Dlk1/FA1 is a novel endocrine regulator of bone and fat mass and its serum level is modulated by growth hormone
Dlk1/FA1 is a novel endocrine regulator of bone and fat mass and its serum level is modulated by growth hormone
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DOI：
10.1210/en.2007-0171
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发表时间：
2007-07-01
期刊：
影响因子：
4.8
通讯作者：
Kassem, Moustapha
中科院分区：
文献类型：
--
作者：
Abdallah, Basem M.;Ding, Ming;Kassem, Moustapha
脂肪和骨代谢是两个相互关联的过程，由几种激素因素调节。胎儿抗原1（FA 1）是dlk 1（delta样1）的可溶性形式，dlk 1是Notch-Delta家族的成员。我们以前确定FA 1作为骨髓间充质干细胞分化的负调节因子。在这里，我们研究了循环FA 1对体内脂肪和骨量的影响，通过使用基于流体动力学的基因转移程序产生表达高血清水平FA 1的小鼠（FA 1小鼠）。我们发现，血清FA 1水平增加导致总体重，脂肪量和骨量以剂量依赖性方式显着减少。FA 1小鼠骨量减少与矿物质沉积率和骨形成率分别抑制58%和72%相关。由于FA 1与GH共定位于垂体，我们探讨了GH对血清FA 1的可能调节作用。在FA 1小鼠中，IGF-I和IGF结合蛋白的血清水平没有变化，而使用基于流体动力学的基因转移程序在正常小鼠中增加血清GH使血清FA 1水平显著降低60%。相反，垂体切除小鼠的血清FA 1增加了450%，而GH治疗期间，这一高水平降低了40%。总之，我们的数据确定FA 1作为一种新的内分泌因子调节体内骨量和脂肪量，其血清水平由GH调节。因此，FA 1提供了一类新的发育分子，调节出生后生物体的生理功能。
Fat and bone metabolism are two linked processes regulated by several hormonal factors. Fetal antigen 1 (FA1) is the soluble form of dlk1 (delta-like 1), which is a member of the Notch-Delta family. We previously identified FA1 as a negative regulator of bone marrow mesenchymal stem cell differentiation. Here, we studied the effects of circulating FA1 on fat and bone mass in vivo by generating mice expressing high serum levels of FA1 (FA1 mice) using the hydrodynamic-based gene transfer procedure. We found that increased serum FA1 levels led to a significant reduction in total body weight, fat mass, and bone mass in a dose-dependent manner. Reduced bone mass in FA1 mice was associated with the inhibition of mineral apposition rate and bone formation rates by 58 and 72%, respectively. Because FA1 is colocalized with GH in the pituitary gland, we explored the possible modulation of serum FA1 by GH. Serum levels of IGF-I and IGF binding proteins did not change in FA1 mice, whereas increasing serum GH in normal mice using hydrodynamic-based gene transfer procedure dramatically reduced serum FA1 levels by 60%. Conversely, serum FA1 was increased 450% in hypophysectomized mice, and this high level was reduced by 40% during GH treatment. In conclusion, our data identify the FA1 as a novel endocrine factor regulating bone mass and fat mass in vivo, and its serum levels are regulated by GH. FA1 thus provides a novel class of developmental molecules that regulate physiological functions of the postnatal organisms.