A Novel Adipocyte Population Arises From Bone Marrow Progenitor Cells

描述(由申请人提供)：肥胖和体重增加与发病率和死亡率的增加有关，在美国和其他发达国家，肥胖和体重增加影响着相当大的和不断增加的人口。肥胖的特征是由于现有脂肪细胞肥大和新脂肪细胞的生成而导致脂肪组织质量增加。一般认为新的脂肪细胞完全来源于常驻脂肪组织、前脂肪细胞或间质间充质细胞。然而，来自我的实验室的初步数据显示，骨髓(BM)来源的循环前体细胞在小鼠的脂肪组织中分化为新生的脂肪细胞群。这些新的脂肪细胞表达常规的脂肪细胞标志物，像棕色脂肪细胞一样有多个脂滴，但缺乏棕色脂肪细胞标志物解偶联蛋白-1。这些新的多房(ML)脂肪细胞还显示出高线粒体含量，这表明这些细胞在氧化燃料处理中具有潜在的作用。噻唑烷二酮-罗格列酮(ROSI)或高脂饲料可增加ML脂肪细胞的数量。根据这些结果，我们推测，噻唑烷二酮类化合物和高脂喂养增加了间充质祖细胞/干细胞向脂肪组织的转运，并促进其向参与脂肪组织功能的多室脂肪细胞分化。四个具体目标将检验这一假设。第一个目标将测试骨髓来源的间充质细胞和造血祖细胞是否产生ML脂肪细胞，并确定祖细胞是否具有干细胞特征。第二个目的是研究TZDS和高脂喂养促进骨髓来源的祖细胞分化为ML脂肪细胞的机制(S)。具体目标3是一个验证原则的目标，将确定来自野生型小鼠的骨髓来源的ML脂肪细胞是否能够在瘦素缺乏的受体小鼠中重建瘦素的产生。最后，Aim 4将测试ML脂肪细胞是否比传统的白色和棕色脂肪细胞表现出更高的脂肪酸摄取、酯化和/或氧化速率。这一假说的成功检验将证明非驻留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的氧化，对脂肪组织功能和全球能量代谢产生有益的影响。这些实验还应该揭示调控骨髓来源的祖细胞向ML脂肪细胞募集和分化的机制。然后，这些机制可以形成治疗或预防肥胖症、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有关，并影响美国相当大且不断增加的人口。肥胖的特征是由于现有脂肪细胞的生长和新脂肪细胞的生成而导致脂肪组织质量增加。人们一直认为，新的脂肪细胞完全来自于脂肪组织中的祖细胞。然而，来自我的实验室的初步数据表明，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。本申请提出的研究将探索骨髓祖细胞形成新脂肪细胞的控制机制，并探讨新脂肪细胞在脂肪组织功能中的作用。这一假说的成功检验将证明非驻留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前体细胞形成新脂肪细胞的机制。然后，这些机制可以形成治疗或预防肥胖症、糖尿病和相关疾病的新疗法的基础。

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.