Histone lactylation mediated by Fam172a in POMC neurons regulates energy balance

Zhuo Chen, Baocheng Wan, Hong Zhang, Lina Zhang, Rong Zhang, Lianxi Li, Yi Zhang () and Cheng Hu ()
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Zhuo Chen: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Baocheng Wan: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Hong Zhang: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Lina Zhang: Shanghai Jiao Tong University School of Medicine
Rong Zhang: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Lianxi Li: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yi Zhang: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Cheng Hu: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Glycolysis-derived lactate was identified as substrate for histone lactylation, which has been regarded as a significant role in transcriptional regulation in many tissues. However, the role of histone lactylation in the metabolic center, the hypothalamus, is still unknown. Here, we show that hypothalamic pro-opiomelanocortin (POMC) neuron-specific deletion of family with sequence similarity 172, member A (Fam172a) can increase histone lactylation and protect mice against diet-induced obesity (DIO) and related metabolic disorders. Conversely, overexpression of Fam172a in POMC neurons led to an obesity-like phenotype. Using RNA-seq and CUT&Tag chromatin profiling analyzes, we find that knockdown of Fam172a activates the glycolytic process and increases peptidylglycine α-amidating monooxygenase (PAM), which affects the synthesis of α-MSH, via H4K12la (histone lactylation). In addition, pharmacological inhibition of lactate production clearly abrogates the anti-obesity effect of PFKO (POMC-Cre, Fam172aloxP/loxP, POMC neurons Fam172a knockout). These findings highlight the importance of Fam172a and lactate in the development of obesity and our results mainly concern male mice.

Date: 2024
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DOI: 10.1038/s41467-024-54488-4

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