Mapping the Developing Beige Fat by Massively Parallel Single Cell Analysis

项目摘要/摘要 肥胖是心血管疾病和糖尿病等代谢紊乱的主要危险因素 糖尿病。肥胖及其代谢后果仍然是最重要的生物医学之一 当今美国和世界面临的挑战。近三分之一(33.8%)和17%(或1250万)的成年人 在美国，儿童和青少年都很肥胖。在没有改进的治疗方法的情况下，进一步增加的是 预计与肥胖密切相关的严重疾病的数量。所有的减肥药 目前由FDA法案批准，通过抑制食欲或抑制能量摄入 肠道脂肪吸收。然而，由于副作用，包括抑郁，油性大便和 脂溢症，迫切需要替代治疗方法。这项研究具有重要意义，因为它可能 用完全相反的方法，即通过“增加”能量来阐明对抗肥胖的新药。 支出。 哺乳动物体内存在两种脂肪组织。棕色脂肪组织(BAT)是一种特殊的脂肪组织 它能消散能量以产生热量，而白色脂肪组织(Wat)则起到储存多余能量的作用 能量。研究表明，蝙蝠的减少与人类能量消耗的减少和肥胖有关； 因此，通过再生蝙蝠来“增加”能量消耗可能会有效地对抗肥胖。 某些生理信号，如慢性冷暴露，会将WAT转化为富含线粒体的能量 消耗蝙蝠样的脂肪细胞。这种“棕色”的脂肪细胞被称为“米色脂肪细胞”，最近 包括我们在内的研究表明，成年蝙蝠主要由米色脂肪细胞组成。的目标是 这项拟议的研究是为了确定产生米色脂肪细胞的所有细胞亚型。在这个项目中，我 将专注于皮下水所特有的细胞类型。已经知道，皮下积水可以 很容易被外部暗示“变色”，然而，这种转换在内脏水中观察到的要少得多。我 假设在皮下水中存在预先确定要分化为 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)和 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 然后确定仓库特定种群的遗传生物标记物。这些生物标志物将用于 米色脂肪细胞干细胞的分离及其对新型细胞基质的开发 对抗人类肥胖的治疗学或药理学策略。

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.