Mechanisms How Adipocytes Affect Bone in Aging Mice

描述（由申请人提供）： 脂肪组织是脊椎动物的主要能量储存库。除了其作为三酰基甘油（脂肪细胞中储存的主要脂质）的储存和动员位点的功能之外，现在非常明显的是，脂肪细胞分泌大量的脂质和蛋白质，称为脂肪因子或脂肪细胞因子，其可以以自分泌、旁分泌或内分泌方式发挥各种各样的作用。有大量证据支持脂肪细胞之间存在异质性。此外，脂肪库的功能存在区域差异。骨髓内的脂肪细胞可能构成一个仓库，由于其与骨的关系而具有独特性。骨量和骨髓脂肪组织与增龄和骨质疏松呈明显的负相关。本提案的目的是了解机制如何脂肪细胞，无论是在骨髓和外周仓库，影响骨的生长和维护过程中老化。具体目的是1）检验以下假设，即在骨髓内发现的脂肪细胞构成脂肪组织的独特贮库，其特征不同于其它脂肪组织贮库，使得骨髓脂肪细胞独特地专门化以影响骨生长和维持以及造血; 2）验证了脂肪酶的作用影响骨髓微环境和激素清除的假设，通过基因缺失的敏感脂肪酶功能在衰老小鼠中维持高骨量;和3）鉴定和建立负责影响骨代谢的脂肪来源的介质的相对重要性。

DESCRIPTION (provided by applicant): Adipose tissue constitutes the major repository of energy stores for vertebrate organisms. In addition to its function as a site of storage and mobilization of triacylglycerols (the major lipid stored in adipose cells), it is now quite apparent that adipose cells secrete a large number of lipids and proteins, termed adipokines or adipocytokines, that can exert a wide variety of effects in an autocrine, paracrine or endocrine fashion. There is substantial evidence to support the presence of heterogeneity among adipose cells. Moreover, there are regional differences in the function of adipose depots. Adipocytes within the bone marrow might constitute a depot that is unique due to its relationship to bone. There is a strong inverse relationship between bone mass and bone marrow adipose tissue with aging and osteoporosis. The objective of this proposal is to understand the mechanisms how adipocytes, both within the bone marrow and in peripheral depots, affect bone growth and maintenance during aging. The specific aims are 1) to test the hypothesis that adipose cells found within the bone marrow constitute a distinct depot of adipose tissue whose characteristics differ from other adipose tissue depots such that marrow adipose cells are uniquely specialized to influence bone growth and maintenance, as well as hematopoiesis; 2) to test the hypothesis that the actions of hormone-sensitive lipase affect the micro-environment of the bone marrow and that removal of hormone-sensitive lipase function by gene deletion maintains high bone mass in aging mice; and 3) to identify and establish the relative importance of adipose-derived mediators responsible for influencing bone metabolism.