Age- and Sex-associated Production of Adipocytes from Bone Marrow Stem Cells

 描述(由申请人提供)： 退伍军人比年龄和性别相近的非退伍军人更有可能超重。此外，使用退伍军人事务部(VA)护理的退伍军人中肥胖的比例比那些不使用VA护理的退伍军人更大。考虑到退伍军人中肥胖给退伍军人带来的巨大负担，了解肥胖增加的潜在机制和后果，对于开发更成功的计划来帮助退伍军人减肥、减缓体重进一步增加和管理共病状况至关重要。制定这些策略将需要更好地了解组成不同身体部位脂肪组织的脂肪细胞(脂肪细胞)群体，控制其产生的发育过程，以及它们对慢性疾病的贡献。重要的是，不同身体区域的脂肪细胞表现出不同的功能特征。这些差异通常归因于现有脂肪细胞的变化或由驻留在脂肪组织中的前脂肪细胞产生不同的脂肪细胞群。我们对这一领域的新颖和范式转换的贡献表明，一些白色脂肪细胞是由来自骨髓的非常驻祖细胞产生的。这些独特的细胞可能在一定程度上解释了脂肪在身体不同部位的不同组成和功能，以及伴随着衰老和循环性腺激素丢失而增加的内脏脂肪的有害影响。这个试点项目的目标是评估年龄和性别作为与骨髓祖细胞(BMP)来源的脂肪细胞积累相关的因素，并评估BMP来源的脂肪细胞积累的代谢影响。我们将通过人类和小动物研究相结合的方式来实现这些目标。为了测试BMP来源的脂肪细胞是否随着年龄的增长而积累并产生有害的生理影响(目标1)，我们将研究BMP来源的脂肪细胞选择性地消融或照常积累的小鼠(对照)。我们假设BMP来源的脂肪细胞缺陷小鼠与对照小鼠相比将具有更健康的代谢特征(即较低的炎性细胞因子和更好的胰岛素敏感性)。为了测试BMP来源的脂肪细胞在人类体内的积累是否与年龄和性别(目标2a)直接相关，我们将从接受过骨髓移植的女性和男性身上获取腹部皮下脂肪组织活检。我们假设，BMP来源的脂肪细胞的数量，通过脂肪细胞嵌合体的测量，将随着年龄和移植后的时间而增加，并且女性高于男性。在目标2b中，我们试图确定一个生物标记物来识别和测量BMP来源的脂肪细胞在健康人体中的积累。我们期望这一试点项目能够为BMP来源的脂肪细胞如何影响代谢健康，以及年龄和性别是否为其积累的重要决定因素做出新的发现。了解BMP来源的脂肪细胞的积累和由此产生的生理后果有望导致预防肥胖对健康的负面影响的新疗法，并更清楚地了解老年性肥胖是否不同于传统肥胖症。此外，如果我们的假设得到支持，这将导致对肥胖相关疾病的原因进行一系列新的研究，这是老年退伍军人和平民人口中的一个重要健康问题。

 DESCRIPTION (provided by applicant): Veterans are more likely to be overweight than non-veterans of a similar age and sex. Moreover, a larger proportion of veterans who use Veteran Affairs (VA) care are obese than among those veterans who do not use VA care. Considering the significant burden from obesity among the veterans cared for by the VA system, understanding the mechanisms underlying, and consequences resulting from, increased accumulation of adiposity is critical for development of more successful programs to help veterans lose weight, attenuate further weight gain, and manage comorbid conditions. Development of these strategies will require a better understanding of the fat cell (adipocyte) populations that comprise fat tissue in different body locations, the developmental processes that govern their production, and their contribution to chronic disease. Importantly, adipocytes in different body regions exhibit distinct functional characteristics. These differences are generally attributed to changes in existing adipocytes or to the production of distinct adipocyte populations from adipose tissue-resident preadipocytes. Our novel and paradigm-shifting contribution to this field demonstrated that some white adipocytes are generated from non-resident progenitors arising from bone marrow. These unique cells may explain, in part, the heterogeneous composition and function of fat in different body regions, and the harmful impact of increased visceral adiposity that accompanies aging and the loss of circulating gonadal hormones. The goals of this pilot project are to evaluate age and sex as factors associated with the accumulation of bone marrow progenitor (BMP)-derived adipocytes and to assess the metabolic impact of BMP-derived adipocyte accumulation. We will accomplish these goals through a combination of human and small animal studies. To test whether BMP-derived adipocytes accumulate with age and have a harmful physiological impact (Aim 1), we will study mice in which BMP-derived adipocytes are selectively ablated or accumulate as usual (control). We hypothesize that BMP-derived adipocyte-deficient mice will have a healthier metabolic profile (i.e., lower inflammatory cytokines and better insulin sensitivity) compared to control mice. To test whether the accumulation of BMP-derived adipocytes in humans is directly related to age and sex (Aim 2a), we will obtain subcutaneous abdominal adipose tissue biopsies from women and men of a wide age range who have undergone bone marrow transplantation. We hypothesize that the number of BMP-derived adipocytes, as measured by adipocyte chimerism, will increase with age and time since transplant and be higher in women than men. In Aim 2b we seek to determine a biomarker to identify and measure the accumulation of BMP-derived adipocytes in healthy humans. We expect this pilot project to contribute novel discoveries of how BMP-derived adipocytes impact metabolic health and whether age and sex serve as important determinants of their accumulation. Understanding the accumulation of BMP-derived adipocytes and the resultant physiological consequences is expected to lead to novel therapies for preventing the negative health impacts of obesity and a more clear understanding of whether geriatric obesity differs from classic obesity. Furthermore, if our hypotheses are supported, this will lead to an array of novel research on causes of obesity-related diseases, an important health issue in both the aging veteran and civilian populations.