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Exogenous FABP4 interferes with differentiation, promotes lipolysis and inflammation in adipocytes

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Abstract

Purpose

Fatty acid binding protein 4 (FABP4) has been demonstrated to be secreted from adipocytes in an unconventional pathway associated with lipolysis. Circulating FABP4 is elevated in metabolic disorders and has been shown to affect various peripheral cells such as pancreatic β-cells, hepatocytes and macrophages, but its effects on adipocytes remains unclear. The aim of this study was to investigate the effects of exogenous FABP4 (eFABP4) on adipocyte differentiation and function.

Methods

3T3-L1 pre-adipocytes or mature adipocytes were treated with recombinant FABP4 in the absence or presence of FABP4 inhibitor I-9/p38 MAPK inhibitor SB203580; Meanwhile male C57BL/6J mice were subcutaneously injected twice a day with recombinant FABP4 (0.35 mg/kg) with or without I-9 (50 mg/kg) for 2 weeks. The effects of eFABP4 on differentiation, lipolysis and inflammation were determined by triglyceride measurement or lipolysis assay, western blotting, or RT-qPCR analysis.

Results

eFABP4 treatment significantly reduced intracellular triglyceride content and decreased expression of adipogenic markers peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer binding protein alpha (C/EBPα), intracellular FABP4, and adiponectin in 3T3-L1 cells. Besides, eFABP4 promoted lipolysis and inflammation in differentiated 3T3-L1 adipocytes as well as in adipose tissue of eFABP4-treated C57BL/6J mice, with elevated gene expression of monocyte chemoattractant protein (MCP)-1, tumor necrosis factor (TNF)-α, and elevated protein expression of adipose triglyceride lipase (ATGL), phosphorylation of hormone-sensitive lipase (HSL) (Ser-660), p38, and nuclear factor-kappa B (NF-κB). The pro-inflammatory and pro-lipolytic effects of eFABP4 could be reversed by SB203580/I-9.

Conclusions

These findings indicate that eFABP4 interferes with adipocyte differentiation, induces p38/HSL mediated lipolysis and p38/NF-κB mediated inflammation in adipocytes in vitro and in vivo.

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Acknowledgements

This work was supported by grants from the “Personalized Medicines—Molecular Signature-based Drug Discovery and Development”, Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12040336); the National Natural Science Foundation of China (81473262, 81773791); National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program”, China (2018ZX09711002–002–007); Institutes for Drug Discovery and Development, Chinese Academy of Sciences (CASIMM0120164014).

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  1. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Hui-Xia Dou, Ting Wang, Hai-Xia Su, Ye-Chun Xu & He-Yao Wang

  2. University of Chinese Academy of Sciences, 100049, Beijing, China

    Hui-Xia Dou, Hai-Xia Su & He-Yao Wang

  3. School of Pharmacy, Fudan University, Shanghai, 201203, China

    Ding-Ding Gao & Ying-Xia Li

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Dou, HX., Wang, T., Su, HX. et al. Exogenous FABP4 interferes with differentiation, promotes lipolysis and inflammation in adipocytes. Endocrine 67, 587–596 (2020). https://doi.org/10.1007/s12020-019-02157-8

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