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MIF tautomerase inhibitor 4-IPP alleviates HFD-induced obesity by restoring CD137-mediated browning of white adipocytes in mice

Acta Pharmacologica Sinica (2026)Cite this article

Abstract

Macrophage migration inhibitory factor (MIF) is a cytokine that possesses multiple enzymatic activities, such as keto-enol tautomerase and thiol-oxidoreductase. We previously found that lack of MIF tautomerase activity significantly alleviated high fat diet (HFD)-induced obesity in mice. In this study, we investigated the regulatory mechanisms of MIF tautomerase in obesity. HFD-induced obese mouse model was established. Adipogenic differentiation was induced in mouse preadipocyte cell line 3T3-L1 and mouse adipose-derived mesenchymal stem cells (ADSCs) in vitro. We showed that MIF tautomerase inhibitors ISO-1 or 4-IPP dose-dependently promoted lipid degradation and mitochondrial thermogenesis by enhancing basal oxygen consumption rate and proton leak, accompanied by increased expression of browning markers (UCP1, PGC-1α, DIO2, CD137) in 3T3-L1 cells under adipogenic induction conditions. In HFD-induced obese mice, administration of 4-IPP (5, 10 mg/kg, i.p.) every 2 days for 12 weeks significantly ameliorated HFD-induced obesity, improved insulin sensitivity, and enhanced energy expenditure. In white adipocytes, 4-IPP (1, 5, 10 μM) dose-dependently promoted CD137 expression, and restored CD137-mediated activation of the PI3K/AKT signaling to improve lipid metabolism. CD137 deficiency abrogated the browning effect of 4-IPP in white adipocytes in vitro. CD137−/− mice exhibited increased susceptibility to HFD-induced obesity and almost abolished the anti-obesity effects of 4-IPP. Simulation of the protein interaction revealed a direct interaction between MIF and CD137: MIF competitively bound to CD137 on white adipocytes with the endogenous ligand of CD137, which was further confirmed by co-immunoprecipitation. Furthermore, 4-IPP and recombinant CD137 protein inhibited the tautomerase activity of MIF in vitro. In conclusion, MIF promotes obesity by binding CD137 through its tautomerase domain, suppressing CD137-mediated the activation of the PI3K/AKT signaling. MIF tautomerase inhibitors disrupt this interaction, restore CD137 function, and enhance adipocyte browning, offering a promising therapeutic strategy for obesity management.

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Fig. 1: Effect of MIF inhibitors ISO-1 and 4-IPP on the browning of WA cells.
Fig. 2: Effect of 4-IPP on HFD-induced obese mice.
Fig. 3: Effect of 4-IPP on energy metabolism in HFD-induced obese mice.
Fig. 4: Effect of 4-IPP on CD137 expression in WA cells.
Fig. 5: Effect of CD137 deficiency on the anti-obesity effect of 4-IPP in WA cells in vitro.
Fig. 6: Effect of CD137 deficiency on the anti-obesity effect of 4-IPP in HFD-induced obese mice.
Fig. 7: Effect of 4-IPP on energy metabolism in HFD-induced obese CD137−/− mice.
Fig. 8: Protein interaction analysis of CD137 and MIF in WA cells.
Fig. 9: Schematic illustration of MIF-induced obesity via suppression of CD137 signaling and the counteracting anti-obesity effect of 4-IPP.

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (2022YFA1104300 to HBX and KYD) and the National Natural Science Foundation of China (82470454, 82270302 to HBX and 81970256 to KYD).

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Authors and Affiliations

  1. State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang, 330047, China

    Chuan-jun Chen, You-qiong Zhuo & Hong-bo Xin

  2. The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China

    Chuan-jun Chen, Ding-wen Guo, Qing-yun Yuan, You-qiong Zhuo, Shi-fen Yang, Hao-min Xu, You-rong Wang, Xiao-hui Guan, Ke-yu Deng & Hong-bo Xin

  3. College of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China

    Shi-fen Yang, Hao-min Xu, Xiao-hui Guan, Ke-yu Deng & Hong-bo Xin

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  1. Chuan-jun Chen
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Contributions

HBX and CJC designed research; CJC, DWG, QYY, YQZ, SFY and HMX performed the experiments; YQZ and YRW conducted data collection and analyzed the data; XHG supervised the project; CJC wrote the manuscript; KYD and HBX revised the manuscript; All authors read and approved the submitted manuscript.

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Correspondence to Ke-yu Deng or Hong-bo Xin.

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Chen, Cj., Guo, Dw., Yuan, Qy. et al. MIF tautomerase inhibitor 4-IPP alleviates HFD-induced obesity by restoring CD137-mediated browning of white adipocytes in mice. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-026-01755-3

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