Bone-derived Sclerostin has endocrine actions in adipocyte precursors and pancreatic beta-cells

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Medicine and Health Sciences


Osteocyte (Ot)-derived Sclerostin (Scl) has local actions in bone mediated by Lrp 4/5/6 receptors, inhibiting bone formation and stimulating bone resorption by antagonizing Wnt signaling. Emerging evidence suggests that Scl also exerts functions in distant tissues. We report here that mice with activated β-catenin in Ots (daβcatOt) and mice lacking Lrp4 in Ots (Lrp4Ot), two different genetic mouse models that exhibit high se-rum Scl, display a 2-fold increase in whole-body fat and peripheral white (WAT) and brown (BAT) adipose tissue mass. The goal of this study was to determine the contribution of Ot-derived Scl to the regulation of peripheral fat mass and glucose metabolism. To determine Scl’s contribution to the high fat phenotype, daβcatOt mice were crossed with SOST knockout mice. Deletion of SOST restored to control levels the elevated body-fat mass and WAT mass, but not BAT, in daβcatOt mice. In contrast, blockade of Scl signaling in bone via genetic deletion of Lrp4 in Ots, did not alter the elevated body fat displayed by daβcatOt mice, demonstrating that Scl actions on adi-pose tissue were not mediated by Scl actions on Ots. Consistent with direct effects of Scl on adipose tissue, treatment with recombinant Scl enhanced by 20% adipogenic differentiation of murine adipocyte precursors (preAd) in vitro, and increased the expression of mitochondrial related genes Pgc1a, Ucp1, and Prdm16 in preAds as well as in ex vivo fat organ cultures established from WAT. Further, Scl augmented mitochondrial respiration in preAds by inducing a 15% increase in maximal respiration and spare capacity, suggesting that Scl promotes adipogenesis in preAds by regulating mitochondrial oxidative phosphorylation. Both models of high serum Scl, daβcatOt and LRP4Ot mice, also were hypoglycemic and exhibited impaired glucose tolerance com-pared to control littermates. Genetic deletion of SOST restored to control values the glucose levels in blood and glucose tolerance, showing that serum Scl regulates glucose metabolism. Further, Scl fully prevented the increase in insulin mRNA expression induced by Wnt3a in rat pancreatic β-cells and decreased by 45% insulin secretion induced by high-glucose media, demonstrating that Scl acts directly on pancreatic β-cells to impair insulin production. In concert, these findings demonstrate that Scl exerts endocrine actions in fat tissues and the pancreas to regulate body composition and glucose metabolism, respectively. Further, our results provide new evidence supporting that endocrine actions of Scl mediate the crosstalk between bone and fat and the pancreas.


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