Sirt1 Promotes a Thermogenic Gene Program in Bone Marrow Adipocytes: From Mice to (Wo)Men
Bone marrow adipose tissue (MAT) is influenced by nutritional cues, and participates in whole body energy metabolism. To investigate the role of Sirtuin1 (Sirt1), a key player in metabolism, in MAT, marrow adiposity was evaluated in inbred 5-month-old 129/Sv Sirt1 haplo-insufficient (Sirt1Δ/+) and w...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-02-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fendo.2019.00126/full |
| _version_ | 1819113712811769856 |
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| author | Hanna Artsi Irina Gurt Madi El-Haj Ralph Müller Gisela A. Kuhn Gal Ben Shalom Einav Cohen-Kfir Eva Abramowitz Leonid Kandel Ori Safran Rivka Dresner-Pollak |
| author_facet | Hanna Artsi Irina Gurt Madi El-Haj Ralph Müller Gisela A. Kuhn Gal Ben Shalom Einav Cohen-Kfir Eva Abramowitz Leonid Kandel Ori Safran Rivka Dresner-Pollak |
| author_sort | Hanna Artsi |
| collection | DOAJ |
| description | Bone marrow adipose tissue (MAT) is influenced by nutritional cues, and participates in whole body energy metabolism. To investigate the role of Sirtuin1 (Sirt1), a key player in metabolism, in MAT, marrow adiposity was evaluated in inbred 5-month-old 129/Sv Sirt1 haplo-insufficient (Sirt1Δ/+) and wild type (WT) mice. Decreased expression of the thermogenic genes: Prdm16, Pgc1α, Foxc2, Dio2, and β3AR was detected in whole tibiae derived from Sirt1Δ/+ compared to WT female mice. Similarly, decreased expression of Prdm16 and Pgc1α was observed in primary bone marrow mesenchymal stem cell (BM-MSC) cultures obtained from Sirt1Δ/+ compared to WT female mice, suggesting a cell autonomous effect of Sirt1 in BM-MSCs. In vitro, Sirt1 over-expression in the mesenchymal embryonic fibroblast stem cell line C3HT101/2 increased Pgc1α and Prdm16 protein level. Similarly, pharmacologic activation of Sirt1 by SRT3025 increased Foxc2, Pgc1α, Dio2, Tfam, and Cyc1 expression while inhibition of Sirt1 by EX527 down-regulated UCP1 in C3HT101/2 cells. Importantly, in human femoral BM-MSCs obtained from female patients undergoing hip operations for fracture or osteoarthritis, Sirt1 activation by SRT3025 increased PGC1α mRNA and protein level. Blocking sclerostin, an inhibitor of the WNT pathway and a Sirt1 target, by the monoclonal humanized antibody (Sc-AbII), stimulated β3AR, PRDM16, and UCP1 gene expression, and increased PGC1α protein level. These results show that Sirt1 stimulates a thermogenic gene program in marrow adipocytes in mice and humans via PGC1α activation and sclerostin inhibition. The implications of these findings to bone health, hematopoiesis and whole body energy metabolism remain to be investigated. |
| first_indexed | 2024-12-22T04:33:46Z |
| format | Article |
| id | doaj.art-94bf9e96b1304174871557465ef40c03 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-12-22T04:33:46Z |
| publishDate | 2019-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-94bf9e96b1304174871557465ef40c032022-12-21T18:38:57ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922019-02-011010.3389/fendo.2019.00126417080Sirt1 Promotes a Thermogenic Gene Program in Bone Marrow Adipocytes: From Mice to (Wo)MenHanna Artsi0Irina Gurt1Madi El-Haj2Ralph Müller3Gisela A. Kuhn4Gal Ben Shalom5Einav Cohen-Kfir6Eva Abramowitz7Leonid Kandel8Ori Safran9Rivka Dresner-Pollak10Division of Medicine, Department of Endocrinology and Metabolism, Faculty of Medicine, The Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, IsraelDivision of Medicine, Department of Endocrinology and Metabolism, Faculty of Medicine, The Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, IsraelDepartment of Orthopedics, Faculty of Medicine, The Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, IsraelDepartment of Health Sciences and Technology, Institute for Biomechanics, ETH Zurich, Zurich, SwitzerlandDepartment of Health Sciences and Technology, Institute for Biomechanics, ETH Zurich, Zurich, SwitzerlandDivision of Medicine, Department of Endocrinology and Metabolism, Faculty of Medicine, The Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, IsraelDivision of Medicine, Department of Endocrinology and Metabolism, Faculty of Medicine, The Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, IsraelDivision of Medicine, Department of Endocrinology and Metabolism, Faculty of Medicine, The Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, IsraelDepartment of Orthopedics, Faculty of Medicine, The Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, IsraelDepartment of Orthopedics, Faculty of Medicine, The Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, IsraelDivision of Medicine, Department of Endocrinology and Metabolism, Faculty of Medicine, The Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, IsraelBone marrow adipose tissue (MAT) is influenced by nutritional cues, and participates in whole body energy metabolism. To investigate the role of Sirtuin1 (Sirt1), a key player in metabolism, in MAT, marrow adiposity was evaluated in inbred 5-month-old 129/Sv Sirt1 haplo-insufficient (Sirt1Δ/+) and wild type (WT) mice. Decreased expression of the thermogenic genes: Prdm16, Pgc1α, Foxc2, Dio2, and β3AR was detected in whole tibiae derived from Sirt1Δ/+ compared to WT female mice. Similarly, decreased expression of Prdm16 and Pgc1α was observed in primary bone marrow mesenchymal stem cell (BM-MSC) cultures obtained from Sirt1Δ/+ compared to WT female mice, suggesting a cell autonomous effect of Sirt1 in BM-MSCs. In vitro, Sirt1 over-expression in the mesenchymal embryonic fibroblast stem cell line C3HT101/2 increased Pgc1α and Prdm16 protein level. Similarly, pharmacologic activation of Sirt1 by SRT3025 increased Foxc2, Pgc1α, Dio2, Tfam, and Cyc1 expression while inhibition of Sirt1 by EX527 down-regulated UCP1 in C3HT101/2 cells. Importantly, in human femoral BM-MSCs obtained from female patients undergoing hip operations for fracture or osteoarthritis, Sirt1 activation by SRT3025 increased PGC1α mRNA and protein level. Blocking sclerostin, an inhibitor of the WNT pathway and a Sirt1 target, by the monoclonal humanized antibody (Sc-AbII), stimulated β3AR, PRDM16, and UCP1 gene expression, and increased PGC1α protein level. These results show that Sirt1 stimulates a thermogenic gene program in marrow adipocytes in mice and humans via PGC1α activation and sclerostin inhibition. The implications of these findings to bone health, hematopoiesis and whole body energy metabolism remain to be investigated.https://www.frontiersin.org/article/10.3389/fendo.2019.00126/fullsirtuin1marrow adipose tissuePGC1-alphabone marrow mesenchymal stem cellsthermogenic genes |
| spellingShingle | Hanna Artsi Irina Gurt Madi El-Haj Ralph Müller Gisela A. Kuhn Gal Ben Shalom Einav Cohen-Kfir Eva Abramowitz Leonid Kandel Ori Safran Rivka Dresner-Pollak Sirt1 Promotes a Thermogenic Gene Program in Bone Marrow Adipocytes: From Mice to (Wo)Men Frontiers in Endocrinology sirtuin1 marrow adipose tissue PGC1-alpha bone marrow mesenchymal stem cells thermogenic genes |
| title | Sirt1 Promotes a Thermogenic Gene Program in Bone Marrow Adipocytes: From Mice to (Wo)Men |
| title_full | Sirt1 Promotes a Thermogenic Gene Program in Bone Marrow Adipocytes: From Mice to (Wo)Men |
| title_fullStr | Sirt1 Promotes a Thermogenic Gene Program in Bone Marrow Adipocytes: From Mice to (Wo)Men |
| title_full_unstemmed | Sirt1 Promotes a Thermogenic Gene Program in Bone Marrow Adipocytes: From Mice to (Wo)Men |
| title_short | Sirt1 Promotes a Thermogenic Gene Program in Bone Marrow Adipocytes: From Mice to (Wo)Men |
| title_sort | sirt1 promotes a thermogenic gene program in bone marrow adipocytes from mice to wo men |
| topic | sirtuin1 marrow adipose tissue PGC1-alpha bone marrow mesenchymal stem cells thermogenic genes |
| url | https://www.frontiersin.org/article/10.3389/fendo.2019.00126/full |
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