AgRP neurons regulate bone remodeling in aging

描述（由申请人提供）：在过去的十年中，中枢神经系统在介导某些外周组织源性激素对骨骼的作用方面起着重要作用。从我们实验室的工作和我们与他人的合作工作中得到的关键发现是脂肪激素瘦素选择性地靶向下丘脑神经元群体，并通过油菜素能系统改变骨量和能量代谢（Fernando-Galaz et al.，2002年Yadav等人，然而，尽管事实上瘦素在后脑中起作用，下丘脑黑皮质素系统仍然是骨稳态的关键下游效应物。特别地，我们发现瘦素的后脑作用以与先前描述的瘦素诱导骨丢失的作用完全一致的方式导致黑皮质素张力的改变（Yadav等人，2009年）。黑皮质素系统由两个不同的下丘脑神经元群体组成。一个群体产生阿黑皮素原（POMC）及其关键衍生物1-黑素细胞刺激激素（1 MSH），其是黑素皮质素4受体（MC 4 R）的激动剂。MC 4 R受体的激活导致饱腹感和交感神经张力增加。据认为，这种增加的交感神经紧张，反过来，抑制成骨细胞的功能，并增加破骨细胞的活性，导致骨丢失。黑皮质素系统的另一个“手臂”是产生神经肽Y（NPY）、抑制性神经递质GABA和AgRP相关蛋白（AgRP）的神经元群体。AgRP是MC 4 R的反向激动剂，并且AgRP/NPY/GABA神经元紧张性地抑制POMC神经元活性（Horvath等人，1992 a，B; Cowley等人，2001），导致对包括交感神经系统在内的许多输出的POMC效应的抑制。虽然不是所有影响骨骼代谢的激素都通过调节黑皮质素系统和交感神经流出到骨骼来起作用，但我们的假设是黑皮质素系统的活性在调节骨骼稳态中具有关键作用。具体而言，我们假设增加NPY/AgRP张力，抑制POMC神经元的活动，降低骨骼交感神经张力，从而促进骨愈合。基于初步数据，其表明活性氧物质（ROS）对NPY/AgRP神经元功能的有害作用，但ROS对POMC神经元放电的允许作用（Andrews等人，2008），我们还预测，在衰老过程中黑皮质素系统的ROS暴露增加是衰老相关的骨丢失和骨质疏松症发病机制的关键因素。

DESCRIPTION (provided by applicant): Over the past decade it has became evident that the central nervous system plays a major role in mediating the actions of certain peripheral tissue-derived hormones on the skeleton. A key finding resulting from work on our lab and our collaborative work with others was that the adipose hormone, leptin, selectively targets hypothalamic neuronal populations and alters bone mass and energy metabolism via the raphae serotoninergic system (Fernandez-Galaz et al., 2002 Yadav et al., 2009), However despite the fact that leptin acts in the hind brain, the hypothalamic melanocortin system remains a key downstream effector for bone homeostasis. In particular, we found that the hindbrain action of leptin results in alteration in melanocortin tone in a manner entirely consistent with the previously described action of leptin to induce bone loss (Yadav et al., 2009). The melanocortin system consists of two distinct populations of hypothalamic neurons. One population produces proopiomelanocortin (POMC) and its key derivate, 1-melanocyte stimulating hormone (1MSH), which is the agonist for the melanocortin 4 receptor (MC4R). Activation of MC4R receptors leads to satiety and increased sympathetic tone. It is thought that this increased sympathetic tone, in turn, suppresses osteoblast function and increases osteoclast activity resulting in bone loss. The other "arm" of the melanocortin system is the population of neurons that produce neuropeptide Y (NPY), the inhibitory neurotransmitter, GABA, and Agouti- related protein (AgRP). AgRP is an inverse agonist of the MC4R, and, the AgRP/NPY/GABA neurons and tonically inhibit POMC neuronal activity (Horvath et al., 1992a,b; Cowley et al., 2001) leading to the suppression of the POMC effect on many outputs including the sympathetic nervous system. While not all hormones that affect skeletal metabolims act by modulating the melanocortin system and sympathetic outflow to the skeleton, it is our hypothesis that the activity of the melanocortin system has a critical role in regulating skeletal homeostasis. Specifically, we hypothesize that increased NPY/AgRP tone, suppresses POMC neuronal activity, reduces skeletal sympathetic tone and thereby promotes bone anabolism. Based on preliminary data which demonstrate a detrimental effect of reactive oxygen species (ROS) on NPY/AgRP neuronal function but a permissive effect of ROS on POMC neuronal firing (Andrews et al., 2008), we also predict that increasing ROS exposure of the melanocortin system during aging is a critical contributor to aging-associated bone loss and the pathogenesis of osteoporosis.