A Novel Adipocyte Population Arises From Bone Marrow Progenitor Cells

骨髓祖细胞产生新的脂肪细胞群

• 批准号: 7874412
• 负责人: Dwight J Klemm
• 金额: $ 30.74万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7874412
• 关键词: 2,4-thiazolidinedione; Address; Adhesions; Adipocytes; Adipose tissue; Affect; Appearance; Autocrine Communication; Bone Marrow; Cardiovascular Diseases; Cell Proliferation; Cell surface; Cells; Characteristics; Data; Deposition; Developed Countries; Development; Diabetes Mellitus; Energy Metabolism; Esterification; Exhibits; Fatty Acids; Fatty acid glycerol esters; Generations; Goals; Growth; Hematopoietic; Hematopoietic stem cells; Hypertrophy; In Vitro; Individual; Knowledge; Laboratories; Leptin; Lipids; Location; Longitudinal Studies; Mesenchymal; Mesenchymal Stem Cells; Metabolic; Methods; Mitochondria; Morbidity - disease rate; Mus; NIH Program Announcements; Nonesterified Fatty Acids; Obesity; Population; Production; Recruitment Activity; Regulation; Research; Role; Signal Transduction; Source; Stem cells; Telomerase; Testing; Thiazolidinediones; Tissues; Visceral; Weight Gain; Wild Type Mouse; adipokines; base; cell type; fatty acid oxidation; feeding; in vivo; interstitial; mortality; novel; oxidation; paracrine; prevent; progenitor; public health relevance; reconstitution; regenerative; research study; response; rosiglitazone; subcutaneous; trafficking; uncoupling protein 1; uptake

DESCRIPTION (provided by applicant): Obesity and weight gain are associated with increased morbidity and mortality, and affect a sizable and increasing population in the U.S. and other developed countries. Obesity is characterized by an increase in adipose tissue mass due to hypertrophy of existing fat cells and the generation of new adipocytes. It has been tacitly assumed that new adipocytes arise solely from resident adipose tissue preadipocytes or interstitial mesenchymal cells. However, preliminary data from my laboratory shows that bone marrow (BM)-derived circulating progenitor cells differentiate into a de novo population of adipocytes in the adipose tissue of mice. These novel adipocytes express conventional adipocyte markers, have multiple lipid droplets like brown adipocytes, but lack uncoupling protein-1, a brown adipocyte marker. These new multilocular (ML) adipocytes also exhibit high mitochondrial content, suggesting a potential role for these cells in oxidative fuel disposal. The number of ML adipocytes is increased by the thiazolidinedione rosiglitazone (ROSI) or high fat feeding. Based on these results we hypothesize that thiazolidinediones and high fat feeding increase the trafficking of mesenchymal progenitor/stem cells to adipose tissue and promote their differentiation to multilocular adipocytes that participate in adipose tissue function. Four Specific Aims will test this hypothesis. The first Aim will test whether BM-derived mesenchymal and hematopoietic progenitor cells give rise to ML adipocytes, and determine whether the progenitor cells exhibit stem cell characteristics. The second Aim will investigate the mechanism(s) by which TZDs and high fat feeding promote the appearance of ML adipocytes from BM- derived progenitor cells. Specific Aim 3 is a proof-of-principle aim that will determine whether BM-derived ML adipocytes from wild type mice can reconstitute leptin production in leptin-deficient recipient mice. Finally, Aim 4 will test whether ML adipocytes exhibit higher rates of fatty acid uptake, esterification and/or oxidation than conventional white and brown adipocytes. Successful testing of this hypothesis will demonstrate the importance of non-resident cells in the development of adipose tissue. We predict that the novel ML adipocytes will have a beneficial impact on adipose tissue function and global energy metabolism via the release of leptin and by increasing adipose fatty acid oxidation. These experiments should also reveal mechanisms for regulating the recruitment and differentiation of BM-derived progenitor cells to ML adipocytes. Such mechanisms could then form the basis for novel therapies to treat or prevent obesity, diabetes and related conditions. PUBLIC HEALTH RELEVANCE: Obesity and weight gain are associated with diabetes and cardiovascular disease, and affect a sizable and increasing population in the U.S. Obesity is characterized by an increase in fat tissue mass due to growth of existing fat cells and the generation of new fat cells. It has been assumed that new fat cells arise solely from progenitor cells that reside within fat tissue. However, preliminary data from my laboratory shows that bone marrow-derived progenitor cells can become new fat cells in the fat tissue of mice. The research proposed in this application will explore the mechanisms that control the formation of new fat cells from bone marrow- derived progenitor cells, and investigate the role of the new fat cells in the function of fat tissue. Successful testing of this hypothesis will demonstrate the importance of non-resident cells in the development of fat tissue. These experiments should also reveal mechanisms for regulating the formation of new fat cells from bone marrow progenitor cells. Such mechanisms could then form the basis for novel therapies to treat or prevent obesity, diabetes and related conditions.

描述（由申请人提供）：肥胖和体重增加与发病率和死亡率增加相关，并影响美国和其他发达国家相当大且不断增加的人口。肥胖症的特征在于由于现有脂肪细胞肥大和新脂肪细胞的产生而导致的脂肪组织质量增加。人们一直默认新的脂肪细胞只产生于固有的脂肪组织、前脂肪细胞或间质间充质细胞。然而，从我的实验室的初步数据显示，骨髓（BM）来源的循环祖细胞分化成一个从头群体的脂肪细胞在小鼠的脂肪组织。这些新的脂肪细胞表达传统的脂肪细胞标志物，有多个脂滴像棕色脂肪细胞，但缺乏解偶联蛋白-1，棕色脂肪细胞标志物。这些新的多室（ML）脂肪细胞也表现出高线粒体含量，这表明这些细胞在氧化燃料处理中的潜在作用。通过噻唑烷二酮罗格列酮（ROSI）或高脂喂养，ML脂肪细胞的数量增加。基于这些结果，我们假设噻唑烷二酮类和高脂肪喂养增加了间充质祖细胞/干细胞向脂肪组织的运输，并促进其分化为参与脂肪组织功能的多室脂肪细胞。四个具体目标将检验这一假设。第一个目标将测试BM衍生的间充质和造血祖细胞是否产生ML脂肪细胞，并确定祖细胞是否表现出干细胞特征。第二个目的将研究TZD和高脂肪喂养促进从BM衍生的祖细胞出现ML脂肪细胞的机制。具体目标3是一个原理验证目标，将确定来自野生型小鼠的BM衍生的ML脂肪细胞是否可以在瘦素缺陷受体小鼠中重建瘦素产生。最后，目标4将测试ML脂肪细胞是否表现出比常规白色和棕色脂肪细胞更高的脂肪酸摄取、酯化和/或氧化速率。这一假设的成功验证将证明非常驻细胞在脂肪组织发育中的重要性。我们预测新型ML脂肪细胞将通过释放瘦素和增加脂肪脂肪酸氧化对脂肪组织功能和全球能量代谢产生有益影响。这些实验还应该揭示调节BM衍生的祖细胞向ML脂肪细胞的募集和分化的机制。这样的机制可以成为治疗或预防肥胖、糖尿病和相关疾病的新疗法的基础。公共卫生相关性：肥胖和体重增加与糖尿病和心血管疾病相关，并且影响美国相当大且不断增加的人口。肥胖的特征在于由于现有脂肪细胞的生长和新脂肪细胞的产生而导致的脂肪组织质量的增加。据推测，新的脂肪细胞只产生于脂肪组织内的祖细胞。然而，我实验室的初步数据显示，骨髓来源的祖细胞可以成为小鼠脂肪组织中的新脂肪细胞。本次申请提出的研究将探索控制骨髓源性祖细胞形成新脂肪细胞的机制，并调查新脂肪细胞在脂肪组织功能中的作用。这一假设的成功验证将证明非常驻细胞在脂肪组织发育中的重要性。这些实验还应该揭示调节骨髓祖细胞形成新脂肪细胞的机制。这样的机制可以成为治疗或预防肥胖、糖尿病和相关疾病的新疗法的基础。