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：
10611475
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/10611475
关键词：
Address Adipocytes Adipose tissue Adult Affinity Chromatography Attention Automobile Driving Binding Biological Assay Brown Fat Calories Cell Culture Techniques Cell Differentiation process Cells ChIP-seq Circadian Rhythms Classification 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 Temperature Thermogenesis Transcriptional Regulation Transgenic Mice Translating United States blood glucose regulation cell type comorbidity conditional knockout diet-induced obesity dietary control disorder control energy balance epigenome epigenomic profiling epigenomics experimental study feeding improved in vivo mouse model new therapeutic target novel novel therapeutic intervention nutrient metabolism obesity management obesity prevention progenitor programs recruit response single nucleus RNA-sequencing success therapeutic target transcription factor transcriptomic profiling transdifferentiation

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.

肥胖症是一种与糖尿病在内的代谢性疾病有关的美国，并使糖尿病造成了糖尿病。与经典的棕色脂肪细胞相比，有效的抗肥胖，可以保留稳定的细胞身份，米色的脂肪细胞Ique ique complular，能够完整的相互转化的bro骨和白色的脂肪细胞，并通过明显的表观依赖性的重新编程。良好的研究发现米色脂肪细胞的“去分化”潜力。米色脂肪细胞募集的机制。此外，在高脂肪饮食后，对饮食诱发的肥胖症的敏感性增加了。 NFIL3。 AIM 3中的脂肪细胞规范3。 Ofil3云母脂肪细胞重编程，全身能量和营养。