Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Nat Commun. 2024 Nov 22;15(1):10111. doi: 10.1038/s41467-024-54488-4.
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, Fam172a, 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.
糖酵解衍生的乳酸被鉴定为组蛋白乳酰化的底物，组蛋白乳酰化在许多组织的转录调控中被认为具有重要作用。然而，组蛋白乳酰化在代谢中心——下丘脑——中的作用尚不清楚。在这里，我们表明，下丘脑促阿黑皮素原（POMC）神经元特异性敲除家族与序列相似性 172 成员 A（Fam172a）可以增加组蛋白乳酰化，并保护小鼠免受饮食诱导的肥胖（DIO）和相关代谢紊乱。相反，Fam172a 在 POMC 神经元中的过表达导致肥胖样表型。使用 RNA-seq 和 CUT&Tag 染色质分析，我们发现 Fam172a 的敲低激活了糖酵解过程，并增加了肽基甘氨酸α-酰胺化单加氧酶（PAM），通过 H4K12la（组蛋白乳酰化）影响α-MSH 的合成。此外，乳酸生成的药理学抑制明显消除了 PFKO（POMC-Cre、Fam172a、POMC 神经元 Fam172a 敲除）的抗肥胖作用。这些发现强调了 Fam172a 和乳酸在肥胖发展中的重要性，我们的结果主要涉及雄性小鼠。
