Mechanisms How Adipocytes Affect Bone in Aging Mice

描述(申请人提供)：脂肪组织构成脊椎动物生物体能量储存的主要储存库。除了作为储存和动员三酰甘油(储存在脂肪细胞中的主要脂肪)的场所之外，现在非常明显的是，脂肪细胞分泌大量的脂类和蛋白质，称为脂肪因子或脂肪细胞因子，可以以自分泌、旁分泌或内分泌的方式发挥广泛的作用。有大量证据支持脂肪细胞之间存在异质性。此外，脂肪库的功能也存在地区差异。骨髓中的脂肪细胞可能构成了一个独特的储存库，因为它与骨骼的关系。骨量和骨髓脂肪组织与衰老和骨质疏松症呈强烈的负相关关系。这项建议的目的是了解骨髓和外周脂肪细胞如何在衰老过程中影响骨生长和维持的机制。其具体目的是1)检验如下假说：骨髓中的脂肪细胞构成不同的脂肪组织库，其特征不同于其他脂肪组织库，从而使骨髓脂肪细胞具有独特的专一性，可影响骨的生长和维持以及造血；2)测试激素敏感型脂肪酶的作用会影响骨髓微环境，并且通过基因缺失去除激素敏感型脂肪酶功能可在衰老小鼠中维持高骨量的假说；以及3)确定和确定影响骨代谢的脂肪衍生介质的相对重要性。

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.