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

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