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Valproate-Induced Epigenetic Upregulation of Hypothalamic Fto Expression Potentially Linked with Weight Gain

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Abstract

Valproate (VPA), a widely-used antiepileptic drug, is a selective inhibitor of histone deacetylase (HDAC) that play important roles in epigenetic regulation. The patient with different diseases receiving this drug tend to exhibit weight gain and abnormal metabolic phenotypes, but the underlying mechanisms remain largely unknown. Here we show that VPA increases the Fto mRNA and protein expression in mouse hypothalamic GT1-7 cells. Interestingly, VPA promotes histone H3/H4 acetylation and the FTO expression which could be reversed by C646, an inhibitor for histone acetyltransferase. Furthermore, VPA weakens the FTO’s binding and enhances the binding of transcription factor TAF1 to the Fto promoter, and C646 leads to reverse effect of the VPA, suggesting an involvement of the dynamic of histone H3/H4 acetylation in the regulation of FTO expression. In addition, the mice exhibit an increase in the food intake and body weight at the beginning of 2-week treatment with VPA. Simultaneously, in the hypothalamus of the VPA-treated mice, the FTO expression is upregulated and the H3/H4 acetylation is increased; further the FTO’s binding to the Fto promoter is decreased and the TAF1′s binding to the promoter is enhanced, suggesting that VPA promotes the assembly of the basal transcriptional machinery of the Fto gene. Finally, the inhibitor C646 could restore the effects of VPA on FTO expression, H3/H4 acetylation, body weight, and food intake; and loss of FTO could reverse the VPA-induced increase of body weight and food intake. Taken together, this study suggests an involvement of VPA in the epigenetic upregulation of hypothalamic FTO expression that is potentially associated with the VPA-induced weight gain.

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Acknowledgements

We are indebted to Dr. Shu-Jing Liu (Guangzhou Sports University, Guangzhou China) for kindly providing the C57BL/6J Fto knockout mice and the C57BL/6J wild-type mice. This work was supported by Grants from the Guangzhou Science and Technology Program Key Projects (201804020046), the Innovative Academic Teams of Guangzhou Education System (1201610025), the National Natural Science Foundation of China (Grant Number 81671112).

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  1. Huan Zhang and Ping Lu have contributed equally to this work.

Authors and Affiliations

  1. Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, 250 Changang East Road, Guangzhou, 510260, China

    Huan Zhang, Ping Lu, Hui-Ling Tang, Hua-Juan Yan, Wei Jiang, Hang Shi, Si-Yu Chen, Mei-Mei Gao, Xiang-Da Zeng & Yue-Sheng Long

  2. Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, 510260, China

    Huan Zhang, Ping Lu, Hui-Ling Tang, Hua-Juan Yan, Wei Jiang, Hang Shi, Si-Yu Chen, Mei-Mei Gao, Xiang-Da Zeng & Yue-Sheng Long

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  1. Huan Zhang
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Contributions

HZ and YSL conceived and designed the experiments. HZ, PL, HLT, WJ, HS, SYC, MMG and XDZ performed experiments. HZ and PL interpreted primary data and edited the manuscript. YSL wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yue-Sheng Long.

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Zhang, H., Lu, P., Tang, HL. et al. Valproate-Induced Epigenetic Upregulation of Hypothalamic Fto Expression Potentially Linked with Weight Gain. Cell Mol Neurobiol 41, 1257–1269 (2021). https://doi.org/10.1007/s10571-020-00895-2

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