Skeletal Response to Leptin

描述（由申请人提供）： 瘦素是Ob基因的蛋白质产物，作用于多个器官，包括骨骼。瘦素缺乏的ob/ob小鼠和瘦素受体缺乏的db/db小鼠表现出镶嵌骨骼表型;与野生型小鼠相比，突变小鼠的骨长度和总骨量减少，但松质骨表现出位点特异性增加。这些异常表明，瘦素充足是正常的骨生长，营业额和功能所必需的。然而，瘦素调节骨代谢以产生这些变化的确切机制仅部分已知，部分原因是瘦素具有通过多种途径影响骨细胞的潜力;间接途径涉及下丘脑中继，直接途径涉及瘦素与软骨和骨细胞上的受体结合。我们推测瘦素对骨代谢的调节比目前所认识的更为复杂。我们建议，瘦素的下丘脑行动的明显的骨骼阻力发生作为一个负反馈回路的结果，涉及传入信号通过骨骼中的感觉神经元和传出信号从下丘脑通过交感神经元。此外，第二个负反馈回路涉及脂肪细胞分化的调节。具体而言，脂肪细胞产生瘦素的比例，其数量和大小，但下丘脑瘦素拮抗骨髓基质细胞分化为脂肪细胞，同时增强成骨细胞分化。我们将在ob/ob和db/db小鼠中通过完成以下具体目标来测试这些假设：1）确定外周（血清瘦素和骨骼产生的瘦素）和下丘脑瘦素对骨生长和周转的各自作用，和2）确定瘦素是否调节骨髓源性基质细胞向脂肪细胞和成骨细胞的分化。目的1验证瘦素对骨具有外周和下丘脑介导作用的假说。此外，它将测试的假设，下丘脑的激素的行动是自我限制的，因为一个负反馈回路涉及传入信号通过感觉神经元和传出信号通过交感神经元。重要的是，拟议的研究将确定是否可以解释下丘脑瘦素对生长板，皮质骨和松质骨的短暂隔室特异性作用的假设相反的外周和下丘脑介导的激素的行动。目的2验证下丘脑和/或外周血瘦素对骨髓基质细胞向成骨细胞或脂肪细胞分化的调控作用。这些研究将确定瘦素对基质细胞分化的外周效应是否与下丘脑介导的激素作用相反。我们研究的长期目标是了解生活方式因素如何与遗传学相互作用，以确定峰值骨量。这项研究将阐明瘦素诱导骨生长和结构调节的细胞机制.了解瘦素的作用及其对骨生长的复杂作用机制是重要的，因为低峰值质量是骨质疏松症的危险因素。

DESCRIPTION (provided by applicant): Leptin, the protein product of the Ob gene, acts on multiple organs, including bone. Leptin deficient ob/ob mice and leptin receptor-deficient db/db mice exhibit a mosaic skeletal phenotype; compared to wild-type mice, mutant mice have reduced bone length and overall bone mass but exhibit site-specific increases in cancellous bone. These abnormalities suggest that leptin sufficiency is essential for normal bone growth, turnover and function. However, the precise mechanisms by which leptin regulates bone metabolism to produce these changes are only partially known, in part, because leptin has the potential to affect bone cells through multiple pathways; an indirect pathway involving a hypothalamic relay and a direct pathway involving the binding of leptin to its receptors on cartilage and bone cells. We hypothesize that the regulation of bone metabolism by leptin is even more complex than currently appreciated. We propose that the apparent skeletal resistance to the hypothalamic actions of leptin occurs as a result of a negative feedback loop involving afferent signaling via sensory neurons in bone and efferent signaling from the hypothalamus via sympathetic neurons. Furthermore, a second negative feedback loop involves regulation of adipocyte differentiation. Specifically, adipocytes produce leptin in proportion to their number and size but hypothalamic leptin antagonizes differentiation of bone marrow stromal cells to adipocytes while enhancing osteoblast differentiation. We will test these hypotheses in ob/ob and db/db mice by accomplishing the following specific aims; 1) determine the respective roles of peripheral (serum leptin and leptin produced by the skeleton) and hypothalamic leptin on bone growth and turnover, and 2) determine if leptin regulates the differentiation of bone marrow-derived stromal cells to adipocytes and osteoblasts. Aim 1 will test the hypothesis that leptin has peripheral-mediated as well as hypothalamic-mediated actions on bone. Additionally, it will test the hypothesis that the hypothalamic actions of the hormone are self limiting because of a negative feed back loop involving afferent signaling via sensory neurons and efferent signaling via sympathetic neurons. Importantly, the proposed studies will establish whether the transient compartment-specific effects of hypothalamic leptin on growth plate, cortical bone and cancellous bone can be explained by the hypothesized opposing peripheral- and hypothalamic-mediated actions of the hormone. Aim 2 will test the hypothesis that hypothalamic and/or peripheral leptin regulates the differentiation of bone marrow stromal cells to form osteoblasts or adipocytes. These studies will establish whether the peripheral effects of leptin on stromal cell differentiation are opposed by hypothalamic-mediated actions of the hormone. The long-term goal of our research is to understand how lifestyle factors interact with genetics to determine peak bone mass. The proposed research will clarify the cellular mechanisms for leptin- induced regulation of bone growth and architecture. An understanding of the role of leptin and its complex mechanisms of action on bone growth is important because a low peak mass is a risk factor for osteoporosis.