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似的非退伍军人更容易超重。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高于不使用VA护理的退伍军人。考虑到退伍军人系统照顾的退伍军人中肥胖的重大负担，了解肥胖积累增加的机制和后果对于制定更成功的计划以帮助退伍军人减肥，减轻进一步的体重增加和管理共病状况至关重要。这些策略的发展将需要更好地了解脂肪细胞（脂肪细胞）群体，包括不同身体部位的脂肪组织，控制其生产的发育过程，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来自脂肪组织驻留的前脂肪细胞的不同脂肪细胞群体的产生。我们对这一领域的新的和范式转变的贡献表明，一些白色脂肪细胞产生于骨髓产生的非居民祖细胞。这些独特的细胞可以部分解释不同身体区域脂肪的异质组成和功能，以及伴随衰老和循环性腺激素丧失的内脏肥胖增加的有害影响。本试验项目的目的是评价年龄和性别作为与骨髓祖细胞（BMP）衍生脂肪细胞蓄积相关的因素，并评估BMP衍生脂肪细胞蓄积的代谢影响。我们将通过人类和小动物研究的结合来实现这些目标。为了测试BMP衍生的脂肪细胞是否随着年龄的增长而积累并具有有害的生理影响（目的1），我们将研究BMP衍生的脂肪细胞选择性消融或照常积累的小鼠（对照）。我们假设BMP衍生的脂肪细胞缺陷小鼠将具有更健康的代谢特征（即，较低的炎性细胞因子和较好的胰岛素敏感性）。为了测试BMP衍生的脂肪细胞在人体中的积累是否与年龄和性别直接相关（目的2a），我们将从接受骨髓移植的广泛年龄范围的女性和男性中获得皮下腹部脂肪组织活检。我们假设BMP衍生的脂肪细胞的数量，如脂肪细胞嵌合体所测量的，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，我们寻求确定一种生物标志物，以鉴定和测量健康人体中BMP衍生的脂肪细胞的积累。我们希望这个试点项目有助于BMP衍生的脂肪细胞如何影响代谢健康以及年龄和性别是否是其积累的重要决定因素的新发现。了解BMP衍生的脂肪细胞的积累和由此产生的生理后果，预计将导致新的治疗方法，用于预防肥胖对健康的负面影响，并更清楚地了解老年肥胖症是否与经典肥胖症不同。此外，如果我们的假设得到支持，这将导致一系列关于肥胖相关疾病原因的新研究，这是老年退伍军人和平民人口的重要健康问题。

 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.