AgRP neurons regulate bone remodeling in aging

AgRP 神经元调节衰老过程中的骨重塑

• 批准号: 8321998
• 负责人: TAMAS L HORVATH
• 金额: $ 37.5万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8321998
• 关键词: ART protein; Adipose tissue; Affect; Age; Aging; Agonist; Amphetamines; Anabolism; Animals; Bone remodeling; Brain; Brain region; Cocaine; Data; Development; Energy Metabolism; Etiology; Genetic Models; Grant; Homeostasis; Hormones; Hypothalamic structure; Impairment; Lead; Leptin; Mediating; Medical; Melanocortin 4 Receptor; Melanocyte stimulating hormone; Metabolism; Neuraxis; Neurons; Neurotransmitters; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Output; Pathogenesis; Peripheral; Play; Population; Pro-Opiomelanocortin; Process; Production; Proteins; Reactive Oxygen Species; Regulation; Role; Satiation; Signal Transduction; Skeleton; Sympathetic Nervous System; System; Testing; Tissues; Work; aged; arm; base; bone; bone loss; bone mass; bone metabolism; combat; gamma-Aminobutyric Acid; hindbrain; insight; neuropeptide Y; novel; receptor; response; skeletal

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.

描述（由申请人提供）：在过去的十年中，已经很明显中枢神经系统在介导某些外围组织衍生的激素在骨骼上的作用中起着重要作用。在我们的实验室工作以及与他人的合作工作所产生的关键发现是，脂肪激素，瘦素有选择地靶向下丘脑神经元人群，通过raphae羟色胺能系统改变骨骼质量和能量代谢，但尽管脑静脉素能系统（Fernandez-Galaz et al。黑色皮质素系统仍然是骨稳态的关键下游效应器。特别是，我们发现瘦素的后脑作用会导致黑色皮质素张力的改变，其方式与瘦素先前描述的诱导骨质流失的作用完全一致（Yadav等，2009）。黑素皮质素系统由两个不同的下丘脑神经元组成。一个人群产生proOpiomelananocortin（POMC）及其键衍生物1-甲状腺细胞刺激激素（1MSH），这是黑色素皮质素4受体（MC4R）的激动剂。 MC4R受体的激活会导致饱腹感和同情性的增加。据认为，这种同情的语调反过来抑制成骨细胞功能，并增加破骨细胞活性，从而导致骨质流失。黑色素皮质系统的另一个“组”是产生神经肽Y（NPY），抑制性神经递质，GABA和AGOUTI-相关蛋白（AGRP）的神经元群体。 AGRP是MC4R的反向激动剂，AGRP/NPY/GABA神经元和音调抑制POMC神经元活性（Horvath等，1992a，b; Cowley等，2001），导致POMC对包括同情性神经系统在内的许多输出的抑制。虽然并非所有影响骨骼代谢物的激素都通过调节黑色皮质素系统和与骨骼的交感神经流出来起作用，但我们的假设是，黑色素质素系统的活性在调节骨骼稳态方面具有关键作用。具体而言，我们假设增加了NPY/AGRP张力，抑制POMC神经元活性，减少骨骼交感神经张力，从而促进骨变性。基于初步数据，证明了活性氧（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，2008），我们还预测，在衰减过程中，梅拉素素系统的ROS暴露在衰减过程中增加了重大损害的梅拉基素系统，这是对衰减的关键作用。