TRANSCRIPTIONAL REGULATION OF BEIGE ADIPOCYTE CELLULAR PLASTICITY

米色脂肪细胞可塑性的转录调控

基本信息

批准号：
10276132
负责人：
Hyun Cheol Roh
金额：
$ 42.69万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-06 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10276132
关键词：
Address Adipocytes Adipose tissue Adult Affinity Chromatography Americas Attention Automobile Driving Binding Biological Assay Brown Fat Calories Cell Culture Techniques Cell Differentiation process Cell Nucleus Cells ChIP-seq Circadian Rhythms Consumption Data Data Analyses Defect Desire for food Development Diabetes Mellitus Energy Metabolism Exercise Fatty acid glycerol esters Gene Expression Generations Genes Goals Health High Fat Diet Homeostasis Immune Immunofluorescence Microscopy Impairment In Vitro Intake Interleukins Knockout Mice Mediating Metabolic Metabolic Diseases Methods Microscopy Molecular Mus Nature Nuclear Nutrient Obesity Obesity Epidemic Pathway interactions Physiologic pulse Physiology Population Predisposition Process Proliferating Regulation Research Ribosomes Role Route Small Nuclear RNA Temperature Thermogenesis Transcriptional Regulation Transgenic Mice Translating United States base blood glucose regulation cell type comorbidity conditional knockout diet-induced obesity dietary control energy balance epigenome epigenomics experimental study feeding improved in vivo mouse model new therapeutic target novel novel therapeutic intervention nutrient metabolism obesity management obesity prevention progenitor recruit response success therapeutic target transcription factor transcriptome sequencing transcriptomics

Address Adipocytes Adipose tissue Adult Affinity Chromatography Americas Attention Automobile Driving Binding Biological Assay Brown Fat Calories Cell Culture Techniques Cell Differentiation process Cell Nucleus Cells ChIP-seq Circadian Rhythms Consumption Data Data Analyses Defect Desire for food Development Diabetes Mellitus Energy Metabolism Exercise Fatty acid glycerol esters Gene Expression Generations Genes Goals Health High Fat Diet Homeostasis Immune Immunofluorescence Microscopy Impairment In Vitro Intake Interleukins Knockout Mice Mediating Metabolic Metabolic Diseases Methods Microscopy Molecular Mus Nature Nuclear Nutrient Obesity Obesity Epidemic Pathway interactions Physiologic pulse Physiology Population Predisposition Process Proliferating Regulation Research Ribosomes Role Route Small Nuclear RNA Temperature Thermogenesis Transcriptional Regulation Transgenic Mice Translating United States base blood glucose regulation cell type comorbidity conditional knockout diet-induced obesity dietary control energy balance epigenome epigenomics experimental study feeding improved in vivo mouse model new therapeutic target novel novel therapeutic intervention nutrient metabolism obesity management obesity prevention progenitor recruit response success therapeutic target transcription factor transcriptome sequencing transcriptomics

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项目摘要

Obesity is a widespread and growing health problem the United States, associated with metabolic disorders, including diabetes. Major efforts have been made to mitigate obesity through diet control, exercise or appetite suppression. These methods have been met with limited success and high rates of rebound, urging the development of new strategies. Thermogenic beige adipocytes have attracted considerable attention as a new therapeutic target due to their potent anti-obesity activity in adult humans. Unlike classical brown adipocytes that retain a stable cellular identity, beige adipocytes have a unique cellular plasticity, capable of completely interconverting between brown and white adipocyte states via significant epigenomic reprogramming. The extraordinary plastic nature of beige adipocyte cellular identity and its underlying molecular mechanisms have yet to be well understood. Our recent studies led to a striking finding defining the ‘dedifferentiation’ potential of beige adipocytes. We found that upon cold exposure, a subpopulation of whitened beige adipocytes (beige adipocytes turned to white adipocytes), dedifferentiated into progenitor-like cells, proliferated, and possibly redifferentiated into thermogenic adipocytes. This reprogramming process serves as a potential novel mechanism of beige adipocyte recruitment. Our epigenomic analysis identified NFIL3 (Nuclear Factor, Interleukin 3 Regulated) as a key transcription factor, potentially mediating cold-induced beige adipocyte reprogramming. NFIL3 expression was induced by cold exposure, specifically in beige but not in brown adipocytes, and located in dedifferentiating beige adipocytes. Furthermore, both in vitro cell culture and in vivo mouse models deficient with NFIL3 in adipocytes demonstrated that NFIL3 is necessary for adipose tissue browning during cold exposure. In addition, NFIL3 loss in adipocytes resulted in increased susceptibility to diet- induced obesity after high fat diet feeding. Based on these data, we hypothesize that NFIL3 is a key transcription factor that controls beige adipocyte plasticity by mediating the transition from white to brown adipocytes, thereby regulating energy balance and glucose homeostasis. In aim 1, we will elucidate whitened beige adipocyte reprogramming during browning and a role for NFIL3. We will perform beige adipocyte pulse- chase experiments in NFIL3 knockout (KO) mice using microscopy, single nuclei RNA-seq and cell culture. In aim 2, we will determine the role of NFIL3 in cold tolerance and glucose homeostasis by conducting comprehensive physiology studies with adipocyte-specific NFIL3 KO mice. In aim 3, we will identify molecular mechanisms by which NFIL3 regulates adipocyte identity by using ChIP-seq to define the NFIL3 cistrome in beige adipocytes. These studies will uncover novel aspects of beige adipocyte cellular plasticity. We will establish the role of NFIL3 as a new regulator of beige adipocyte reprogramming, systemic energy balance and nutrient homeostasis. Therefore, the successful completion of these studies will lead to the development of new therapeutic approaches for obesity, and other co-morbid metabolic diseases.

肥胖是美国的宽度和越来越多的健康问题，与包括糖尿病在内的代谢疾病有关。通过饮食控制，运动或抑制食欲，已经做出了重大努力来减轻肥胖症。这些方法的成功有限，反弹的速度很高，敦促开发新策略。热米色脂肪细胞因成年人的有效抗肥胖活动而引起了人们的注意作为一种新的治疗靶点。与保留稳定细胞同一性的经典棕色脂肪细胞不同，米色脂肪细胞具有独特的细胞塑性，能够通过显着的表观基因组重编程在棕色和白色脂肪细胞状态下完全相互转换。米色脂肪细胞细胞身份及其潜在的分子机制的非凡塑性性质尚未得到充分了解。我们最近的研究导致了一个引人注目的发现，定义了米色脂肪细胞的“脱育”潜力。我们发现，在冷暴露后，对白色米色脂肪细胞的亚群（米色脂肪细胞变成白色脂肪细胞），将分化成祖细胞样细胞，增殖，并可能将其重新分化为热脂肪细胞。这种重编程过程是米色脂肪细胞募集的潜在新机制。我们的表观基因组分析确定NFIL3（核）因子，白介素3被调节）是关键转录因子，可能介导冷诱导的米色脂肪细胞重编程。 NFIL3的表达是通过冷暴露诱导的，特别是在米色，而不是在棕色脂肪细胞中，并位于去分化的米色脂肪细胞中。此外，在脂肪细胞中缺乏NFIL3缺乏的体外细胞培养和体内小鼠模型都表明，在冷暴露期间，NFIL3对于脂肪组织褐变是必不可少的。此外，脂肪细胞中的NFIL3损失导致高脂饮食喂养后对饮食诱导的肥胖症的敏感性增加。基于这些数据，我们假设NFIL3是通过介导从白色到棕色脂肪细胞的过渡来控制米色脂肪细胞可塑性的关键转录因子，从而调节能量平衡和葡萄糖稳态。在AIM 1中，我们将阐明在褐变期间重新编程的白色脂肪细胞重编程和NFIL3的作用。我们将使用显微镜，单核RNA-Seq和细胞培养在NFIL3敲除（KO）小鼠中进行脂肪细胞脉冲追踪实验。在AIM 2中，我们将通过使用脂肪细胞特异性NFIL3 KO小鼠进行全面的生理学研究来确定NFIL3在冷耐受性和葡萄糖稳态中的作用。在AIM 3中，我们将通过使用chip-seq来定义米色脂肪细胞中的NFIL3 Cistrome来调节NFIL3调节脂肪细胞身份的分子机制。这些研究将发现米色脂肪细胞细胞可塑性的新方面。我们将确定NFIL3作为米色脂肪细胞重编程，全身能量平衡和营养稳态的新调节剂的作用。因此，这些研究的成功完成将导致开发肥胖症的新治疗方法和其他联合莫比利代谢疾病。