The microbiota regulates the progression of obesity through a highly conserved family of microRNAs

微生物群通过高度保守的 microRNA 家族调节肥胖的进展

• 批准号: 10180957
• 负责人: Monica Teresa Jimenez
• 金额: $ 0.95万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10180957
• 关键词: 3' Untranslated Regions; Address; Adipocytes; Adipose tissue; Affect; Aryl Hydrocarbon Receptor; Blood Circulation; Body Weight; CRISPR/Cas technology; Candidate Disease Gene; Cardiovascular Diseases; Data; Development; Disease; Distal; Energy Intake; Energy Metabolism; Family; Fatty acid glycerol esters; Functional disorder; Gene Expression; Genes; Health; Homeostasis; Human; In Vitro; Individual; Indoles; Insulin Resistance; Knowledge; Light; Lipids; Mammals; Mediating; Metabolic; Metabolic dysfunction; Metabolism; MicroRNAs; Molecular; Mouse Strains; Mus; Mutate; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Organ; Organism; Phenotype; Process; Regulation; Reporter; Repression; Risk Factors; Signal Transduction; Signaling Molecule; System; Testing; Thinness; Time; Transcriptional Activation; Tryptophan; Vertebrates; Work; blood glucose regulation; diet-induced obesity; dietary; dysbiosis; environmental change; experimental study; gene repression; gut microbiota; in vivo; inhibitor/antagonist; insight; insulin sensitivity; insulin signaling; knock-down; metabolomics; microbial; microbiota; microbiota metabolites; microorganism; mouse genetics; new therapeutic target; obesity development; overexpression; receptor; response; therapeutic target; tool; transcription factor; transcriptome sequencing

Project Abstract White adipose tissue (WAT) is the main energy storage depot in vertebrates and tightly controls glucose homeostasis in mammals. The gut microbiota is now recognized as a central regulator of WAT in healthy organisms and significantly contributes to WAT dysfunction during obesity. Yet how the gut microbiota regulates WAT functions remains largely unknown. This proposal is focused on defining the mechanistic basis by which the microbiota controls host metabolism through the regulation of WAT functions. For the first time, we have now revealed that a highly conserved family of microRNAs acts as a central controller of WAT functions in response to microbiota-derived signals. In this proposal, we aim to dissect the mechanisms by which the microbiota regulates host metabolism and WAT functions through the modulation of this miRNA family, which will reveal critical new insights into the interactions between the microbiota and host metabolism. It is well-established that the gut microbiota controls WAT functions that determine fat mass and insulin sensitivity in healthy organisms, and dysregulation of these processes leads to the development of obesity and insulin resistance (IR), which affect millions of people worldwide. However, the microbial-derived signals and the molecular mechanisms by which the gut microbiota regulates WAT functions in health and disease are largely unknown. Excitingly, we have discovered that the microbiota induces the expression of a highly conserved family of miRNAs (miR-181) specifically in white adipocytes, to regulate energy expenditure and insulin sensitivity. Moreover, our findings reveal that dysregulation of the gut microbiota-miR-181 axis is critical for the development of obesity and IR in mice. Thus, I hypothesize that modulation of miR-181 levels in white adipocytes by the microbiota represents a central mechanism by which commensal microorganisms control host metabolism, and that its dysregulation leads to obesity. In search of the microbiota-derived signal regulating miR-181 in white adipocytes, we have discovered that circulating microbiota-derived metabolites are significantly dysregulated in obese mice and humans, including a potential negative regulator of miR-181, indole. Yet still, how the microbiota regulates miR-181 levels in WAT and how this miRNA family controls WAT functions in response to microbial signals is unknown. I propose to address this gap in knowledge in the following aims: Aim 1 will determine if indole regulates miR-181 expression in WAT adipocytes to control the progression of obesity and IR. Aim 2 will elucidate the mechanisms by which miR-181 controls white adipose functions. These studies will shed light on the mechanisms by which the expression of a critical family of microRNAs is tuned in response to dietary and environmental changes, and how these changes alter the progression of obesity and IR. As our preliminary data shows that indole and MIR-181 levels are dysregulated in obese human individuals, MIR-181 may represent a potential therapeutic target to modulate WAT function in the context of obesity.

项目摘要 白色脂肪组织（WAT）是脊椎动物的主要能量储存库，严格控制葡萄糖 哺乳动物体内的稳态。肠道微生物群现已被认为是健康人群中 WAT 的中央调节因子 生物体并显着导致肥胖期间 WAT 功能障碍。然而肠道微生物群如何调节 WAT 的功能在很大程度上仍然未知。该提案的重点是通过以下方式定义机械基础： 微生物群通过调节 WAT 功能来控制宿主代谢。首次， 我们现在发现一个高度保守的 microRNA 家族充当 WAT 功能的中央控制器 响应微生物群衍生的信号。在本提案中，我们旨在剖析 微生物群通过调节该 miRNA 家族来调节宿主代谢和 WAT 功能，这将 揭示了微生物群与宿主代谢之间相互作用的重要新见解。 众所周知，肠道微生物群控制着决定脂肪量和胰岛素敏感性的 WAT 功能 在健康有机体中，这些过程的失调会导致肥胖和胰岛素的发展 耐药性（IR），影响着全世界数百万人。然而，微生物衍生的信号和 肠道微生物群在健康和疾病中调节 WAT 功能的分子机制在很大程度上是 未知。令人兴奋的是，我们发现微生物群诱导高度保守家族的表达 miRNA (miR-181) 特别存在于白色脂肪细胞中，以调节能量消耗和胰岛素敏感性。 此外，我们的研究结果表明，肠道微生物群-miR-181轴的失调对于发育至关重要 小鼠的肥胖和IR。因此，我推测白色脂肪细胞中 miR-181 水平的调节是通过 微生物群代表共生微生物控制宿主的中心机制 新陈代谢，其失调会导致肥胖。寻找微生物群衍生的信号调节 miR-181 在白色脂肪细胞中，我们发现循环微生物群衍生的代谢物显着 在肥胖小鼠和人类中失调，包括 miR-181 的潜在负调节因子吲哚。然而， 微生物群如何调节 WAT 中的 miR-181 水平以及该 miRNA 家族如何控制 WAT 功能 对微生物信号的反应尚不清楚。我建议通过以下目标来解决这一知识差距： 1将确定吲哚是否调节WAT脂肪细胞中的miR-181表达以控制肥胖的进展 和红外。目标 2 将阐明 miR-181 控制白色脂肪功能的机制。这些研究 将阐明关键的 microRNA 家族的表达响应调整的机制 饮食和环境变化，以及这些变化如何改变肥胖和IR的进展。作为我们的 初步数据显示肥胖人群中吲哚和 MIR-181 水平失调，MIR-181 可能是在肥胖背景下调节 WAT 功能的潜在治疗靶点。