Mechanisms of human adipose depot development and impact of Diabetes

人体脂肪库发育机制及糖尿病的影响

• 批准号: 10418655
• 负责人: Silvia Corvera
• 金额: $ 49.41万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-17 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10418655
• 关键词: Abdomen; Adipocytes; Adipose tissue; Affect; Body fat; Cell Differentiation process; Cells; Cellular Metabolic Process; Cellular Structures; Characteristics; Clone Cells; Defect; Derivation procedure; Deterioration; Development; Diabetes Mellitus; Fatty acid glycerol esters; Female; Functional disorder; Generations; Genes; Genomics; Goals; Health; Heart Diseases; Heterogeneity; Hormonal; Human; Impairment; Individual; Insulin; Lead; Mesenchymal Stem Cells; Metabolic; Metabolic Diseases; Metabolism; Methods; Multipotent Stem Cells; Mus; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Onset of illness; Pathway interactions; Peripheral; Persons; Physiological; Positioning Attribute; Property; Research; Resolution; Risk; Stem Cell Development; Testing; Tissues; Variant; Weight Gain; Work; adipocyte differentiation; disorder risk; impaired capacity; improved; in vivo; insight; male; mouse model; novel; progenitor; response; stem cell population; stem cells; tissue repair; transcriptome; transcriptomics

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.

抽象的 脂肪组织在中央和外围沉积物中的相对分布不仅仅是总肥胖。 2型糖尿病（T2DM）和心脏代谢疾病风险的关键决定因素。目标的目标 建议是使用新型的间充质祖细胞推导和单细胞克隆基因组测序 充分识别和表征构成这些人类沉积物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近方法 从人类脂肪组织产生大量间充质祖细胞，而 多责任。这些细胞分化为与原始仓库相似的脂肪细胞， 它们的转录组揭示了至少存在三种“白人”人类脂肪细胞的存在，以及 热“米色/龄”类型。我们现在处于强大的位置，可以检验代谢的假设 独特的人脂肪沉积物，臀肌和腹部，由不同的脂肪细胞类别组成 从特定的间充质祖细胞中发展，并提供这些完整的转录组。 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 响应能力。我们将测试人类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异常的脂肪组织发育。我们的具体目的是： 1。检验以下假设：人脂肪组织沉积的不同功能特性是由于 其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：测试T2DM优先损害特定间质的发展的假设 祖细胞子集和源自这些细胞的脂肪细胞，以及3：定义的物理特性 通过体内组织产生的脂肪细胞亚型。这些研究将提供新的高分辨率观点 人脂肪组织沉积物的细胞结构，导致脂肪细胞的发育机制 亚型，以及对有助于T2DM生理病理学的发展变化的洞察力。