The Role of eIF4G1 and eIF4G2 in Translational Control of Adipogenesis and Obesity

eIF4G1 和 eIF4G2 在脂肪生成和肥胖转化控制中的作用

• 批准号: 10464460
• 负责人: Rachel Elizabeth Turn
• 金额: $ 6.72万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464460
• 关键词: 3T3-L1 Cells; Address; Adipocytes; Adipose tissue; Adult; BODIPY; Binding; Binding Sites; Biological; Biological Assay; Biological Models; Cell Proliferation; Cell physiology; Cells; Chronic; Cilia; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Cues; Cyclic AMP; Data; Degenerative polyarthritis; Deposition; Development; Diabetes Mellitus; Disease; Event; Failure; Fatty Acids; Fatty acid glycerol esters; Future; G-Protein-Coupled Receptors; Gene Targeting; Generations; Genes; Genetic Models; Genetic Transcription; Goals; Harvest; Health; Heart Diseases; Histology; Homologous Protein; Hormones; Human; Hypertension; Hypertrophy; In Vitro; Incidence; Inflammation; Inflammatory; Insulin; Insulin Resistance; Kinetics; Knock-out; Knockout Mice; Lead; Life; Ligands; Link; Lipids; Maintenance; Malignant Neoplasms; Mammals; Mediating; Mesenchymal Stem Cells; Messenger RNA; Metabolic; Metabolic Diseases; Metabolism; Modification; Morbid Obesity; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Omega-3 Fatty Acids; Pancreatitis; Parkinson Disease; Pathology; Pathway interactions; Patients; Peptide Initiation Factors; Population; Prevalence; Process; Proteins; Regulation; Ribosomes; Risk; Role; Signal Transduction; Sorting - Cell Movement; Source; Stains; Supplementation; Surface; Symptoms; System; Techniques; Testing; Therapeutic; Time; Tissues; Training; Transcript; Translation Initiation; Translations; Triglycerides; United States; Weight Gain; Work; adipocyte differentiation; base; chemokine; cytokine; fatty liver disease; genome wide screen; genome-wide; in vivo; inhibitor; insight; lipid biosynthesis; mouse genetics; mouse model; neurotransmission; novel; predictive test; prevent; programs; receptor; recruit; reduce symptoms; screening; targeted treatment; therapeutic development; therapeutic target; vision development

PROJECT SUMMARY Obesity, a disease caused by elevated fat mass, has increased in prevalence over the past few decades. Over 30% of the population suffers from obesity, and over time it can lead to increased incidence of life- threatening pathologies, including Type II Diabetes, heart disease, and cancer. Much study has been devoted to finding new treatments, which remain ineffective because 1) obesity is highly polygenic, and 2) they ameliorate symptoms rather than target the disease source. It is urgent to identify pathways disrupted in obesity to develop better therapeutics that more precisely treat the case-specific source of fat mass expansion. My lab contributed to this effort by performing a genome-wide screen for fat mass-regulating GPCRs and discovered FFAR4, a ciliary GPCR that binds ω-3 fatty acids to promote preadipocyte differentiation into new adipocytes (adipogenesis) instead of depositing lipids in existing tissue, causing inflammation (hypertrophy). This discovery is especially useful to human health because even though adipogenesis and hypertrophy both cause weight gain, hypertrophy is ultimately much more pernicious because the chronic inflammation leads to complications, including hypertension and diabetes. Therefore, understanding how FFAR4 drives preadipocyte differentiation may help us circumvent hypertrophic obesity and downstream pathology. The mechanism by which FFAR4 drives adipogenesis has yet to be elucidated. To do so, the Jackson lab performed the first genome-wide CRISPR knockout screen for FFAR4-pathway adipogenesis regulators using preadipocytes harvested at different time points post-differentiation. Our lab discovered that translation initiation factors eIF4G1 and eIF4G2, highly homologous proteins that compete for the same ribosomal binding site to drive transcript recruitment, have opposite effects on adipogenesis downstream of FFAR4: eIF4G2 was the strongest inhibitor and eIF4G1 was one of the strongest drivers of adipogenesis. I will test my central hypothesis that the switch from eIF4G2-dependent to eIF4G1-dependent translation (by degradation of eIF4G2 and activation of eIF4G1), downstream of FFAR4-induced cAMP signaling, drives fate change through converting to the translation of transcripts that specifically promote adipogenesis. I will use a combination of 3T3-L1 preadipocytes and mouse genetic models to gain mechanistic insight into eIF4G1/2 functions on a cellular and systemic level. In Aim 1, I will determine the mechanism of eIF4G1/2 function in preadipocyte differentiation in vitro. I will tease apart the pathway(s) through which eIF4G1 and eIF4G2 act by probing mechanism, tracking their kinetics in adipogenesis, determining if they are necessary/sufficient to drive adipogenesis, and identifying the transcripts they each regulate. In Aim 2, I will determine the role of eIF4G1/2 in fat expansion and metabolism in vivo using mouse model systems to see how eIF4G1 and eIF4G2 function relates to multicellular systems. Taken together, my work will pave the way for exploring the network of signaling events that drive adipogenesis downstream of the cilium and may pave the way for therapeutics targeting monogenic sources of obesity.

项目总结