AUTHOR=Artsi Hanna , Gurt Irina , El-Haj Madi , Müller Ralph , Kuhn Gisela A. , Ben Shalom Gal , Cohen-Kfir Einav , Abramowitz Eva , Kandel Leonid , Safran Ori , Dresner-Pollak Rivka 

TITLE=Sirt1 Promotes a Thermogenic Gene Program in Bone Marrow Adipocytes: From Mice to (Wo)Men

JOURNAL=Frontiers in Endocrinology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2019.00126

DOI=10.3389/fendo.2019.00126

ISSN=1664-2392

ABSTRACT=<p>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 <italic>Sirt1</italic> haplo-insufficient (<italic>Sirt1</italic><sup>Δ/+</sup>) and wild type (WT) mice. Decreased expression of the thermogenic genes: <italic>Prdm16, Pgc1</italic>α<italic>, Foxc2, Dio2</italic>, and β<italic>3AR</italic> was detected in whole tibiae derived from <italic>Sirt1</italic><sup>Δ/+</sup> compared to WT female mice. Similarly, decreased expression of <italic>Prdm16</italic> and <italic>Pgc1</italic>α was observed in primary bone marrow mesenchymal stem cell (BM-MSC) cultures obtained from <italic>Sirt1</italic><sup>Δ/+</sup> compared to WT female mice, suggesting a cell autonomous effect of Sirt1 in BM-MSCs. <italic>In vitro</italic>, 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 <italic>Foxc2, Pgc1</italic>α<italic>, Dio2, Tfam</italic>, and <italic>Cyc1</italic> expression while inhibition of Sirt1 by EX527 down-regulated <italic>UCP1</italic> 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 <italic>PGC1</italic>α mRNA and protein level. Blocking sclerostin, an inhibitor of the WNT pathway and a Sirt1 target, by the monoclonal humanized antibody (Sc-AbII), stimulated β<italic>3AR, PRDM16</italic>, and <italic>UCP1</italic> 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.</p>