Serum leptin level is a regulator of bone mass
Serum leptin level is a regulator of bone mass
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DOI：
10.1073/pnas.0308744101
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发表时间：
2004-03-02
影响因子：
11.1
通讯作者：
Karsenty, G
中科院分区：
文献类型：
--
作者：
Elefteriou, F;Takeda, S;Karsenty, G
瘦素是体内骨形成的强有力抑制剂。这种抗成骨功能涉及瘦素与下丘脑腹内侧神经元、自主神经系统和成骨细胞上的β-肾上腺素能受体的结合。然而，瘦素控制下丘脑腹内侧抗成骨神经元功能的机制尚不清楚。在这项研究中，我们比较了瘦素调节体重和骨量的能力，并表明瘦素抗成骨和骨形成功能受到相似量的瘦素的影响。在瘦素基因座中敲入LacZ，我们未能检测到中枢神经系统中的任何瘦素合成。然而，增加血清瘦素水平，甚至显着，减少骨量。相反，通过过度表达瘦素的可溶性受体来降低无血清瘦素水平会增加骨量。与这些结果一致，脂肪营养不良小鼠的高骨量可以通过恢复血清瘦素水平来纠正，这表明瘦素是控制骨量所必需和足够的脂肪细胞产物。与脂肪营养不良小鼠的高骨量表型一致，我们观察到脂肪营养不良患者的骨龄提前，这是骨过早形成的间接反映。总之，这些结果表明，脂肪细胞衍生的循环瘦素是骨形成的决定因素，并表明瘦素抗成骨功能是保守的脊椎动物。
Leptin is a powerful inhibitor of bone formation in vivo. This antiosteogenic function involves leptin binding to its receptors on ventromedial hypothalamic neurons, the autonomous nervous system and beta-adrenergic receptors on osteoblasts. However, the mechanisms whereby leptin controls the function of ventromedial hypothalamic antiosteogenic neurons remain unclear. In this study, we compared the ability of leptin to regulate body weight and bone mass and show that leptin antiosteogenic and anorexigenic functions are affected by similar amounts of leptin. Using a knock-in of LacZ in the leptin locus, we failed to detect any leptin synthesis in the central nervous system. However, increasing serum leptin level, even dramatically, reduced bone mass. Conversely, reducing serum-free leptin level by overexpressing a soluble receptor for leptin increased bone mass. Congruent with these results, the high bone mass of lipodystrophic mice could be corrected by restoring serum leptin level, suggesting that leptin is an adipocyte product both necessary and sufficient to control bone mass. Consistent with the high bone mass phenotype of lipodystrophic mice, we observed an advanced bone age, an indirect reflection of premature bone formation, in lipodystrophic patients. Taken together, these results indicate that adipocyte-derived circulating leptin is a determinant of bone formation and suggests that leptin antiosteogenic function is conserved in vertebrates.