Mapping the Developing Beige Fat by Massively Parallel Single Cell Analysis

项目总结/摘要 肥胖是心血管疾病和代谢紊乱如糖尿病的主要危险因素 糖尿病。肥胖及其代谢后果仍然是最重要的生物医学问题之一， 今天美国和全世界的挑战。近三分之一的成年人（33.8%）和17%（1250万）的 在美国，儿童和青少年肥胖。在没有改进的治疗方法的情况下， 与肥胖密切相关的严重疾病的数量。所有抗肥胖药物 目前FDA批准通过抑制食欲或抑制 肠道脂肪吸收。然而，由于副作用，包括抑郁症，油性排便， 然而，迫切需要采取替代办法。这项研究意义重大，因为它可能 阐明新的药物，以完全相反的方法来对抗肥胖，即通过“增加”能量 支出 哺乳动物体内有两种脂肪组织。棕色脂肪组织（BAT）是一种特殊的脂肪组织 而白色脂肪组织（WAT）的功能是储存多余的 能源研究表明，BAT的损失与人类能量消耗减少和肥胖有关; 因此，通过BAT的再生“增加”能量消耗可以有效地对抗肥胖。 某些生理线索，如长期寒冷暴露，将WAT转化为富含维生素A的能量， 消耗BAT样脂肪细胞这种“褐色”脂肪细胞被称为“米色脂肪细胞”， 包括我们在内的研究表明，成年人BAT主要由米色脂肪细胞组成。的目标 这项研究的目的是确定产生米色脂肪细胞的所有细胞亚型。在这个项目中，我 将重点关注皮下WAT特有的细胞类型。已知皮下WAT可以 容易被外部线索“褐化”，而这种转换在内脏WAT中观察到的要少得多。我 假设在皮下WAT中存在预定分化为 米色脂肪细胞。为了验证这一假设，我将采用一种新的方法（单细胞RNA测序）， 确定皮下和内脏白色脂肪组织中细胞类型的数量和特征。我 然后确定特定仓库种群的遗传生物标志物。这些生物标志物将用于 米色脂肪细胞干细胞的前瞻性分离有助于开发新的基于细胞的 治疗或药理学策略来对抗人类肥胖。

Project Summary/Abstract Obesity is a primary risk factor for cardiovascular disease and metabolic disorders such as diabetes mellitus. Obesity and its metabolic consequences continue to be among the most important biomedical challenges in the U.S. and worldwide today. Nearly one-third of adults (33.8%) and 17% (or 12.5 million) of children and adolescents are obese in the U.S.. In the absence of improved therapies, further increases are expected in the number of serious conditions closely associated with obesity. All anti-obesity medications currently approved by the FDA act to repress energy intake, either by suppressing appetite or by inhibiting intestinal fat absorption. However, due to side effects including depression, oily bowel movements and steatorrhea, there is an urgent need for alternative approaches. This study is significant because it may elucidate new drug to counteract obesity by the completely opposite method, namely, via "increasing" energy expenditure. Two types of fat tissue exist in mammals. Brown adipose tissue (BAT) is a specialized adipose tissue that dissipate energy for heat generation, whereas white adipose tissue (WAT) functions as storage of excess energy. Studies suggest that loss of BAT is linked to decreased energy expenditure and obesity in humans; thus “increasing” energy expenditure through regeneration of BAT could be effective to counteract obesity. Certain physiological cues, such as chronic cold exposure, convert WAT into mitochondria-rich, energy consuming BAT-like adipocyte. This “browned” adipocyte is referred to as a “beige adipocyte” and recent studies including ours indicate that adult human BAT is mostly composed of beige adipocytes. The objective of the proposed research is to determine all subtypes of cells that give rise to beige adipocytes. In this project, I will focus on cell types that are specific to subcutaneous WAT. It has been known that subcutaneous WAT can easily be “browned” by external cues, whereas, this conversion is much less observed in a visceral WAT. I hypothesize that there are discreet cell types in subcutaneous WAT that are predetermined to differentiate to beige adipocytes. To test this hypothesis, I will employ a novel methodology (single cell RNA sequencing) and determine the number and characteristics of cell types in subcutaneous and visceral white adipose tissue. I then identify genetic biomarker for the depot-specific populations. These biomarkers will be used for the prospective isolation of stem cell of beige adipocytes which contribute to the development of novel cell based therapeutics or pharmacological strategies to counteract obesity in humans.