Role of adipose mRNA modifications in metabolic disease

脂肪 mRNA 修饰在代谢疾病中的作用

基本信息

批准号：
10453266
负责人：
LIANGYOU RUI
金额：
$ 47.42万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10453266
关键词：
Adipocytes Adipose tissue Adrenergic Agents Binding Brown Fat Catalytic Domain Cells Complex Development Diabetes Mellitus Embryo Exercise Fatty Liver Fatty acid glycerol esters Functional disorder Gene Expression Profiling Gene Proteins Genetic Genetic Transcription Glycerol Growth High Fat Diet Hormones Impairment Insulin Insulin Resistance Knockout Mice Life Life Cycle Stages Link Lipase Lipolysis Liver Mediating Messenger RNA Metabolic Metabolic Diseases Metabolism Methylation Methyltransferase Modeling Modification Monoacylglycerol Lipases Mus Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Nuclear Export Obesity Obesity associated disease Outcome Pathway interactions Post-Translational Protein Processing Process Protein Biosynthesis Protein Family Proteins RNA RNA Binding RNA Splicing Reaction Reader Research Resistance Role Signal Transduction Starvation Sympathetic Nervous System System Testing Tissue Expansion Tissues Transcript Translations Triglycerides adipokines adiponectin base cell behavior diet-induced obesity driving force epitranscriptomics fatty liver disease gain of function glucose metabolism improved insulin signaling mRNA Decay mRNA Precursor mutant neonatal death new therapeutic target non-alcoholic fatty liver disease novel obesity treatment obesogenic overexpression trafficking

项目摘要

Abstract Excessive white adipose tissue (WAT) is a hallmark of obesity and a causal factor for obesity-associated disease. Adipose secretion of adipokines is also dysregulated in obesity, further impairing WAT crosstalk with other tissues. Extensive research has been focused on gene transcriptions and protein posttranslational modifications and substantially advanced our understanding of WAT growth and functions. Importantly, mRNA connects the genetic control to translation of proteins responsible for cellular activities and functions. Like protein modifications, RNA is also extensively and reversibly modified in its life cycle. N6-methyladenosine (m6A) is the predominant RNA modification and catalyzed by a Mettl3/Mettl14 methyltransferase complex (m6A writer). YTHD family proteins (m6A readers) bind to m6A-methylated RNAs and regulate pre-mRNA splicing, nuclear export, decay, and/or translation of target transcripts. Global deletion of Mettl3, Mettl14, or Ythdc1 results in embryonic/neonatal death in mice, demonstrating the essential role of the m6A system in development and survival. However, m6A-based epitranscriptomic reprogramming has not been explored in WAT, and there is a gap in our understanding of RNA modifications and metabolism in obesity. In the preliminary study, we generated and characterized adipocyte-specific Mettl14 (Mettl14Δfat) and Ythdc1 (Ythdc1Δfat) knockout mice. Remarkably, both Mettl14Δfat and Ythdc1Δfat mice were resistant to diet-induced obesity, type 2 diabetes, and liver steatosis. Gene expression analysis suggested that Mettl14 and Ythdc1 target the lipolysis machinery, β adrenergic signaling (stimulating lipolysis), insulin signaling (suppressing lipolysis), and adipokine secretion. Consistently, WAT lipolysis was substantially elevated in Mettl14Δfat mice and Ythdc1Δfat mice, particularly under β adrenergic-stimulated conditions, contributing to WAT reduction. Adipose adiponectin expression was elevated in Mettl14Δfat and Ythdc1Δfat mice, contributing to improved insulin resistance, glucose metabolism, and liver steatosis. We hypothesize that Mettl14 induces m6A methylation selectively in mRNAs governing the lipolysis machinery, β adrenergic signaling, insulin signaling, and adipokine expression. Ythdc1 directly binds to and regulates the metabolism (pre-mRNA splicing, nuclear export, decay) of these m6A-modificed mRNAs, thereby guiding lipolysis, WAT growth, and adipokine- mediated adipose crosstalk with other tissues. We will test this hypothesis in 3 Aims. Aim 1 is to determine whether Mettl14 inhibits lipolysis and increases WAT expansion through RNA m6A methylation. Aim 2 is to determine whether Ythdc1 suppresses lipolysis and promotes WAT expansion by regulating metabolism of its bound RNAs. Aim 3 is to delineate whether Mettl14/Ythdc1 axis coordinates adipose crosstalk with other tissues via adipokines. The outcomes are expected to establish a new adipose Mettl14/m6A/Ythdc1-based epitranscriptomic reprogramming paradigm in obesity and metabolic disease.

抽象的过多的白色脂肪组织（WAT）是肥胖的标志，也是肥胖相关疾病的致病因素肥胖症中脂肪因子的脂肪分泌也失调，进一步损害了 WAT 与脂肪因子的相互作用。其他组织的广泛研究集中在基因转录和蛋白质翻译后。修改并极大地增进了我们对 WAT 生长和功能的理解。将遗传控制与负责细胞活动和功能的蛋白质的翻译联系起来。蛋白质修饰，RNA 在其生命周期中也常见且可逆地修饰。 (m6A) 是主要的 RNA 修饰，由 Mettl3/Mettl14 甲基转移酶复合物催化（m6A writer）。YTHD 家族蛋白（m6A reader）与 m6A 甲基化 RNA 结合并调节前 mRNA。目标转录本的剪接、核输出、衰变和/或翻译。Mettl3、Mettl14 或的全局删除。 Ythdc1 导致小鼠胚胎/新生儿死亡，证明 m6A 系统在小鼠胚胎/新生儿死亡中的重要作用然而，基于 m6A 的表观转录组重编程尚未得到探索。 WAT，我们对肥胖中 RNA 修饰和代谢的理解存在差距。初步研究，我们生成并表征了脂肪细胞特异性 Mettl14 (Mettl14Δfat) 和 Ythdc1 (Ythdc1Δfat) 敲除小鼠值得注意的是，Mettl14Δfat 和 Ythdc1Δfat 小鼠对饮食诱导具有抵抗力。肥胖、2 型糖尿病和肝脂肪变性基因表达分析表明 Mettl14 和 Ythdc1。针对脂肪分解机制、β 肾上腺素信号传导（刺激脂肪分解）、胰岛素信号传导（抑制一致地，Mettl14Δfat 小鼠的 WAT 脂肪分解显着升高和 Ythdc1Δfat 小鼠，特别是在 β 肾上腺素刺激的条件下，有助于减少 WAT。 Mettl14Δfat 和 Ythdc1Δfat 小鼠的脂肪脂联素表达升高，有助于改善我们研究了 Mettl14 诱导 m6A 的机制。 mRNA 选择性甲基化，控制脂解机制、β 肾上腺素信号传导、胰岛素信号传导、 Ythdc1 直接结合并调节代谢（前 mRNA 剪接、核）。这些 m6A 修饰的 mRNA 的输出（衰减），从而引导脂肪分解、WAT 生长和脂肪因子我们将在 3 个目标中测试这一假设，目标 1 是确定。 Mettl14 是否通过 RNA m6A 甲基化抑制脂肪分解并增加 WAT 扩增目的 2。确定Ythdc1是否通过调节其代谢来抑制脂肪分解并促进WAT扩张目标 3 是描绘 Mettl14/Ythdc1 轴是否与其他轴协调脂肪串扰。预计结果将建立基于 Mettl14/m6A/Ythdc1 的新脂肪。肥胖和代谢疾病的表观转录组重编程范例。