An obesogenic FTO allele causes accelerated development, growth and insulin resistance in human skeletal muscle cells
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 FTO rs9939609-A into hESC-derived...
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-53820-2 |
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| author | Lu Guang Shilin Ma Ziyue Yao Dan Song Yu Chen Shuqing Liu Peng Wang Jiali Su Yuefan Wang Lanfang Luo Ng Shyh-Chang |
| author_facet | Lu Guang Shilin Ma Ziyue Yao Dan Song Yu Chen Shuqing Liu Peng Wang Jiali Su Yuefan Wang Lanfang Luo Ng Shyh-Chang |
| author_sort | Lu Guang |
| collection | DOAJ |
| description | 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 FTO rs9939609-A into hESC-derived tissue models, to elucidate potentially hidden roles of FTO during development. We find that among human tissues, FTO rs9939609-A most robustly affect human muscle progenitors’ proliferation, differentiation, senescence, thereby accelerating muscle developmental and metabolic aging. An edited FTO rs9939609-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 FTO rs9939609-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. |
| format | Article |
| id | doaj-art-af27e984e484499aa6a2a88b8dcad5ed |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-af27e984e484499aa6a2a88b8dcad5ed2025-08-20T01:57:27ZengNature PortfolioNature Communications2041-17232025-03-0116111810.1038/s41467-024-53820-2An obesogenic FTO allele causes accelerated development, growth and insulin resistance in human skeletal muscle cellsLu Guang0Shilin Ma1Ziyue Yao2Dan Song3Yu Chen4Shuqing Liu5Peng Wang6Jiali Su7Yuefan Wang8Lanfang Luo9Ng Shyh-Chang10Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesKey Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesKey Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesKey Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesKey Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesKey Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesKey Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesKey Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesKey Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesKey Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesKey Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesAbstract 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 rs9939609-A into hESC-derived tissue models, to elucidate potentially hidden roles of FTO during development. We find that among human tissues, FTO rs9939609-A most robustly affect human muscle progenitors’ proliferation, differentiation, senescence, thereby accelerating muscle developmental and metabolic aging. An edited FTO rs9939609-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 FTO rs9939609-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.https://doi.org/10.1038/s41467-024-53820-2 |
| spellingShingle | Lu Guang Shilin Ma Ziyue Yao Dan Song Yu Chen Shuqing Liu Peng Wang Jiali Su Yuefan Wang Lanfang Luo Ng Shyh-Chang An obesogenic FTO allele causes accelerated development, growth and insulin resistance in human skeletal muscle cells Nature Communications |
| title | An obesogenic FTO allele causes accelerated development, growth and insulin resistance in human skeletal muscle cells |
| title_full | An obesogenic FTO allele causes accelerated development, growth and insulin resistance in human skeletal muscle cells |
| title_fullStr | An obesogenic FTO allele causes accelerated development, growth and insulin resistance in human skeletal muscle cells |
| title_full_unstemmed | An obesogenic FTO allele causes accelerated development, growth and insulin resistance in human skeletal muscle cells |
| title_short | An obesogenic FTO allele causes accelerated development, growth and insulin resistance in human skeletal muscle cells |
| title_sort | obesogenic fto allele causes accelerated development growth and insulin resistance in human skeletal muscle cells |
| url | https://doi.org/10.1038/s41467-024-53820-2 |
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