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Biophysical and genetic cues regulating lipid droplet packaging and alterations in obesity

调节脂滴包装和肥胖改变的生物物理和遗传线索

基本信息

批准号：
10663948
负责人：
Sayeepriyadarshini Anakk
金额：
$ 50.98万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
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：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10663948
关键词：
Address Adipocytes Adipose tissue Adult Affect Behavior Bile Acid Biosynthesis Pathway Bile Acids Biogenesis Biological Models Biomechanics Biophysics Brown Fat Calories Cryoelectron Microscopy Cues Data Development Diet Digestion Emulsions Endoplasmic Reticulum Epidemic Exposure to Extracellular Matrix Fat emulsion Fatty acid glycerol esters Gene Expression Genetic Genetic Transcription Goals Growth Impairment In Vitro Individual Knock-out Knockout Mice Knowledge Laser Scanning Confocal Microscopy Lipids Liquid substance Mechanics Membrane Metabolic syndrome Modeling Mus Nonesterified Fatty Acids Obesity Overnutrition Overweight Phase Physical condensation Physiological Pilot Projects Prevalence Probability Process Property Regulation Risk Factors Roentgen Rays Role Signal Transduction Signaling Molecule Structure Testing Time Tissue Expansion Tissues Transcriptional Regulation Transgenic Organisms Triglycerides United States Vascularization adiponectin design dietary epigenome experimental study gene synthesis genome-wide interdisciplinary approach lipid biosynthesis lipid metabolism mimetics novel nutrition obesity development obesogenic receptor response sterol ester sugar surfactant transcriptome unilamellar vesicle western diet

项目摘要

Summary Obesity is a major epidemic, which affects one in three individuals in the United States. Extensive remodeling of the adipose tissue and biogenesis of lipid droplets (LDs) occur in constant overnutrition to store the additional fat. The biophysical and genetic mechanisms controlling fat expansion are yet to be fully understood. Bile acids (BAs)—the body’s major natural surfactants— not only facilitate fat digestion but also act as signaling molecules to regulate fat metabolism by activating its receptors. Our preliminary data suggests that in response to BAs, LDs isolated from brown adipose tissue (BAT, containing small multilocular LDs) remain the same size whereas white (WAT, containing large unilocular LDs) adipose LDs integrate BAs in their core capturing TAGs that can rapidly shuttle from droplet to droplet. We will test the hypothesis that LD ripening, regulated by BA surfactants, is a dominant mechanism of LD growth instead of coalescence. We also found that fat is packed in layers in LDs. Additionally, we found that the extracellular matrix (ECM) of BAT is significantly more aligned that WAT’s ECM. We will investigate how the interplay between fat and ECM packing is altered in obesity. Finally, we developed a giant unilamellar vesicle (GUV) that mimics the endoplasmic reticulum LD biogenesis to tease these fat packaging differences. Our pilot experiments show that TAG distributes evenly in the GUV membrane before accumulating in a nascent TAG condensate. We will investigate a novel hypothesis for LD biogenesis that, in addition to membrane-tension, is controlled by liquid-liquid phase separation. We detected the presence of several BAs in adipose tissue and discovered that adipocyte-specific knockout of Farnesoid X Receptor (Fxr)—a BA receptor—resulted in a larger LD size and downregulated expression of genes controlling lipid metabolism. These surprising results indicate that LD remodeling may be transcriptionally regulated through the BA-Fxr axis. Further, we uncovered that a critical BA synthesis gene, Cyp27a1, was specifically induced upon adipogenesis and that its deletion of Cyp27a1 in preadipocytes impaired growth, indicating an important role of Cyp27a1 in adipogenesis. In addition to the focused approaches, we will also investigate the alterations in the transcriptome and epigenome of adipose remodeling during the development of obesity. Our exciting preliminary data underscores the importance of BAs' role (surfactant and signaling) in regulating LD size and expansion. This proposal will (1) determine how diet and BA regulation affect LD structure and biogenesis and (2) delineate the genetic mechanisms that regulate LD expansion during obesity. Overall, this project will uncover fundamental principles that govern LD dynamics in obesity.

摘要肥胖是一种主要的流行病，在美国每三个人中就有一个受到影响。广泛性脂肪组织的重塑和脂滴(LDS)的生物发生持续发生过多的营养来储存额外的脂肪。控制脂肪的生物物理和遗传机制扩张还没有完全被理解。胆汁酸(BAS)--人体主要的天然表面活性物质-- 不仅促进脂肪消化，而且作为信号分子通过以下方式调节脂肪代谢激活它的受体。我们的初步数据表明，作为对bas的反应，从棕色脂肪组织(BAT，包含小的多房性LD)保持相同的大小，而白色(Wat，包含大的单眼LD)脂肪LD在其核心捕获中整合了BA 标签可以从一滴快速穿梭到另一滴。我们将测试Ld成熟的假设，受BA表面活性剂的调节，是LD生长的主要机制，而不是聚结。我们还发现脂肪在LDS中是层层包装的。此外，我们发现细胞外基质英美烟草的ECM明显比WAT的ECM更一致。我们将调查这种相互作用是如何脂肪和细胞外基质之间的包装在肥胖时发生了变化。最后，我们开发出了一种巨大的单层膜模拟内质网LD生物发生的囊泡(GUV)，以梳理这些脂肪包装不同之处。我们的中试实验表明，在此之前，Tag均匀地分布在Gv膜中。积聚在一种新生的标签冷凝物中。我们将研究LD的一个新假说除膜张力外，还受液-液分离控制的生物发生。我们检测到脂肪组织中存在几种bas，并发现脂肪细胞特异性敲除法尼类X受体(FXR)-BA受体-导致更大的LD大小和控制脂代谢的基因表达下调。这些令人惊讶的结果表明 LD的重塑可能通过BA-FXR轴在转录水平上进行调节。此外，我们发现一个关键的BA合成基因Cyp27a1是在脂肪生成及其在前脂肪细胞中Cyp27a1的缺失损害了生长，表明 Cyp27a1在脂肪形成中的重要作用除了重点关注的方法外，我们还将探讨脂肪重塑过程中转录组和表观基因组的变化肥胖的发展。我们令人兴奋的初步数据强调了BAS的作用的重要性 (表面活性物质和信号转导)调节LD的大小和扩张。这项提案将(1)确定饮食和BA调节如何影响LD的结构和生物发生；(2)描述遗传肥胖时调节LD扩张的机制。总体而言，这个项目将揭示控制肥胖症学习障碍动力学的基本原则。