m(6)A deficiency impairs hypothalamic neurogenesis of feeding-related neurons in mice and human organoids and leads to adult obesity in mice.

N(6)-methyladenosine (m(6)A), 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 m(6)A signaling, especially in humans, remains unclear. Here, we showed that deletion of m(6)A 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 m(6)A-tagged transcripts. Deletion of m(6)A writer Mettl3 or m(6)A 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 m(6)A 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.