An obesogenic FTO allele causes accelerated development, growth and insulin resistance in human skeletal muscle cells

Lu Guang, Shilin Ma, Ziyue Yao, Dan Song, Yu Chen, Shuqing Liu, Peng Wang, Jiali Su, Yuefan Wang, Lanfang Luo and Ng Shyh-Chang ()
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Lu Guang: Chinese Academy of Sciences
Shilin Ma: Chinese Academy of Sciences
Ziyue Yao: Chinese Academy of Sciences
Dan Song: Chinese Academy of Sciences
Yu Chen: Chinese Academy of Sciences
Shuqing Liu: Chinese Academy of Sciences
Peng Wang: Chinese Academy of Sciences
Jiali Su: Chinese Academy of Sciences
Yuefan Wang: Chinese Academy of Sciences
Lanfang Luo: Chinese Academy of Sciences
Ng Shyh-Chang: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Human GWAS have shown that obesogenic FTO polymorphisms correlate with lean mass, but the mechanisms have remained unclear. It is counterintuitive because lean mass is inversely correlated with obesity and metabolic diseases. Here, we use CRISPR to knock-in FTOrs9939609-A into hESC-derived tissue models, to elucidate potentially hidden roles of FTO during development. We find that among human tissues, FTOrs9939609-A most robustly affect human muscle progenitors’ proliferation, differentiation, senescence, thereby accelerating muscle developmental and metabolic aging. An edited FTOrs9939609-A allele over-stimulates insulin/IGF signaling via increased muscle-specific enhancer H3K27ac, FTO expression and m6A demethylation of H19 lncRNA and IGF2 mRNA, with excessive insulin/IGF signaling leading to insulin resistance upon replicative aging or exposure to high fat diet. This FTO-m6A-H19/IGF2 circuit may explain paradoxical GWAS findings linking FTOrs9939609-A to both leanness and obesity. Our results provide a proof-of-principle that CRISPR-hESC-tissue platforms can be harnessed to resolve puzzles in human metabolism.

Date: 2025
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DOI: 10.1038/s41467-024-53820-2

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