A Novel Adipocyte Population Arises From Bone Marrow Progenitor Cells

描述(申请人提供)：三分之二的美国人超重或肥胖。过多的体脂，特别是腹部的脂肪，与心血管疾病、2型糖尿病、某些形式的癌症和其他医疗条件有关。预防体重增加或其对健康的有害影响的战略成效有限。这个项目将研究某些类型的脂肪转化细胞(脂肪细胞)是如何在腹部脂肪中产生的。这一结果可能会为治疗确定新的目标，以预防体重增加和脂肪相关的慢性疾病。在过去的7年里，我们已经确定了一组脂肪细胞，这些细胞是由骨髓中的干细胞产生的。这些干细胞从骨髓中剥离，进入脂肪组织，在那里它们成为新的脂肪细胞。这些骨髓源性脂肪细胞优先聚集在雌性动物的腹部脂肪中，并表现出潜在的损害特征。这个项目旨在确定为什么这些细胞是在腹部脂肪中产生的，以及它们的产生是否比其他类型的脂肪储存细胞更快。第一个目的是测试炎性蛋白，单核细胞抑制蛋白-1a(MIP-1a)是否促进干细胞的招募 从骨髓到脂肪的细胞和下一代骨髓源性脂肪细胞 腹部脂肪。这将通过跟随标记的骨髓祖细胞到MIP-1a已被基因擦除的MCE中的脂肪组织来实现。目的2将测试卵巢激素，雌激素和黄体酮，是否也参与骨髓脂肪细胞的产生，并解释优先考虑 这些脂肪细胞在女性受试者体内的积累。最后，Aim 3将使用一种新的标记技术来测量骨髓来源的脂肪细胞和其他储存脂肪的细胞在不同身体位置的脂肪产生的速度。这些研究的完成将为控制骨髓源性脂肪细胞产生的因素和过程提供一个全面的图景。这一结果可能会突出控制这些脂肪细胞生成的新目标，从而减轻它们对健康的严重影响。这一结果也可能解释为什么男性和女性的脂肪储存不同，以及为什么女性的脂肪储存在更年期后会发生变化。我们预测，这些实验将进一步强调干细胞和祖细胞在不同身体部位脂肪发育中的重要性及其对健康的不同影响。

DESCRIPTION (provided by applicant): Two thirds of Americans are overweight or obese. Excess body fat, particularly in the abdomen, has been linked to cardiovascular disease, type 2 diabetes, certain forms of cancer and other medical conditions. Strategies to prevent weight gain or its harmul effects on health have had limited success. This project will investigate how certain types of fat-toring cells (adipocytes) are produced in abdominal fat. The results may identify new targets for therapie to prevent weight gain and fat-related chronic disease. Over the last 7 years we have identified a population of adipocytes that are produced from stem cells in the bone marrow. These stem cells leae the marrow and travel to fat tissue where they become new adipocytes. These bone marrow-derived adipocytes accumulate preferentially in abdominal fat in female animals, and exhibit potentially hamful characteristics. This project is designed to determine why these cells are produced in abdominal fa, and if their production is more rapid than other types of fat-storing cells. The first aim will tes whether the inflammatory protein, monocyte inhibitory protein-1a (MIP-1a), promotes the recruitment of stem cells from the bone marrow to fat and the subsequent generation of bone marrow-derived adipocyte in abdominal fat. This will be accomplished by following labeled marrow progenitors to fat tissue in mce in which MIP-1a has been genetically erased. Aim 2 will test whether the ovarian hormones, estrogen an progesterone, are also involved in bone marrowadipocyte production and account for the preferential accumulation of these fat cells in female subjects. Finally, Aim 3 will use a novel labeling technoogy to measure the rate at which bone marrow-derived adipocytes and other fat-storing cells are produced i fat in different body locations. Completion of these studies will provide a comprehensive picture o the factors and processes that control bone marrow-derived adipocyte production. The results are likelyto highlight new targets for controlling the generation of these fat cells and thereby mitigate their armful effects on health. The results may also ex- plain why fat is stored differently between men and womn, and why fat storage in women changes after menopause. We predict that these experiments will furthe underscore the importance of stem cells and progenitor cells in the development of fat in differentbody locations and its differential impact on health.