Lee Na Kyung, Sowa Hideaki, Hinoi Eiichi, Ferron Mathieu, Ahn Jong Deok, Confavreux Cyrille, Dacquin Romain, Mee Patrick J, McKee Marc D, Jung Dae Young, Zhang Zhiyou, Kim Jason K, Mauvais-Jarvis Franck, Ducy Patricia, Karsenty Gerard
Department of Genetics & Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Cell. 2007 Aug 10;130(3):456-69. doi: 10.1016/j.cell.2007.05.047.
The regulation of bone remodeling by an adipocyte-derived hormone implies that bone may exert a feedback control of energy homeostasis. To test this hypothesis we looked for genes expressed in osteoblasts, encoding signaling molecules and affecting energy metabolism. We show here that mice lacking the protein tyrosine phosphatase OST-PTP are hypoglycemic and are protected from obesity and glucose intolerance because of an increase in beta-cell proliferation, insulin secretion, and insulin sensitivity. In contrast, mice lacking the osteoblast-secreted molecule osteocalcin display decreased beta-cell proliferation, glucose intolerance, and insulin resistance. Removing one Osteocalcin allele from OST-PTP-deficient mice corrects their metabolic phenotype. Ex vivo, osteocalcin can stimulate CyclinD1 and Insulin expression in beta-cells and Adiponectin, an insulin-sensitizing adipokine, in adipocytes; in vivo osteocalcin can improve glucose tolerance. By revealing that the skeleton exerts an endocrine regulation of sugar homeostasis this study expands the biological importance of this organ and our understanding of energy metabolism.
脂肪细胞衍生激素对骨重塑的调节意味着骨可能对能量稳态发挥反馈控制作用。为了验证这一假设，我们寻找在成骨细胞中表达、编码信号分子并影响能量代谢的基因。我们在此表明，缺乏蛋白酪氨酸磷酸酶OST-PTP的小鼠出现低血糖，并且由于β细胞增殖、胰岛素分泌和胰岛素敏感性增加而免受肥胖和葡萄糖不耐受的影响。相反，缺乏成骨细胞分泌分子骨钙素的小鼠表现出β细胞增殖减少、葡萄糖不耐受和胰岛素抵抗。从OST-PTP缺陷小鼠中去除一个骨钙素等位基因可纠正其代谢表型。在体外，骨钙素可刺激β细胞中的细胞周期蛋白D1和胰岛素表达以及脂肪细胞中脂联素（一种胰岛素增敏脂肪因子）的表达；在体内，骨钙素可改善葡萄糖耐量。通过揭示骨骼对糖稳态发挥内分泌调节作用，本研究扩展了该器官的生物学重要性以及我们对能量代谢的理解。
