Mechanisms of human adipose depot development and impact of Diabetes

摘要 除了总肥胖率，脂肪组织在中央和外围储存库中的相对分布是 2型糖尿病(T2 DM)和心脏代谢性疾病风险的关键决定因素。这样做的目的是 建议使用新的间充质祖细胞衍生和单细胞克隆基因组测序 充分鉴定和表征脂肪细胞多样性的方法，这些脂肪细胞组成这些人类储藏库和 它们的发育机制。为此，我们将利用最近令人振奋的方法，从而我们可以 从人脂肪组织中诱导大量间充质祖细胞 多功能性。这些细胞分化为脂肪细胞，与来源来源的脂肪细胞相似，并且 他们的转录本揭示了至少三种“白色”人类脂肪细胞的存在，以及 产热“米色/褐煤”型。我们现在处于有利地位，可以测试新陈代谢的假设 不同的人类脂肪库，臀部和腹部，由不同类型的脂肪细胞组成，这些脂肪细胞 从特定的间充质祖细胞发展而来，并提供这些细胞的完整转录图谱 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， 导致生成健康脂肪细胞和修复组织的能力受损，进一步恶化胰岛素 响应性。我们将检验人类T2 DM改变间充质祖细胞多样性的假设 并确定这种缺陷是如何导致体内脂肪组织异常发育的。我们的具体目标是： 1.检验人类脂肪组织储存库的不同功能特性是由于 特定间充质祖细胞来源的脂肪细胞亚型含量的内在差异 细胞。2：检验T2 DM优先损害特定间充质发育的假设 从这些细胞衍生的祖细胞亚群和脂肪细胞，以及3：定义 体内脂肪细胞通过组织生成进行亚型划分。这些研究将提供一个新的高分辨率视角 人类脂肪组织储存库的细胞结构，导致脂肪细胞的发育机制 亚型，以及对导致T2 DM生理病理的发育变化的洞察。

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.