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: 10450198
• 负责人: Monica Teresa Jimenez
• 金额: $ 3.31万
• 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/10450198
• 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）是脊椎动物体内主要的能量储存库，并严格控制葡萄糖 哺乳动物体内平衡肠道微生物群现在被认为是健康人WAT的中心调节因子。 生物体和显着有助于WAT功能障碍在肥胖症。然而肠道微生物群是如何调节 WAT的功能在很大程度上仍然未知。该建议的重点是通过以下方式确定机制基础： 微生物群通过调节WAT功能来控制宿主代谢。第一次， 我们现在已经揭示了一个高度保守的microRNA家族作为WAT功能的中央控制器， 响应微生物来源的信号。在这一建议中，我们的目的是剖析机制， 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 揭示了微生物群和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WAT功能，决定脂肪量和胰岛素敏感性 在健康的生物体中，这些过程的失调导致肥胖和胰岛素的发展 耐药性（IR），影响全球数百万人。然而，微生物来源的信号和 肠道微生物群在健康和疾病中调节WAT功能的分子机制主要是 未知令人兴奋的是，我们发现微生物群诱导了一个高度保守的家族的表达。 在白色脂肪细胞中特异性地表达miRNAs（miR-181），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轴的失调对于肠道微生物群的发展至关重要。 肥胖和胰岛素抵抗。因此，我假设通过调节白色脂肪细胞中的miR-181水平， 微生物群代表了寄生微生物控制宿主的中心机制 代谢，其失调导致肥胖。微生物源性信号调节的研究 miR-181在白色脂肪细胞中的表达，我们发现循环微生物群衍生的代谢产物显著增加， 在肥胖小鼠和人类中，包括miR-181的潜在负调节因子吲哚的表达异常。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。我建议在以下目标中解决这一知识差距： 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 目的2将阐明miR-181控制白色脂肪功能的机制。这些研究 将揭示一个关键家族的microRNA表达的机制， 饮食和环境的变化，以及这些变化如何改变肥胖和IR的进展。 初步数据显示，吲哚和MIR-181水平在肥胖人类个体中失调，MIR-181 可能代表在肥胖症背景下调节WAT功能的潜在治疗靶点。