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

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 FTO into hESC-derived tissue models, to elucidate potentially hidden roles of FTO during development. We find that among human tissues, FTO most robustly affect human muscle progenitors' proliferation, differentiation, senescence, thereby accelerating muscle developmental and metabolic aging. An edited FTO allele over-stimulates insulin/IGF signaling via increased muscle-specific enhancer H3K27ac, FTO expression and mA 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-mA-H19/IGF2 circuit may explain paradoxical GWAS findings linking FTO 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.