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：
10445307
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/10445307
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

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.

肥胖是美国一个普遍且日益严重的健康问题，与包括糖尿病在内的代谢紊乱有关，人们通过饮食控制、运动或抑制食欲来减轻肥胖，但这些方法的成功率有限，而且反弹率很高。，促使新策略的开发。由于其在成年人中具有有效的抗肥胖活性，生热米色脂肪细胞作为新的治疗靶点引起了相当大的关注，与保留稳定细胞特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可塑性。，有能力的通过显着的表观基因组重编程实现棕色和白色脂肪细胞状态之间的完全相互转换，米色脂肪细胞细胞特性的非凡可塑性及其潜在的分子机制尚未得到充分了解。我们发现，在冷暴露后，白色的米色脂肪细胞亚群（米色脂肪细胞变成白色脂肪细胞）去分化为祖细胞样，并增殖，我们的表观基因组分析发现，NFIL3（核因子，白细胞介素 3 调节）是一种关键转录因子，可能介导冷诱导的米色脂肪细胞重编程。表达是通过冷暴露诱导的，特别是在米色脂肪细胞中，但不在棕色脂肪细胞中，并且位于去分化的米色脂肪细胞中。此外，这两种细胞均在体外。脂肪细胞中缺乏 NFIL3 的培养和体内小鼠模型表明，在寒冷暴露期间，NFIL3 对于脂肪组织褐变是必需的。此外，根据这些数据，脂肪细胞中 NFIL3 的损失导致对饮食诱导的肥胖的易感性增加。我们研究发现NFIL3是一种关键转录因子，通过介导白色脂肪细胞向棕色脂肪细胞的转变来控制米色脂肪细胞的可塑性，从而调节能量平衡和葡萄糖稳态。 1，我们将阐明褐变过程中的白色米色脂肪细胞重编程以及 NFIL3 的作用。我们将使用显微镜、单核 RNA 测序和细胞培养在 NFIL3 敲除 (KO) 小鼠中进行米色脂肪细胞脉冲追踪实验。将通过对脂肪细胞特异性 NFIL3 KO 小鼠进行全面的生理学研究来确定 NFIL3 在耐冷性和葡萄糖稳态中的作用。 3，我们将通过使用 ChIP-seq 定义米色脂肪细胞中的 NFIL3 顺反子来确定 NFIL3 调节脂肪细胞身份的分子机制。这些研究将揭示米色脂肪细胞可塑性的新方面，我们将确立 NFIL3 作为新调节剂的作用。因此，这些研究的成功完成将导致肥胖等新治疗方法的开发。共病代谢性疾病。