Identification and enrichment of beige/brown adipocyte progenitors from white adipose tissue for the generation of functional brown fat in humans

自2009年以来，科学界已经接受了人类成年人中存在功能相关的棕色脂肪组织（BAT）。与储存能量的白色脂肪组织（WAT）相反，BAT利用能量产生热量。最近的数据表明，肥胖患者的BAT活性降低。因此，它成为治疗超重和肥胖的一个有吸引力的药理学靶点。除了白色和棕色脂肪细胞外，最近还描述了第三种脂肪细胞类型，即所谓的米色脂肪细胞。在小鼠中，这种细胞类型在某些情况下出现在WAT库中。人类米色脂肪细胞募集的细胞和分子基础知之甚少。然而，棕色和米色脂肪细胞都是产热的，可以促进能量消耗的增加。我们的研究小组最近证实，人类白色和棕色脂肪细胞的祖细胞具有不同的基因表达特征。在差异表达的基因中有许多表面蛋白，这些蛋白可能被用于富集棕色脂肪细胞。该建议的基本假设是，能够分化成功能性棕色或米色脂肪细胞的特定祖细胞存在于白色脂肪组织库的基质血管部分中。具体目标是：1。我们想鉴定人类白色和米色/棕色脂肪细胞祖细胞的表面标志物。2.我们希望使用这些标记物从白色脂肪组织中富集米色/棕色脂肪细胞祖细胞。3.我们将验证所鉴定的标志物是否对米色/棕色脂肪细胞的产生起因果作用。4.利用移植实验，我们想测试从WAT富集的祖细胞是否可以在体内产生功能性米色/棕色脂肪细胞组织，所述祖细胞在体外显示米色/棕色基因特征。在小鼠中，BAT的移植可以预防或逆转饮食诱导的肥胖及其相关的合并症。我们的愿景是为人类制定这样的策略。计划中的实验为这一方法提供了科学依据。

The existence of functional relevant brown adipose tissue (BAT) in human adults has been accepted in the scientific community since 2009. In contrast to the energy storing white adipose tissue (WAT), BAT utilizes energy to generate heat. Recent data demonstrated that BAT activity is reduced in obese patients. Therefore it became an attractive pharmacological target for the treatment of overweight and obesity. Besides white and brown adipocytes a third adipocyte type has been recently described, the so-called beige adipocyte. In mice, this cell type emerges under certain circumstances within the WAT depot. The cellular and molecular basis for the recruitment of beige adipocytes in humans is only poorly understood. However, both brown and beige adipocytes are thermogenic and can contribute to an increase in energy expenditure. Our group demonstrated recently that human progenitor cells of white and brown adipocytes have distinct gene expression signatures. Among the differentially expressed genes were many surface proteins, which could potentially be used to enrich brown adipocytes. The fundamental hypothesis of this proposal is that specific progenitor cells, which are able to differentiate into functional brown or beige adipocytes reside in the stromal-vascular fraction of white adipose tissue depots. Specific aims are: 1. We want to identify surface markers of human white and beige/brown adipocyte progenitors. 2. We want to use these markers to enrich beige/brown adipocyte progenitor cells from white adipose tissue. 3. We will investigat if the identified markers play a causal role for the generation of beige/brown adipocytes. 4. Taking advantage of transplantation experiments, we want to test if progenitor cells enriched from WAT which display a beige/brown gene signature in vitro can give rise to functional beige/brown adipocyte tissue in vivo. In mice, transplantation of BAT can prevent or revert diet-induced obesity and its associated comorbidities. Our vision is to develop such a strategy for humans. The planned experiments provide a scientific basis for this approach.