AgRP neurons regulate bone remodeling in aging

描述（由申请人提供）：在过去的十年中，中枢神经系统在调节某些外周组织来源的激素对骨骼的作用方面起着重要作用已经变得很明显。我们实验室和我们与他人合作的一个重要发现是，脂肪激素瘦素选择性地靶向下丘脑神经元群，并通过血清素能系统改变骨量和能量代谢（Fernandez-Galaz et al., 2002 Yadav et al., 2009）。然而，尽管瘦素在后脑起作用，下丘脑黑素皮质素系统仍然是骨稳态的关键下游效应体。特别是，我们发现瘦素的后脑作用导致黑素皮质素音调的改变，其方式与先前描述的瘦素诱导骨质流失的作用完全一致（Yadav et al., 2009）。黑素皮质素系统由两个不同的下丘脑神经元群组成。一个群体产生促黑素皮质素（POMC）及其关键衍生物，1-黑色素细胞刺激激素（1MSH），这是黑色素皮质素4受体（MC4R）的激动剂。MC4R受体的激活导致饱腹感和交感神经张力的增加。据认为，这种增加的交感神经张力，反过来，抑制成骨细胞的功能，增加破骨细胞的活动，导致骨质流失。黑素皮质素系统的另一支“手臂”是产生神经肽Y （NPY）、抑制性神经递质、GABA和Agouti相关蛋白（AgRP）的神经元群。AgRP是MC4R和AgRP/NPY/GABA神经元的反向激动剂，并强张性地抑制POMC神经元的活性（Horvath et al., 1992a,b; Cowley et al., 2001），导致POMC对包括交感神经系统在内的许多输出系统的作用受到抑制。虽然不是所有影响骨骼代谢的激素都通过调节黑素皮质素系统和交感神经向骨骼的流出来起作用，但我们的假设是黑素皮质素系统的活性在调节骨骼稳态中起着关键作用。具体来说，我们假设NPY/AgRP张力增加，抑制POMC神经元活动，降低骨骼交感神经张力，从而促进骨合成代谢。根据初步数据显示活性氧（ROS）对NPY/AgRP神经元功能的有害影响，但对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，黑素皮素系统ROS暴露的增加是衰老相关骨质流失和骨质疏松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.