宾夕法尼亚大学 宋红军研究小组在研究中取得进展。他们的研究显示，m⁶A缺乏损害小鼠和人类类器官中与喂养相关的下丘脑神经发生，并导致小鼠成年肥胖。该研究于2025年3月19日发表于国际一流学术期刊《细胞—干细胞》杂志上。

该研究组发现，在无主题胚胎下丘脑中缺失m⁶A写入者Mettl14会导致成人肥胖，并伴有葡萄糖-胰岛素稳态受损和能量摄入增加。从机制上说，Mettl14的缺失导致下丘脑弓状核神经发生缺陷，与摄食相关的神经元产生减少，神经发生相关的m6a标记转录物失调。m⁶A写入器Mettl3或m⁶A读取器YTHDC1的缺失具有相似的表型。Mettl14或YTHDC1敲低也导致人类大脑亚区特异性弓形核类器官中与进食相关的神经元的产生减少。他们的研究揭示了m⁶A信号在小鼠和人类类器官弓形核神经发生中的保守作用，并揭示了食物摄入和能量稳态的表转录组调控的发育基础。

据悉，N⁶-甲基腺苷（N⁶-methylladenosine, m⁶A）是mRNA上最常见的内部修饰，在神经系统中起着重要作用。下丘脑是控制食欲的关键区域，其神经发生是否受到m⁶A信号的调控，尤其是在人类中，目前尚不清楚。

附：英文原文

Title: m6A deficiency impairs hypothalamic neurogenesis of feeding-related neurons in mice and human organoids and leads to adult obesity in mice

Author: Yachen Shen, Samuel Zheng Hao Wong, Tong Ma, Feng Zhang, Qing Wang, Riki Kawaguchi, Daniel H. Geschwind, Jeremy Wang, Chuan He, Guo-li Ming, Hongjun Song

Issue&Volume: 2025-03-19

Abstract: N6-methyladenosine (m6A), the most prevalent internal modification on mRNAs, plays important roles in the nervous system. Whether neurogenesis in the hypothalamus, a region critical for controlling appetite, is regulated by m6A signaling, especially in humans, remains unclear. Here, we showed that deletion of m6A writer Mettl14 in the mouse embryonic hypothalamus led to adult obesity, with impaired glucose-insulin homeostasis and increased energy intake. Mechanistically, deletion of Mettl14 leads to hypothalamic arcuate nucleus neurogenesis deficits with reduced generation of feeding-related neurons and dysregulation of neurogenesis-related m6A-tagged transcripts. Deletion of m6A writer Mettl3 or m6A reader Ythdc1 shared similar phenotypes. METTL14 or YTHDC1 knockdown also led to reduced generation of feeding-related neurons in human brain subregion-specific arcuate nucleus organoids. Our studies reveal a conserved role of m6A signaling in arcuate nucleus neurogenesis in mice and human organoids and shed light on the developmental basis of epitranscriptomic regulation of food intake and energy homeostasis.

DOI: 10.1016/j.stem.2025.02.011

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(25)00079-7