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<p>Human GWAS have shown that obesogenic <i>FTO</i> 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 <i>FTO</i><sup>rs9939609-A</sup> into hESC-derived tissue models, to elucidate potentially hidden roles of <i>FTO</i> during development. We find that among human tissues, <i>FTO</i><sup>rs9939609-A</sup> most robustly affect human muscle progenitors’ proliferation, differentiation, senescence, thereby accelerating muscle developmental and metabolic aging. An edited <i>FTO</i><sup>rs9939609-A</sup> allele over-stimulates insulin/IGF signaling via increased muscle-specific enhancer H3K27ac, FTO expression and m<sup>6</sup>A demethylation of <i>H19</i> lncRNA and <i>IGF2</i> mRNA, with excessive insulin/IGF signaling leading to insulin resistance upon replicative aging or exposure to high fat diet. This FTO-m<sup>6</sup>A-<i>H19/IGF2</i> circuit may explain paradoxical GWAS findings linking <i>FTO</i><sup>rs9939609-A</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月7日

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  • Lu Guang,
  • Shilin Ma,
  • Ziyue Yao,
  • Dan Song,
  • Yu Chen,
  • Shuqing Liu,
  • Peng Wang,
  • Jiali Su,
  • Yuefan Wang,
  • Lanfang Luo,
  • Ng Shyh-Chang

摘要

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.