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米色脂肪细胞分化过程中代谢与翻译控制之间的相互作用

Cross-talks between Metabolic and Translational Controls during Beige Adipocyte Differentiation.

作者信息

Youn Daehwa, Kim Boseon, Jeong Dahee, Lee Ju Yeon, Kim Seha, Sumberzul Dulguun, Ginting Rehna Paula, Lee Min-Woo, Song Ju Hwan, Park Ye Seul, Kim Yumin, Oh Chang-Myung, Lee Mihye, Cho Jun

机构信息

Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju, 61005, Republic of Korea.

Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan, 31151, Republic of Korea.

出版信息

Nat Commun. 2025 Apr 9;16(1):3373. doi: 10.1038/s41467-025-58665-x.

DOI:10.1038/s41467-025-58665-x
PMID:40204764
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11982337/
Abstract

Whether and how regulatory events at the translation stage shape the cellular and metabolic features of thermogenic adipocytes is hardly understood. In this study, we report two hitherto unidentified cross-talk pathways between metabolic and translational regulation in beige adipocytes. By analysing temporal profiles of translation activity and protein level changes during precursor-to-beige differentiation, we found selective translational down-regulation of OXPHOS component-coding mRNAs. The down-regulation restricted to Complexes I, III, IV, and V, is coordinated with enhanced translation of TCA cycle genes, engendering distinct stoichiometry of OXPHOS and TCA cycle components and altering the related metabolic activities in mitochondria of thermogenic adipocytes. Our high-resolution description of ribosome positioning unveiled potentiated ribosome pausing at glutamate codons. The increased stalling is attributable to remodelled glutamate metabolism that decreases glutamates for tRNA charging during pan-adipocyte differentiation. The ribosome pauses decrease protein synthesis and mRNA stability of glutamate codon-rich genes, such as actin cytoskeleton-associated genes.

摘要

翻译阶段的调控事件是否以及如何塑造产热脂肪细胞的细胞和代谢特征，目前还知之甚少。在本研究中，我们报告了米色脂肪细胞中代谢调控与翻译调控之间迄今尚未发现的两种相互作用途径。通过分析前体向米色脂肪细胞分化过程中翻译活性和蛋白质水平变化的时间概况，我们发现氧化磷酸化（OXPHOS）组分编码mRNA存在选择性翻译下调。这种下调仅限于复合体I、III、IV和V，与三羧酸循环（TCA）基因的翻译增强相协调，导致OXPHOS和TCA循环组分的化学计量比不同，并改变了产热脂肪细胞线粒体中的相关代谢活动。我们对核糖体定位的高分辨率描述揭示了核糖体在谷氨酸密码子处的停顿增强。停顿增加归因于重塑的谷氨酸代谢，这种代谢在泛脂肪细胞分化过程中减少了用于tRNA充电的谷氨酸。核糖体停顿降低了富含谷氨酸密码子的基因（如肌动蛋白细胞骨架相关基因）的蛋白质合成和mRNA稳定性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62b4/11982337/630429b9aafb/41467_2025_58665_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62b4/11982337/9533f74f5046/41467_2025_58665_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62b4/11982337/6127b25f15d6/41467_2025_58665_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62b4/11982337/d02f1832eb69/41467_2025_58665_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62b4/11982337/8cd460f679d5/41467_2025_58665_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62b4/11982337/630429b9aafb/41467_2025_58665_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62b4/11982337/9533f74f5046/41467_2025_58665_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62b4/11982337/1c1ef4ef892c/41467_2025_58665_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62b4/11982337/b7e4e0f72bbc/41467_2025_58665_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62b4/11982337/6127b25f15d6/41467_2025_58665_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62b4/11982337/d02f1832eb69/41467_2025_58665_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62b4/11982337/8cd460f679d5/41467_2025_58665_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62b4/11982337/630429b9aafb/41467_2025_58665_Fig7_HTML.jpg

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本文引用的文献

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Reduced adipocyte glutaminase activity promotes energy expenditure and metabolic health.脂肪细胞谷氨酰胺酶活性降低可促进能量消耗和代谢健康。
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SARS-CoV-2 infection engenders heterogeneous ribonucleoprotein interactions to impede translation elongation in the lungs.SARS-CoV-2 感染会产生异质的核糖核蛋白相互作用，从而阻碍肺部的翻译延伸。
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Activation of METTL3 Promotes White Adipose Tissue Beiging and Combats Obesity.
METTL3 的激活促进白色脂肪组织米色化并对抗肥胖。
Diabetes. 2023 Aug 1;72(8):1083-1094. doi: 10.2337/db22-0775.
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Integrated gene expression profiles reveal a transcriptomic network underlying the thermogenic response in adipose tissue.整合基因表达谱揭示了脂肪组织产热反应的转录组网络。
Sci Rep. 2023 May 4;13(1):7266. doi: 10.1038/s41598-023-33367-w.
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Profiling mouse brown and white adipocytes to identify metabolically relevant small ORFs and functional microproteins.对小鼠棕色和白色脂肪细胞进行分析，以鉴定与代谢相关的小开放阅读框和功能性微小蛋白质。
Cell Metab. 2023 Jan 3;35(1):166-183.e11. doi: 10.1016/j.cmet.2022.12.004.
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A critical period of translational control during brain development at codon resolution.在密码子分辨率上，大脑发育过程中的翻译控制的关键时期。
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GSEApy: a comprehensive package for performing gene set enrichment analysis in Python.GSEApy：一个用于在 Python 中进行基因集富集分析的综合软件包。
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The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest.2023 年的 STRING 数据库：针对任何感兴趣的测序基因组的蛋白质-蛋白质关联网络和功能富集分析。
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Chronic cAMP activation induces adipocyte browning through discordant biphasic remodeling of transcriptome and chromatin accessibility.慢性 cAMP 激活通过转录组和染色质可及性的不协调双相重塑诱导脂肪细胞棕色化。
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