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

• 批准号: 10456217
• 负责人: Sayeepriyadarshini Anakk
• 金额: $ 51.47万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 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/10456217
• 关键词: Address; Adipocytes; Adipose tissue; Adult; Affect; Behavior; Bile Acid Biosynthesis Pathway; Bile Acids; Biogenesis; Biological Models; Biomechanics; Biophysics; Blood Vessels; Brown Fat; Calories; Centers for Disease Control and Prevention (U.S.); 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; Physiological; Pilot Projects; Prevalence; 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; 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

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.

总结