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

骨髓干细胞产生与年龄和性别相关的脂肪细胞

• 批准号: 8997800
• 负责人: Dwight J Klemm
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8997800
• 关键词: Abdomen; Address; Adipocytes; Adipose tissue; Affect; Age; Aging; Animal Model; Animals; Attenuated; Benign; Biological Markers; Biopsy; Blood Circulation; Body Regions; Body Weight decreased; Bone Marrow; Bone Marrow Cells; Bone Marrow Stem Cell; Bone Marrow Transplantation; Caring; Cell physiology; Cell surface; Cells; Characteristics; Chimerism; Chronic; Chronic Disease; Clinical; Colorado; Comorbidity; Data; Development; Developmental Process; Disease; Eating; Elderly; Energy Metabolism; Exhibits; Fatty acid glycerol esters; Functional disorder; Goals; Gonadal Hormones; Health; Healthcare; Healthcare Systems; Human; Hypertrophy; Inflammation; Inflammatory; Intra-abdominal; Lead; Link; Location; Marrow; Measurement; Measures; Metabolic; Military Personnel; Mus; Non obese; Obesity; Obesity associated disease; Outcome; Overweight; Patients; Peripheral; Phenotype; Physiological; Physiology; Pilot Projects; Population; Production; Research; Rodent Model; System; Testing; Time; Tissue Sample; Tissues; Transplantation; Veterans; Visceral; Weight; Weight Gain; Woman; Women' s Health; abdominal fat; cytokine; design; education research; gender difference; health difference; insulin sensitivity; men; metabolic phenotype; metabolic profile; mouse model; novel; novel therapeutics; obesity treatment; prevent; progenitor; programs; public health relevance; research study; sex; subcutaneous; success; tool

 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.

 描述（由申请人提供）： 与年龄和性别的非退伍军人相比，退伍军人更有可能超重。此外，与不使用VA护理的退伍军人相比，使用退伍军人事务（VA）的退伍军人比较肥胖。考虑到VA系统所照顾的退伍军人中肥胖的巨大燃烧，了解肥胖积累的基本机制以及肥胖积累所带来的后果对于开发更多成功的计划以帮助退伍军人减轻体重，减轻体重增加的体重增加并管理合并状况至关重要。这些策略的发展将需要更好地了解脂肪细胞（脂肪细胞）种群，这些脂肪细胞（脂肪细胞）包括不同人体位置的脂肪组织，控制其生产的发育过程以及对慢性疾病的贡献。重要的是，不同人体区域的脂肪细胞暴露了不同的功能特征。这些差异通常归因于现有脂肪细胞的变化或与脂肪组织居民前脂肪细胞不同脂肪细胞种群的产生。我们对该领域的新颖和范式转移贡献表明，一些白脂肪细胞是由骨髓引起的非居民祖细胞产生的。这些独特的细胞可能部分解释了不同人体区域中脂肪的异质组成和功能，以及伴随衰老伴随的内脏肥胖和循环性腺恐怖的丧失的有害影响。该试验项目的目标是评估年龄和性别，作为与骨髓祖细胞（BMP）衍生的脂肪细胞的积累相关的因素，并评估BMP衍生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聚并产生有害的生理影响（AIM 1），我们将研究小鼠，其中BMP衍生的脂肪细胞有选择性地烧蚀性地消融或像往常一样（对照）（对照）。我们假设与对照小鼠相比，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更好的胰岛素敏感性）。为了测试人类中BMP衍生的脂肪细胞的积累是否与年龄和性别直接相关（AIM 2A），我们期望来自经历过骨髓移植的男性和男性的皮下腹部脂肪组织活检。我们假设通过脂肪细胞嵌合体测量的BMP衍生的脂肪细胞数量将随着移植以来的年龄和时间增加，而女性的数量将随着年龄和时间的增加而增加。在AIM 2B中，我们试图确定生物标志物，以识别和测量健康人类中BMP衍生的脂肪细胞的积累。我们希望这个试点项目能够为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者的新发现。了解BMP衍生的脂肪细胞的积累以及由此产生的物理后果预计将导致新的疗法，以防止肥胖的负面影响以及对老年肥胖是否与经典肥胖是否不同的更清晰的理解。此外，如果支持我们的假设，这将导致一系列有关肥胖相关疾病原因的新颖研究，这是老年老兵和平民人口的重要健康问题。