Elefteriou F, Takeda S, Ebihara K, Magre J, Patano N, Kim C Ae, Ogawa Y, Liu X, Ware S M, Craigen W J, Robert J J, Vinson C, Nakao K, Capeau J, Karsenty G
Department of Molecular and Human Genetics, Bone Disease Program of Texas, Baylor College of Medicine, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3258-63. doi: 10.1073/pnas.0308744101. Epub 2004 Feb 20.
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.
瘦素是体内一种强大的骨形成抑制剂。这种抗成骨功能涉及瘦素与其在下丘脑腹内侧神经元、自主神经系统以及成骨细胞上的β-肾上腺素能受体上的受体结合。然而，瘦素控制下丘脑腹内侧抗成骨神经元功能的机制仍不清楚。在本研究中，我们比较了瘦素调节体重和骨量的能力，并表明瘦素的抗成骨和厌食功能受相似量的瘦素影响。通过在瘦素基因座敲入LacZ，我们未能在中枢神经系统中检测到任何瘦素合成。然而，即使显著提高血清瘦素水平，骨量也会减少。相反，通过过表达可溶性瘦素受体降低无血清瘦素水平可增加骨量。与这些结果一致，通过恢复血清瘦素水平可以纠正脂肪营养不良小鼠的高骨量，这表明瘦素是一种脂肪细胞产物，对控制骨量既必要又充分。与脂肪营养不良小鼠的高骨量表型一致，我们在脂肪营养不良患者中观察到骨龄提前，这是骨形成过早的间接反映。综上所述，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，并表明瘦素的抗成骨功能在脊椎动物中是保守的。
