The central nervous system is an active and major regulator of bone structure and remodelling. Specifically, signalling within the hypothalamus has been shown to be critical to ensuring that skeletal functions align with whole body metabolic supply and demand. Here, we identify agouti-related peptide (AgRP), an orexigenic peptide exclusively co-expressed with neuropeptide Y (NPY) in the arcuate nucleus (ARC) of the hypothalamus, as another critical player in the central control of bone homeostasis. Using novel mouse models, we show that AgRP deletion leads to an increase in cortical and trabecular bone mass as a result of an increase in bone thickness despite a lean phenotype, particularly in male mice. Interestingly, male AgRP deficient mice display a significant decrease in pro-opiomelanocortin (POMC) expression in the ARC, but no change in NPY or CART expression, suggesting that the increase in bone mass in AgRP-deficient mice is unlikely to be a result of altered NPY signalling. This is consistent with the observation that bone mass is unchanged in response to the specific deletion of NPY from AgRP expressing neurones. By contrast, POMC expression in the ARC is significantly increased in female AgRP deficient mice, although AgRP deletion results in altered respiratory exchange ratio regulation in response to re-feeding after a fast in both sexes. Taken together, the present study identifies AgRP as being directly involved in the regulation of bone mass and highlights the complexity intrinsic to the neuropeptide regulation of the skeleton.

中文翻译：

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AgRP信号负调节骨量

中枢神经系统是骨骼结构和重塑的活跃而主要的调节者。具体而言，下丘脑内的信号传导已被证明对于确保骨骼功能与全身新陈代谢的供需一致至关重要。在这里，我们确定刺骨相关肽（AgRP），一种与下丘脑弓状核（ARC）中神经肽Y（NPY）共表达的致癌肽，是骨稳态稳态控制的另一个关键因素。使用新颖的小鼠模型，我们表明，尽管表型较瘦，但由于骨厚度增加，AgRP缺失导致皮质和小梁骨质量增加，特别是在雄性小鼠中。有趣的是，雄性AgRP缺陷型小鼠在ARC中显示了促视神经黑皮质素（POMC）表达的显着降低，但NPY或CART表达无变化，这表明AgRP缺陷型小鼠的骨量增加不太可能是NPY信号改变的结果。这与观察到的骨量相对于表达AgRP的神经元中的NPY的特异性缺失没有变化的观察结果一致。相比之下，雌性AgRP缺陷型小鼠的ARC中POMC的表达显着增加，尽管AgRP缺失会导致禁食后两性对重新喂养的呼吸交换比调节发生变化。综上，本研究确定AgRP直接参与骨量的调节，并突出了骨骼神经肽调节固有的复杂性。这表明缺乏AgRP的小鼠的骨量增加不太可能是NPY信号改变的结果。这与观察到的骨量相对于表达AgRP的神经元中的NPY的特异性缺失没有变化的观察结果一致。相比之下，雌性AgRP缺陷型小鼠的ARC中POMC的表达显着增加，尽管AgRP缺失会导致禁食后两性对重新喂养的呼吸交换比调节发生变化。综上，本研究确定AgRP直接参与骨量的调节，并突出了骨骼神经肽调节固有的复杂性。这表明缺乏AgRP的小鼠的骨量增加不太可能是NPY信号改变的结果。这与观察到的骨量相对于表达AgRP的神经元中的NPY的特异性缺失没有变化的观察结果一致。相比之下，雌性AgRP缺陷型小鼠的ARC中POMC的表达显着增加，尽管AgRP缺失会导致禁食后两性对重新喂养的呼吸交换比调节发生变化。综上所述，本研究确定了AgRP直接参与骨量的调节，并突出了骨骼神经肽调节固有的复杂性。雌性AgRP缺陷小鼠的ARC中POMC的表达显着增加，尽管AgRP缺失会导致禁食后两性对重新喂养的呼吸交换比调节发生变化。综上所述，本研究确定了AgRP直接参与骨量的调节，并突出了骨骼神经肽调节固有的复杂性。雌性AgRP缺陷小鼠的ARC中POMC的表达显着增加，尽管AgRP缺失会导致禁食后两性对重新喂养的呼吸交换比调节发生变化。综上所述，本研究确定了AgRP直接参与骨量的调节，并突出了骨骼神经肽调节固有的复杂性。