Histone lactylation mediated by Fam172a in POMC neurons regulates energy balance [CUT&TAG]

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 analyses, 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. To illustrate the mechanism whether H4K12la regulated the transcription of genes, we did gene-expression profiles of neuro2a cells treated with Ctrl or Lactate were analyzed.

糖酵解衍生的乳酸已被证实为组蛋白乳酸化（histone lactylation）的底物，而组蛋白乳酸化在多种组织的转录调控中发挥关键作用。然而，组蛋白乳酸化在代谢中枢下丘脑中的功能仍未明确。本研究发现，下丘脑前阿黑皮素原（pro-opiomelanocortin, POMC）神经元中特异性敲除序列相似性家族172成员A（family with sequence similarity 172, member A, Fam172a），可提升组蛋白乳酸化水平，并保护小鼠抵抗饮食诱导肥胖（diet-induced obesity, DIO）及相关代谢紊乱。反之，在POMC神经元中过表达Fam172a则会诱导出肥胖样表型。通过RNA测序（RNA-seq）与CUT&Tag染色质 profiling分析，我们发现敲低Fam172a可通过H4K12位点组蛋白乳酸化（H4K12la，histone lactylation）激活糖酵解过程，并上调肽基甘氨酸α-酰胺化单氧酶（peptidylglycine α-amidating monooxygenase, PAM）的表达，进而影响α-促黑素细胞激素（α-MSH）的合成。此外，通过药理学手段抑制乳酸生成，可显著抵消PFKO（POMC-Cre、Fam172a^loxP/loxP，即POMC神经元特异性Fam172a敲除小鼠）的抗肥胖效应。上述研究结果凸显了Fam172a与乳酸在肥胖发生发展中的重要性。为阐明H4K12la调控基因转录的具体机制，我们对经对照组处理或乳酸处理的Neuro-2a细胞开展了基因表达谱分析。