Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition.
Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition.
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DOI：
10.1016/j.cell.2010.06.002
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发表时间：
2010-07-23
期刊：
影响因子：
64.5
通讯作者：
Clemens TL
中科院分区：
文献类型：
--
作者：
Fulzele K;Riddle RC;DiGirolamo DJ;Cao X;Wan C;Chen D;Faugere MC;Aja S;Hussain MA;Brüning JC;Clemens TL
哺乳动物的整体能量平衡由循环激素的作用控制，这些激素协调代谢活性组织中的燃料产生和利用。骨源性骨钙素，在其羧基化不足，激素形式，调节脂肪沉积，是一种有效的胰岛素促分泌素。在这里，我们表明，胰岛素受体（IR）信号在成骨细胞控制成骨细胞的发展和骨钙素的表达，通过抑制Runx 2抑制剂Twist 2。成骨细胞缺乏IR的小鼠由于骨形成减少和成骨细胞数量不足而具有低的循环低羧基化骨钙素和减少的骨获取。随着年龄的增长，这些小鼠出现明显的外周肥胖和高血糖症，伴有严重的葡萄糖耐受不良和胰岛素抵抗。这些小鼠的代谢异常通过输注外源性低羧化骨钙素得到改善。这些结果表明存在骨-胰腺内分泌环路，通过该环路，成骨细胞中的胰岛素信号传导确保成骨细胞分化并刺激骨钙素产生，骨钙素产生进而调节胰岛素敏感性和胰腺胰岛素分泌以控制葡萄糖稳态。
Global energy balance in mammals is controlled by the actions of circulating hormones that coordinate fuel production and utilization in metabolically active tissues. Bone-derived osteocalcin, in its undercarboxylated, hormonal form, regulates fat deposition and is a potent insulin secretagogue. Here, we show that insulin receptor (IR) signaling in osteoblasts controls osteoblast development and osteocalcin expression by suppressing the Runx2 inhibitor Twist2. Mice lacking IR in osteoblasts have low circulating undercarboxylated osteocalcin and reduced bone acquisition due to decreased bone formation and deficient numbers of osteoblasts. With age, these mice develop marked peripheral adiposity and hyperglycemia accompanied by severe glucose intolerance and insulin resistance. The metabolic abnormalities in these mice are improved by infusion of exogenous undercarboxylated osteocalcin. These results indicate the existence of a bone-pancreas endocrine loop through which insulin signaling in the osteoblast ensures osteoblast differentiation and stimulates osteocalcin production, which in turn regulates insulin sensitivity and pancreatic insulin secretion to control glucose homeostasis.
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