biostudies-literatureKohno DBINDSMEXT | Japan Society for the Promotion of Science (JSPS)Wellcome Trust4919-4961https://www.ebi.ac.uk/biostudies/studies/S-EPMC12436618biostudies-literatureUnknown44(18)N⁶-methyladenosine (m⁶A) is an abundant chemical RNA modification involved in the regulation of many biological processes. The m⁶A demethylase FTO (fat mass and obesity-associated protein) is known to affect body weight, but its systemic context and underlying mechanisms remain unclear. Here, we found that mice lacking or overexpressing Fto in agouti-related peptide-expressing (AgRP) neurons in the hypothalamus exhibited decreased and increased body weight, respectively. FTO demethylated m⁶A on mRNAs for proteins associated with membrane trafficking and alternative splicing in AgRP neurons. Downstream, FTO-modulated alternative splicing of the axonal motor protein Kif1a affected its hinge region, which is relevant to the structure and function of KIF1A. Notably, Kif1a knockdown in AgRP neurons suppressed the weight gain of mice overexpressing Fto. In addition, FTO increased the trafficking and secretion of dense-core vesicles containing neuropeptides NPY and AgRP from AgRP neurons. Collectively, these results reveal a novel regulatory FTO-KIF1A axis in the brain affecting appetite-stimulating AgRP neurons and systemic energy homeostasis, via FTO regulation of the epitranscriptome of AgRP neurons.The EMBO journalFTO promotes weight gain via altering Kif1a splicing and axonal vesicle trafficking in AgRP neurons.PMC12436618JPMXS042060012017K08566JP21am0101120New Paradigms - Establishing Centres for Fostering Medical Researchers of the Future programsthe Promotion Plan for the Platform of Human Resource Development for Cancerthe Fostering Health Professionals for Changing Needs of Cancer23K2161725K0304321H0334925870666JP24wm0625103Hirai HKobayashi RKohno DYoshikawa CHatada IOhashi KSasaki TAriyani WYokota-Hashimoto HMatsui SSuyama SSadakata TSusanti VYKonno ATsuneoka HIchinose SKitamura THarada ANishiyama MKawabata-Iwakawa RYada THorii TfalseFTO promotes weight gain via altering Kif1a splicing and axonal vesicle trafficking in AgRP neurons.N⁶-methyladenosine (m⁶A) is an abundant chemical RNA modification involved in the regulation of many biological processes. The m⁶A demethylase FTO (fat mass and obesity-associated protein) is known to affect body weight, but its systemic context and underlying mechanisms remain unclear. Here, we found that mice lacking or overexpressing Fto in agouti-related peptide-expressing (AgRP) neurons in the hypothalamus exhibited decreased and increased body weight, respectively. FTO demethylated m⁶A on mRNAs for proteins associated with membrane trafficking and alternative splicing in AgRP neurons. Downstream, FTO-modulated alternative splicing of the axonal motor protein Kif1a affected its hinge region, which is relevant to the structure and function of KIF1A. Notably, Kif1a knockdown in AgRP neurons suppressed the weight gain of mice overexpressing Fto. In addition, FTO increased the trafficking and secretion of dense-core vesicles containing neuropeptides NPY and AgRP from AgRP neurons. Collectively, these results reveal a novel regulatory FTO-KIF1A axis in the brain affecting appetite-stimulating AgRP neurons and systemic energy homeostasis, via FTO regulation of the epitranscriptome of AgRP neurons.2025-01-01T00:00:00Z2025 Sep2026-04-08T19:53:57.638Z2026-04-08T14:36:14.986ZS-EPMC124366184063466910.1038/s44318-025-00503-3