Shi Yu, Yadav Vijay K, Suda Nina, Liu X Sherry, Guo X Edward, Myers Martin G, Karsenty Gerard
Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20529-33. doi: 10.1073/pnas.0808701106. Epub 2008 Dec 11.
The leptin regulation of bone remodeling, which has been documented through studies of loss-of-function mutations of this hormone or of its receptor in mice and humans, still raised several unanswered questions. For instance, it has been assumed but not formally demonstrated that this regulation occurs through neuronal means. Likewise, it has not been possible until now to dissociate the influence leptin exerts on appetite and energy expenditure from this function. We show here through mouse genetic studies that a deletion of the leptin receptor in neurons results in an increase in bone formation and bone resorption, resulting in a high bone mass as seen in leptin-deficient mice. In contrast, the same deletion in osteoblasts only does not influence bone remodeling. Furthermore, through the use of l/l mice, a model of gain of function in leptin signaling harboring a Y985L substitution in the leptin receptor, we show that leptin signaling inhibits bone mass accrual by up-regulating sympathetic activity independently of any change in appetite or energy expenditure. This work establishes that in vivo leptin regulates bone mass accrual by acting through neuronal means and provides a direct demonstration that this function of leptin can occur independently of its regulation of energy metabolism.
通过对小鼠和人类中这种激素或其受体的功能丧失突变的研究，已证实瘦素对骨重塑有调节作用，但仍存在几个未解决的问题。例如，人们已假定但尚未正式证实这种调节是通过神经元途径发生的。同样，到目前为止，还无法将瘦素对食欲和能量消耗的影响与该功能区分开来。我们通过小鼠遗传学研究表明，神经元中瘦素受体的缺失会导致骨形成和骨吸收增加，从而导致骨量增加，就像在瘦素缺乏的小鼠中看到的那样。相比之下，仅在成骨细胞中进行相同的缺失不会影响骨重塑。此外，通过使用l/l小鼠（一种在瘦素受体中具有Y985L替代的瘦素信号功能获得模型），我们表明瘦素信号通过上调交感神经活动来抑制骨量积累，而与食欲或能量消耗的任何变化无关。这项工作证实，在体内瘦素通过神经元途径调节骨量积累，并直接证明了瘦素的这一功能可以独立于其对能量代谢的调节而发生。
