Marrow Adipose Tissue as a Novel Regulator of Systemic Metabolism and Inflammation During Aging.

摘要 衰老是一系列疾病的最大风险因素，包括糖尿病、心脏病、神经变性， 癌症和中风衰老的一个核心特征是肥胖增加。脂肪组织是内分泌器官， 假设衰老引起的脂肪功能障碍通过 分泌的分子，在不同的组织范围内发挥作用，以协调有机体的稳态。脂肪 它位于整个身体的不同仓库，并且很可能特定的仓库对 疾病脆弱性。骨髓脂肪组织（MAT）贮库在衰老相关疾病病因学中的作用 还没有很好地建立起来，关于定性表型存在基本的知识差距， MAT在衰老过程中的分泌特征。这项研究的长期目标是确定角色， MAT在整个生命周期中影响健康和疾病的机制。R21的目标 一个建议是确定老化对MAT表型的影响，并确定MAT的潜在贡献 脂肪衍生分子在衰老过程中的系统性分布。我们的中心假设是， MAT中改变其分泌特征的转录反应，其影响全身代谢和 通过直接影响循环肽、脂质和代谢物组成来实现炎症稳态;我们进一步 假设年龄对MAT表型和分泌组的影响是两性异形的。我们的理由是 这个项目是，一旦知道了衰老如何影响MAT的表型和对循环脂肪的贡献， 衍生因子，我们很可能可以靶向MAT重新编程其分泌组，产生新的 和创新方法，以最大限度地延长健康寿命，减少与年龄有关的疾病的脆弱性。指导 强有力的初步数据，我们的中心假设将通过追求两个具体目标进行测试：1）定义性别- MAT对衰老的特异性转录反应，并确定转录反应 与功能结果相关（即，蛋白质组、代谢组、脂质组）和2）确定转移的程度 从MAT到循环肽，脂质和代谢物在老化过程中的概况。在这个项目完成后，我们 我希望已经建立了1）MAT表型对衰老敏感，衰老的时间影响 MAT表型具有性别特异性，2）与其他脂肪组织相比，MAT对衰老的分子反应是独特的。 3）MAT是脂肪源性信号分子循环库的主要贡献者， 衰老这样的结果将从根本上推进脂肪组织生物学领域，并将提供积极的 通过鉴定MAT和MAT内的特异性信号通路作为主要治疗靶点， 用于预防和治疗与衰老有关的疾病。

ABSTRACT Aging is the strongest risk factor for a range of diseases including diabetes, heart disease, neurodegeneration, cancer, and stroke. A central characteristic of aging is increased adiposity. Adipose tissues are endocrine organs, and it is hypothesized that aging-induced adipose dysfunction causally influences disease etiology through the secretion of molecules that act across a diverse range of tissues to coordinate organismal homeostasis. Adipose is located in distinct depots throughout the body, and it is likely that specific depots differentially contribute to disease vulnerability. The role of the bone marrow adipose tissue (MAT) depot in aging-related disease etiology is not well established, and there is a fundamental knowledge gap regarding the qualitative phenotype and secretory profile of MAT during aging. The long-term objective of this research is to define the roles and mechanisms by which MAT influences health and disease throughout the lifespan. The objective of this R21 proposal is to determine the impact of aging on MAT phenotype and establish the potential contribution of MAT to the systemic profile of adipose-derived molecules during aging. Our central hypothesis is that aging induces a transcriptional response in MAT that alters its secretory profile, which influences systemic metabolic and inflammatory homeostasis by directly impacting circulating peptide, lipid, and metabolite composition; we further hypothesize the impact of aging on the MAT phenotype and secretome is sexually dimorphic. Our rationale for this project is that once it is known how aging influences MAT’s phenotype and contribution to circulating adipose- derived factors, it is likely we can pharmacologically target MAT to reprogram its secretome, producing novel and innovative approaches to maximize healthspan and reduce age-related disease vulnerability. Guided by strong preliminary data, our central hypothesis will be tested by pursuing two specific aims: 1) define the sex- specific transcriptional response of MAT to aging and determine the extent to which the transcriptional response relates to functional outcomes (i.e., proteome, metabolome, lipidome) and 2) establish the extent of transference from MAT to circulating peptide, lipid, and metabolite profiles during aging. At the completion of this project, we expect to have established that 1) MAT phenotype is sensitive to aging and the temporal impact of aging on MAT phenotype is sex-specific, 2) the molecular response to aging is unique in MAT compared to other adipose depots, and 3) MAT is a central contributor to the circulating pool of adipose-derived signaling molecules during aging. Such results will fundamentally advance the field of adipose tissue biology and will provide a positive translational impact by identifying MAT, and specific signaling pathways within MAT, as a prime therapeutic target for the prevention and treatment of aging-related diseases.