Abstract
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.
Highlights
Adipose tissue consists of three main fat depots: visceral, subcutaneous, and marrow
Gene expression analysis in tibial marrow adipose tissue (MAT) revealed a dramatic decrease of ∼50% in the thermogenic genes: β3AR, FoxC2, Prdm16, Pgc1α, and Dio2 in Sirt1 /+ compared to wild type (WT) female mice (Figure 2A)
This study reports for the first time a role for Sirt1 in MAT phenotype, demonstrating its stimulatory effect on a thermogenic gene program in marrow adipocytes
Summary
Adipose tissue consists of three main fat depots: visceral, subcutaneous, and marrow. Recent studies have found that MAT responds to nutritional cues and exercise, and participates in whole body fat metabolism [1,2,3,4]. Sirtiun Induces Thermogenic Markers in MAT marrow transplantation have demonstrated trafficking of bone marrow (BM)-derived circulating progenitor cells to adipose tissue, their differentiation into subcutaneous adipocytes and increased representation in obesity [5, 6]. MAT was shown to contribute to circulating adiponectin in mice subjected to calorie restriction and in humans undergoing anticancer therapy [1]. MAT response to nutritional cues can be distinct than visceral and subcutaneous fat depots. Elucidating the mechanisms that regulate MAT may reveal novel pathways that influence bone turnover, hematopoiesis and whole body energy metabolism
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