels and expression of thermogenesis genes.  

Animals were then 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 can easily undergo different chemical optimizations, and are classified as non-mutagenic and 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, opens up the possibility that rhodanine derivatives can be applied to combat obesity and offers BML-260 as a starting reagent.  

This work has mostly been done by student FENG Zhuanghui, and published online in Theranostics on May 26th, 2019, entitled “Identification of a rhodamine derivative BML-260 as a potent stimulator of UCP1 expression”. 

This study was funded by the grants from National Key Research and Development Program and the Strategic Priority Research Program of the Chinese Academy of Sciences, etc. 


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

Media Contact: 
WANG Jin (Ms.) 
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences 
Email: sibssc@sibs.ac.cn