Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia.
Department of Orthopaedic Surgery, Medical College of Georgia, Augusta University, Augusta, Georgia.
J Cell Physiol. 2018 Apr;233(4):2671-2680. doi: 10.1002/jcp.26148. Epub 2017 Sep 12.
Type 2 diabetes is an emerging global health epidemic. Foundations for new therapies are arising from understanding interactions between body systems. Bone-derived factors that reduce RANKL (receptor activator of NF-kappa B ligand) signaling in the liver may prevent insulin resistance and the onset of type 2 diabetes. Here we demonstrate that deletion of the epigenetic regulator, Hdac3, in Osx1-expressing osteoprogenitors prevents insulin resistance induced by high fat diet by increasing serum and skeletal gene expression levels of osteoprotegerin (Opg), a natural inhibitor of RANKL signaling. Removal of one Opg allele in mice lacking Hdac3 in Osx1+ osteoprogenitors increases the insulin resistance of the Hdac3-deficient mice on a high fat diet. Thus, Hdac3-depletion in osteoblasts increases expression of Opg, subsequently preserving insulin sensitivity. The Hdac inhibitor vorinostat also increased Opg transcription and histone acetylation of the Opg locus. These results define a new mechanism by which bone regulates systemic insulin sensitivity.
2 型糖尿病是一种正在出现的全球健康流行症。新疗法的基础来自于对身体系统相互作用的理解。骨源性因子可降低肝脏中 RANKL（核因子 κB 配体受体激活剂）信号，从而预防胰岛素抵抗和 2 型糖尿病的发生。在这里，我们证明了在表达 Osx1 的成骨前体细胞中删除表观遗传调节剂 Hdac3，通过增加血清和骨骼中骨保护素（Opg）的基因表达水平，可预防高脂肪饮食引起的胰岛素抵抗，Opg 是 RANKL 信号的天然抑制剂。在缺乏 Hdac3 的小鼠中去除一个 Opg 等位基因，会增加缺乏 Hdac3 的成骨前体细胞中 Osx1+的小鼠在高脂肪饮食下的胰岛素抵抗。因此，成骨细胞中 Hdac3 的耗竭会增加 Opg 的表达，从而维持胰岛素敏感性。组蛋白去乙酰化酶抑制剂伏立诺他也增加了 Opg 转录和 Opg 基因座的组蛋白乙酰化。这些结果定义了一种新的机制，即骨骼调节全身胰岛素敏感性。
