Mechanisms of human adipose depot development and impact of Diabetes

摘要 与总脂肪相比，中央和外周脂肪组织之间的相对分布是 2 型糖尿病 (T2DM) 和心脏代谢疾病风险的关键决定因素。此举的目标 建议使用新型间充质祖细胞衍生和单细胞克隆基因组测序 充分识别和表征构成这些人类储存库的脂肪细胞多样性的方法 他们的发展机制。为此，我们将利用令人兴奋的最新方法，我们可以 从人类脂肪组织中产生大量间充质祖细胞，且损失最小 多能性。这些细胞分化成与来源库中的脂肪细胞相似的脂肪细胞，并且 他们的转录组揭示了至少三种“白色”人类脂肪细胞的存在，以及 产热“米色/浅褐色”类型。我们现在处于有利地位来检验新陈代谢的假设 不同的人类脂肪库（臀肌和腹部）由不同的脂肪细胞类别组成， 由特定的间充质祖细胞发育而来，并提供这些细胞的完整转录组谱 脂肪细胞及其祖细胞。此外，众所周知，糖尿病会影响多能祖细胞， 导致产生健康脂肪细胞和修复组织的能力受损，胰岛素进一步恶化 反应能力。我们将检验人类 T2DM 改变间充质祖细胞多样性的假设 并确定这种缺陷如何导致体内脂肪组织发育异常。我们的具体目标是： 1. 检验以下假设：人体脂肪组织库的不同功能特性是由于 源自特定间充质祖细胞的脂肪细胞亚型含量的内在差异 细胞。 2：检验 T2DM 优先损害特定间充质细胞发育的假设 祖细胞亚群和源自这些细胞的脂肪细胞，以及 3：定义 通过体内组织生成来识别脂肪细胞亚型。这些研究将提供新的高分辨率视图 人类脂肪组织库的细胞结构，导致脂肪细胞的发育机制 亚型，并深入了解导致 T2DM 病理生理学的发育改变。

ABSTRACT More than total adiposity, the relative distribution of adipose tissue among central and peripheral depots is a critical determinant of Type 2 Diabetes (T2DM) and cardio metabolic disease risk. The goal of this proposal is to use novel mesenchymal progenitor cell derivation and single-cell clone genomic sequencing approaches to fully identify and characterize the diversity of adipocytes that compose these human depots and their developmental mechanisms. To this end, we will leverage exciting recent methods whereby we can generate large numbers of mesenchymal progenitor cells from human adipose tissue with minimal loss of multipotency. These cells differentiate into adipocytes that are similar to those from the depot of origin, and their transcriptomes reveal the existence of at least three types of “white” human adipocytes, as well as the thermogenic “beige/brite” type. We are now in a strong position to test the hypothesis that metabolically distinct human adipose depots, gluteal and abdominal, are composed of different adipocyte classes that develop from specific mesenchymal progenitor cells, and to provide full transcriptomic profiles of these adipocytes and their progenitors. Furthermore, it is known that diabetes affects multipotent progenitor cells, leading to impaired capacity to generate healthy adipocytes and repair tissue, further deterioration of insulin responsiveness. We will test the hypothesis that human T2DM alters mesenchymal progenitor diversity and determine how this defect leads to abnormal adipose tissue development in vivo. Our specific aims are: 1. To test the hypothesis that the different functional properties of human adipose tissue depots are due to intrinsic differences in their content of adipocyte subtypes derived from specific mesenchymal progenitor cells. 2: To test the hypothesis that T2DM preferentially impairs development of specific mesenchymal progenitor subsets and adipocytes derived from these cells, and 3: To define the physiological properties of adipocyte subtypes through tissue generation in vivo. These studies will provide a new high-resolution view of the cellular structure of human adipose tissue depots, of developmental mechanisms that lead to adipocyte subtypes, and insight into developmental alterations that contribute to T2DM physiopathology.