Abstract
The nuclear receptor PPARα is known as a major regulator of lipid metabolism and a pharmacologic target to treat dyslipidemia. However, PPARα role in maintenance of bone mass and bone marrow adipose tissue (BMAT) has not been studied in detail. Previously, we observed that mice with global deletion of PPARα (αKO) have increased BMAT volume and altered bone phenotype. Primary osteocytes isolated from αKO showed 1488 differentially expressed transcripts in Next Generation Sequencing analysis. Interestingly, we found that genes related to osteogenesis, differentiation and secreted proteins were down-regulated while apoptotic genes were up-regulated in αKO osteocytes by DAVID functional clustering analysis. Additionally, majority of cells in bone are osteocytes, thus we hypothesized that PPARα in osteocyte plays an important role in regulation of bone structure and bone marrow fat (BMF) accumulation. To test this hypothesis, we developed osteocyte specific PPARα knock-out, 10kb-Dmp1CrePPARαfl/fl, mouse (αOT-KO). We observed that αOT-KO mice had significantly increased BMF volume in whole tibia. Interestingly marrow fat in the proximal tibia contributed to the increased marrow fat observed in αOT-KO mice. However, bone structure was not different compared to the controls. Likewise, conditioned media (CM) collected from primary cultures of αKO osteocytes increased expressions of adipogenic markers aP2, CD36 and LPL in recipient WT marrow mesenchymal stem cells (MSC) in co-culture experiment. In summary, PPARα deficient osteocytes release factors which support adipocyte differentiation from MSC in vitro. Thus, PPARα controls osteocyte paracrine activities controlling BMAT development, suggesting that this nuclear receptor can be a potential pharmacologic target to control BMAT accumulation.
Published Version
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