Hypothalamic control of bone formation: Distinct actions of leptin and Y2 receptor pathways
Hypothalamic control of bone formation: Distinct actions of leptin and Y2 receptor pathways
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DOI：
10.1359/jbmr.050523
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发表时间：
2005-10-01
影响因子：
6.2
通讯作者：
Gardiner, EM
中科院分区：
文献类型：
--
作者：
Baldock, PA;Sainsbury, A;Gardiner, EM
下丘脑神经肽Y神经元上的瘦素和Y2受体介导瘦素对能量稳态的影响;然而，它们在调节成骨细胞活性中的相互作用尚未建立。在这里，直接测试这种可能性表明不同的机制瘦素抗成骨和Y2（-/-）合成代谢途径在modulating bone formation.Introduction：中央增强骨形成的下丘脑神经元中观察到瘦素缺乏oblob和Y2受体无效小鼠。在这两种模型中，中枢神经肽Y（NPY）表达和对成骨细胞活性的影响相似，表明瘦素和Y2受体在骨生理学的中枢控制中有共同的途径。本研究的目的是测试是否瘦素和Y2受体途径调节骨由相同或不同的mechanism.Materials和方法：在控制骨伴随瘦素和Y2受体缺乏症的相互作用进行了检查，在Y2（-/-）oblob双突变小鼠，以确定是否瘦素和Y2受体缺乏症有累加效应。使用重组腺相关病毒载体过量产生NPY（AAV-NPY）来检查瘦素过量和Y2受体缺失之间的相互作用，以在成年Y2（-/-）小鼠中产生体重增加并因此产生瘦素过量。结果：成骨细胞活性在oblob、Y2（-/-）和Y2（-/-）oblob小鼠中显著升高。然而，与Y2（-/-）相比，oblob和Y2（-/-）oblob小鼠中更大的骨吸收减少了松质骨体积。野生型和Y2（-/-）AAV-NPY小鼠均表现出白色脂肪组织积累的显著升高，因此瘦素表达显著升高，从而降低成骨细胞活性。尽管在肥胖AAV-NPY模型中存在这种抗成骨瘦素作用，但Y2（-/-）AAV-NPY小鼠中的成骨细胞活性仍然显著高于野生型AAV-NPY小鼠。这项研究表明，NPY不是瘦素依赖性成骨细胞活性的关键调节因子，因为瘦素骨形成的刺激不足和骨形成的瘦素过度抑制可在高下丘脑NPY存在下发生。Y2（-/-）通路持续刺激骨形成;相反，瘦素随着循环水平的增加继续抑制骨形成。因此，随着肥胖症变得越来越明显，他们的行为越来越反对。因此，在缺乏瘦素的情况下，不能区分松质骨对Y2受体和瘦素活性丧失的反应。然而，随着瘦素水平增加到生理水平，不同的信号通路被揭示。
Leptin and Y2 receptors on hypothalamic NPY neurons mediate leptin effects on energy homeostasis; however, their interaction in modulating osteoblast activity is not established. Here, direct testing of this possibility indicates distinct mechanisms of action for leptin anti-osteogenic and Y2(-/-) anabolic pathways in modulating bone formation.Introduction: Central enhancement of bone formation by hypothalamic neurons is observed in leptin-deficient oblob and Y2 receptor null mice. Similar elevation in central neuropeptide Y (NPY) expression and effects on osteoblast activity in these two models suggest a shared pathway between leptin and Y2 receptors in the central control of bone physiology. The aim of this study was to test whether the leptin and Y2 receptor pathways regulate bone by the same or distinct mechanisms.Materials and Methods: The interaction of concomitant leptin and Y2 receptor deficiency in controlling bone was examined in Y2(-/-) oblob double mutant mice, to determine whether leptin and Y2 receptor deficiency have additive effects. Interaction between leptin excess and Y2 receptor deletion was examined using recombinant adeno-associated viral vector overproduction of NPY (AAV-NPY) to produce weight gain and thus leptin excess in adult Y2(-/-) mice. Cancellous bone volume and bone cell function were assessed.Results: Osteoblast activity was comparably elevated in oblob, Y2(-/-), and Y2(-/-) oblob mice. However, greater bone resorption in oblob and Y2(-/-) oblob mice reduced cancellous bone volume compared with Y2(-/-). Both wildtype and Y2(-/-) AAV-NPY mice exhibited marked elevation of white adipose tissue accumulation and hence leptin expression, thereby reducing osteoblast activity. Despite this anti-osteogenic leptin effect in the obese AAV-NPY model, osteoblast activity in Y2(-/-) AAV-NPY mice remained significantly greater than in wildtype AAV-NPY mice.Conclusions: This study suggests that NPY is not a key regulator of the leptin-dependent osteoblast activity, because both the leptin-deficient stimulation of bone formation and the excess leptin inhibition of bone formation can occur in the presence of high hypothalamic NPY. The Y2(-/-) pathway acts consistently to stimulate bone formation; in contrast, leptin continues to suppress bone formation as circulating levels increase. As a result, they act increasingly in opposition as obesity becomes more marked. Thus, in the absence of leptin, the cancellous bone response to loss of Y2 receptor and leptin activity can not be distinguished. However, as leptin levels increase to physiological levels, distinct signaling pathways are revealed.