Divergent roles of m6A in orchestrating brown and white adipocyte transcriptomes and systemic metabolism
Abstract N6-methyladenosine (m6A) is among the most abundant mRNA modifications, yet its cell-type-specific regulatory roles remain unclear. Here we show that m6A methyltransferase-like 14 (METTL14) differentially regulates transcriptome in brown versus white adipose tissue (BAT and WAT), leading to...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55694-w |
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| author | Ling Xiao Dario F. De Jesus Cheng-Wei Ju Jiang-Bo Wei Jiang Hu Ava DiStefano-Forti Valeria Salerno Gonzales Tadataka Tsuji Siying Wei Matthias Blüher Yu-Hua Tseng Chuan He Rohit N. Kulkarni |
| author_facet | Ling Xiao Dario F. De Jesus Cheng-Wei Ju Jiang-Bo Wei Jiang Hu Ava DiStefano-Forti Valeria Salerno Gonzales Tadataka Tsuji Siying Wei Matthias Blüher Yu-Hua Tseng Chuan He Rohit N. Kulkarni |
| author_sort | Ling Xiao |
| collection | DOAJ |
| description | Abstract N6-methyladenosine (m6A) is among the most abundant mRNA modifications, yet its cell-type-specific regulatory roles remain unclear. Here we show that m6A methyltransferase-like 14 (METTL14) differentially regulates transcriptome in brown versus white adipose tissue (BAT and WAT), leading to divergent metabolic outcomes. In humans and mice with insulin resistance, METTL14 expression differs significantly from BAT and WAT in the context of its correlation with insulin sensitivity. Mettl14-knockout in BAT promotes prostaglandin secretion, improving systemic insulin sensitivity. Conversely, Mettl14-knockout in WAT triggers adipocyte apoptosis and systemic insulin resistance. m6A-seq and RNA-seq integration revealed upregulated prostaglandin biosynthesis pathways in BAT and apoptotic pathways in WAT with Mettl14 deficiency. Stable METTL14-knockout hBAs/hWAs show METTL14-mediated m6A promotes mRNA decay of PTGES2 and CBR1 in hBAs and TRAIL and TNFR1 in hWAs. These data shed light on the ability of m6A to impact metabolism in a cell-type-specific manner with implications for influencing the pathophysiology of metabolic diseases. |
| format | Article |
| id | doaj-art-a8b305321d974a62bcca8603960a0c77 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a8b305321d974a62bcca8603960a0c772025-01-12T12:30:46ZengNature PortfolioNature Communications2041-17232025-01-0116111910.1038/s41467-024-55694-wDivergent roles of m6A in orchestrating brown and white adipocyte transcriptomes and systemic metabolismLing Xiao0Dario F. De Jesus1Cheng-Wei Ju2Jiang-Bo Wei3Jiang Hu4Ava DiStefano-Forti5Valeria Salerno Gonzales6Tadataka Tsuji7Siying Wei8Matthias Blüher9Yu-Hua Tseng10Chuan He11Rohit N. Kulkarni12Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center; Department of Medicine, BIDMC; Harvard Stem Cell Institute, Harvard Medical SchoolSection of Islet Cell and Regenerative Biology, Joslin Diabetes Center; Department of Medicine, BIDMC; Harvard Stem Cell Institute, Harvard Medical SchoolDepartment of Chemistry, Howard Hughes Medical Institute, The University of ChicagoDepartment of Chemistry, National University of SingaporeSection of Islet Cell and Regenerative Biology, Joslin Diabetes Center; Department of Medicine, BIDMC; Harvard Stem Cell Institute, Harvard Medical SchoolSection of Islet Cell and Regenerative Biology, Joslin Diabetes Center; Department of Medicine, BIDMC; Harvard Stem Cell Institute, Harvard Medical SchoolSection of Islet Cell and Regenerative Biology, Joslin Diabetes Center; Department of Medicine, BIDMC; Harvard Stem Cell Institute, Harvard Medical SchoolSection on Integrative Physiology and Metabolism, Joslin Diabetes Center; Department of Medicine, BIDMC, Harvard Medical School; Harvard Stem Cell InstituteSection of Islet Cell and Regenerative Biology, and CRISPR Screen Core Laboratory, Joslin Diabetes Center; Department of Medicine, BIDMC; Harvard Medical SchoolHelmholtz Institute for Metabolic, Obesity and Vascular ResearchSection on Integrative Physiology and Metabolism, Joslin Diabetes Center; Department of Medicine, BIDMC, Harvard Medical School; Harvard Stem Cell InstituteDepartment of Chemistry, Howard Hughes Medical Institute, The University of ChicagoSection of Islet Cell and Regenerative Biology, Joslin Diabetes Center; Department of Medicine, BIDMC; Harvard Stem Cell Institute, Harvard Medical SchoolAbstract N6-methyladenosine (m6A) is among the most abundant mRNA modifications, yet its cell-type-specific regulatory roles remain unclear. Here we show that m6A methyltransferase-like 14 (METTL14) differentially regulates transcriptome in brown versus white adipose tissue (BAT and WAT), leading to divergent metabolic outcomes. In humans and mice with insulin resistance, METTL14 expression differs significantly from BAT and WAT in the context of its correlation with insulin sensitivity. Mettl14-knockout in BAT promotes prostaglandin secretion, improving systemic insulin sensitivity. Conversely, Mettl14-knockout in WAT triggers adipocyte apoptosis and systemic insulin resistance. m6A-seq and RNA-seq integration revealed upregulated prostaglandin biosynthesis pathways in BAT and apoptotic pathways in WAT with Mettl14 deficiency. Stable METTL14-knockout hBAs/hWAs show METTL14-mediated m6A promotes mRNA decay of PTGES2 and CBR1 in hBAs and TRAIL and TNFR1 in hWAs. These data shed light on the ability of m6A to impact metabolism in a cell-type-specific manner with implications for influencing the pathophysiology of metabolic diseases.https://doi.org/10.1038/s41467-024-55694-w |
| spellingShingle | Ling Xiao Dario F. De Jesus Cheng-Wei Ju Jiang-Bo Wei Jiang Hu Ava DiStefano-Forti Valeria Salerno Gonzales Tadataka Tsuji Siying Wei Matthias Blüher Yu-Hua Tseng Chuan He Rohit N. Kulkarni Divergent roles of m6A in orchestrating brown and white adipocyte transcriptomes and systemic metabolism Nature Communications |
| title | Divergent roles of m6A in orchestrating brown and white adipocyte transcriptomes and systemic metabolism |
| title_full | Divergent roles of m6A in orchestrating brown and white adipocyte transcriptomes and systemic metabolism |
| title_fullStr | Divergent roles of m6A in orchestrating brown and white adipocyte transcriptomes and systemic metabolism |
| title_full_unstemmed | Divergent roles of m6A in orchestrating brown and white adipocyte transcriptomes and systemic metabolism |
| title_short | Divergent roles of m6A in orchestrating brown and white adipocyte transcriptomes and systemic metabolism |
| title_sort | divergent roles of m6a in orchestrating brown and white adipocyte transcriptomes and systemic metabolism |
| url | https://doi.org/10.1038/s41467-024-55694-w |
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