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: 9235134
• 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/9235134
• 关键词: Abdomen; Address; Adipocytes; Adipose tissue; Affect; Age; Aging; Alpha Cell; Animal Model; Animals; Attenuated; Benign; Biological Markers; Biopsy; Blood Circulation; Body Regions; Body Weight decreased; Bone Marrow; 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; bone cell; cytokine; design; education research; experimental study; gender difference; health difference; insulin sensitivity; men; metabolic phenotype; metabolic profile; mouse model; novel; novel therapeutics; obesity treatment; prevent; progenitor; programs; public health relevance; 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）： 此外，考虑到沉重的负担，使用退伍军人事务部 (VA) 护理的退伍军人比不使用 VA 护理的退伍军人肥胖的比例更高。退伍军人管理局系统照顾的退伍军人中存在肥胖问题，了解肥胖积累增加的潜在机制和后果对于制定更成功的计划来帮助退伍军人减肥、减少体重进一步增加和管理共病至关重要。开发这些策略需要更好地了解构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来自脂肪组织驻留前脂肪细胞的不同脂肪细胞群的产生，我们对该领域的新颖且范式转变的贡献表明，一些白色脂肪细胞是由非驻留祖细胞产生的。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而增加的内脏肥胖的有害影响。将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，我们将通过组合来实现这些目标。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产生有害的生理影响（目标 1），我们将研究 BMP 衍生的脂肪细胞被选择性消融或照常积累的小鼠（对照）。与对照小鼠相比，源自脂肪细胞缺陷的小鼠将具有更健康的代谢特征（即较低的炎症细胞因子和更好的胰岛素敏感性）以测试人类中 BMP 衍生的脂肪细胞的积累是否直接相关。根据年龄和性别（目标 2a），我们将从接受转基因骨髓移植的不同年龄范围的女性和男性中获得皮下腹部脂肪组织活检，我们通过脂肪细胞嵌合测量得出 BMP 衍生的脂肪细胞的数量。随着年龄和移植后时间的推移，女性的脂肪细胞含量高于男性，我们希望确定一种生物标志物来识别和测量健康人体中 BMP 衍生脂肪细胞的积累。贡献关于 BMP 衍生的 adip 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以及由此产生的生理后果有望带来预防负面影响的新疗法。肥胖对健康的影响，以及更清楚地了解老年肥胖是否与典型肥胖不同。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的原因的新研究，这对肥胖和肥胖都是一个重要的健康问题。老龄化退伍军人和平民。