Theranostics 2019; 9(12):3501-3514. doi:10.7150/thno.31951

Research Paper

Identification of a rhodanine derivative BML-260 as a potent stimulator of UCP1 expression

Zhuanghui Feng1, Yuda Wei1, Yongxian Zhang1, Yan Qiu1, Xiaojian Liu1, Li Su2, Ningning Liang1, Huiyong Yin1, Qiurong Ding1,3✉

1. CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, P. R. China.
2. Institute of Translational Medicine, Shanghai University, Shanghai, China.
3. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, P. R. China.

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Citation:
Feng Z, Wei Y, Zhang Y, Qiu Y, Liu X, Su L, Liang N, Yin H, Ding Q. Identification of a rhodanine derivative BML-260 as a potent stimulator of UCP1 expression. Theranostics 2019; 9(12):3501-3514. doi:10.7150/thno.31951. Available from http://www.thno.org/v09p3501.htm

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Abstract

Identification of proper agents to increase or activate UCP1+ cells in adipose tissues remains a potent therapeutic strategy to combat obesity. Screening systems for UCP1 activators have been previously established and allow for unbiased discovery of effective compound(s).

Methods: A previously established Ucp1-2A-GFP reporter system was applied to a chemical library containing 33 phosphatase inhibitors. Compounds that can significantly activate UCP1 expression were further tested in vivo in mouse adipose tissues. Possible underlying mechanism was explored via RNA profiling, CMAP analysis, CRISPR targeting as well as inhibitor treatments.

Results: We identified BML-260, a known potent inhibitor of the dual-specific phosphatase JSP-1, that significantly increased UCP1 expression in both brown and white adipocytes. BML-260 treatment also activated oxidative phosphorylation genes, increased mitochondrial activity as well as heat generation in vitro and in vivo. Mechanistic studies revealed that effect of BML-260 on adipocytes was partly through activated CREB, STAT3 and PPAR signaling pathways, and was unexpectedly JSP-1 independent.

Conclusion: The rhodanine derivate BML-260 was previously identified to be a JSP-1 inhibitor, and thus was proposed to treat inflammatory and proliferative disorders associated with dysfunctional JNK signaling. This work provides evidences that BML-260 can also exert a JSP-1-independent effect in activating UCP1 and thermogenesis in adipocytes, and be potentially applied to treat obesity.

Keywords: BML-260, Uncoupling protein 1, Adipocyte browning, Mitochondrial activity