Abstract
METTL14 mediates N6-methyladenosine (m6A) RNA modification, while YTHDC1 and YTHDF2 specifically bind m6A-methylated RNA to regulate RNA fate. POMC neurons constitute the core of the central melanocortin circuit, and POMC deficiency causes obesity in both mice and humans. However, how m6A-based epitranscriptomics regulates melanocortin circuit function remains unclear. Here, we generated and characterized POMC neuron-specific knockout mice lacking Mettl14 (Mettl14ΔPOMC), Ythdc1 (Ythdc1ΔPOMC), or Ythdf2 (Ythdf2 ΔPOMC). Mettl14ΔPOMC and Ythdc1ΔPOMC mice develop hyperphagia, obesity, glucose intolerance, insulin resistance, and hepatic steatosis in both sexes under standard chow conditions, accompanied by POMC downregulation. Conversely, POMC neuron-specific overexpression of METTL14 or YTHDC1 protects against diet-induced obesity. In contrast, Ythdf2 ΔPOMC mice are resistant to obesity, revealing an m6A-dependent balance between YTHDC1 and YTHDF2. Mechanistically, the METTL14/YTHDC1 pathway is indispensable for embryonic POMC neurogenesis, while in adults YTHDC1 maintains melanocortin circuit integrity/function. METTL14 and YTHDC1 directly target POMC and ISL1 transcripts to regulate protein expression. POMC neuron-specific restoration of POMC reverses obesity and metabolic phenotypes in Mettl14ΔPOMC and Ythdc1ΔPOMC mice, defining an anti-obesity METTL14/m6A/YTHDC1/POMC axis. These findings identify METTL14 as the m6A writer for POMC/ISL1 and YTHDC1 and YTHDF2 as their readers, uncovering a critical role of m6A epitranscriptomic regulation in melanocortin circuit development and maintenance.
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Acknowledgements
We thank Feng Jiang, Qiantao Zheng, Ruoyu Zhou, Lorelei Baron, Martin Myers, David Olson, Hui Yu, Ling Qi, Wei-Zhen Zhang, and Christin Carter-Su (University of Michigan) for their advice. We thank Malcolm J. Low (University of Michigan) and Joel K Elmquist (University of Texas Southwestern Medical Center) for providing POMC-CreERT2 mice. We thank Qingchun Tong (University of Texas Health Science Center at Houston) for providing AAV-DIO-POMC and AAV-DIO-α-MSH vectors. We thank Dr. Nathan Qi (University of Michigan) for discussion about CLAMS data analysis. This study was supported by grants R01 DK114220, R01 DK130111, and R01 DK141559 (LR) from the National Institutes of Health and 20POST35210557 (YL) from the American Heart Association (AHA). This work utilized the cores supported by the Michigan Diabetes Research and Training Center (NIH DK020572), Michigan Metabolomics and Obesity Center (DK089503), and the University of Michigan Center for Gastrointestinal Research (NIDDK P30DK034933).
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YL conducted the experiments, YL, MHK, DR, and LR analyzed the data, DR provided Mettl14f/f, Ythdc1f/f, and Ythdf2f/f mice, YL and LR designed the experiments and wrote the paper, YL, MHK, DR, and LR edited the paper.
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Li, Y., Kim, MH., Ren, D. et al. POMC neuron METTL14/m6A/YTHDC1/YTHDF2 pathways safeguard energy balance, body weight, and metabolism. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71672-w
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DOI: https://doi.org/10.1038/s41467-026-71672-w
