{"title":"Depot-specific acetylation profiles of adipose tissues-therapeutic targets for metabolically unhealthy obesity.","authors":"Haoyue Guo, Zhiyi Zhang, Juntao Yang, Jiangfeng Liu, Hongwei Lin, Ningbei Yin","doi":"10.1186/s13098-025-01599-7","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Adipose tissue plays a critical role in the development of metabolically unhealthy obesity (MUO), with distinct adipose depots demonstrating functional differences. This study aimed to investigate the unique characteristics of subcutaneous (SA) and visceral adipose tissue (VA) in MUO.</p><p><strong>Methods: </strong>Paired omental VA and abdominal SA samples were obtained from four male patients with MUO and subjected to Four-Dimensional Data Independent Acquisition (4D-DIA) proteomic and lysine acetylation (Kac) analyses. Differentially expressed proteins and differentially modified Kac sites were identified, quantified, integrated, and subjected to functional analyses. Overlap analysis was performed between our datasets and previously published proteomic datasets in obesity populations. Additionally, differentially modified Kac sites on histones and their related enzymes were identified.</p><p><strong>Results: </strong>A total of 281 differentially expressed proteins and 147 differentially modified Kac sites were identified among 6,201 quantifiable proteins and 1,826 quantifiable Kac sites. Upregulated proteins and acetylated proteins in SA were predominantly enriched in extracellular matrix (ECM) remodeling pathways, while those in VA were enriched in energy metabolism and disease-related pathways. Differential ECM remodeling adaptability between SA and VA was primarily mediated by fibranexin and integrin, with COL6A1, COL6A3, and ITGA5 identified as differentially acetylated proteins overlapping between our dataset and previous studies. Potential unique proteins in MUO were enriched in inflammatory processes and closely associated with acetylated modifications. Specific differentially acetylated sites on histones, including H1.2K63, H1XK90, and H3.7K80, showed increased acetylation in VA, with N-deacetylase/N-sulfotransferase 1 (NDST1) identified as the associated enzyme.</p><p><strong>Conclusions: </strong>This study provided a comprehensive dataset on the proteomic and acetylomic profiles of SA and VA, laying a foundation for investigating the pathogenesis and potential therapeutic approaches for MUO. SA was characterized by pronounced ECM remodeling regulation, while VA exhibited poorer adaptability and more prominent metabolic functional changes. These differential processes were influenced not only by protein expression levels but, more importantly, by acetylated modifications. The regulation of acetylated modifications in white adipose tissue (WAT), particularly for the differential Kac sites enriched in ECM remodeling and inflammation-related pathways, may serve as an effective intervention strategy for MUO, with NDST1 emerging as a promising therapeutic target.</p><p><strong>Trial registration: </strong>Not applicable since this study did not involve clinical intervention.</p>","PeriodicalId":11106,"journal":{"name":"Diabetology & Metabolic Syndrome","volume":"17 1","pages":"36"},"PeriodicalIF":3.4000,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11776295/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Diabetology & Metabolic Syndrome","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13098-025-01599-7","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Adipose tissue plays a critical role in the development of metabolically unhealthy obesity (MUO), with distinct adipose depots demonstrating functional differences. This study aimed to investigate the unique characteristics of subcutaneous (SA) and visceral adipose tissue (VA) in MUO.
Methods: Paired omental VA and abdominal SA samples were obtained from four male patients with MUO and subjected to Four-Dimensional Data Independent Acquisition (4D-DIA) proteomic and lysine acetylation (Kac) analyses. Differentially expressed proteins and differentially modified Kac sites were identified, quantified, integrated, and subjected to functional analyses. Overlap analysis was performed between our datasets and previously published proteomic datasets in obesity populations. Additionally, differentially modified Kac sites on histones and their related enzymes were identified.
Results: A total of 281 differentially expressed proteins and 147 differentially modified Kac sites were identified among 6,201 quantifiable proteins and 1,826 quantifiable Kac sites. Upregulated proteins and acetylated proteins in SA were predominantly enriched in extracellular matrix (ECM) remodeling pathways, while those in VA were enriched in energy metabolism and disease-related pathways. Differential ECM remodeling adaptability between SA and VA was primarily mediated by fibranexin and integrin, with COL6A1, COL6A3, and ITGA5 identified as differentially acetylated proteins overlapping between our dataset and previous studies. Potential unique proteins in MUO were enriched in inflammatory processes and closely associated with acetylated modifications. Specific differentially acetylated sites on histones, including H1.2K63, H1XK90, and H3.7K80, showed increased acetylation in VA, with N-deacetylase/N-sulfotransferase 1 (NDST1) identified as the associated enzyme.
Conclusions: This study provided a comprehensive dataset on the proteomic and acetylomic profiles of SA and VA, laying a foundation for investigating the pathogenesis and potential therapeutic approaches for MUO. SA was characterized by pronounced ECM remodeling regulation, while VA exhibited poorer adaptability and more prominent metabolic functional changes. These differential processes were influenced not only by protein expression levels but, more importantly, by acetylated modifications. The regulation of acetylated modifications in white adipose tissue (WAT), particularly for the differential Kac sites enriched in ECM remodeling and inflammation-related pathways, may serve as an effective intervention strategy for MUO, with NDST1 emerging as a promising therapeutic target.
Trial registration: Not applicable since this study did not involve clinical intervention.
背景：脂肪组织在代谢性不健康肥胖（MUO）的发展中起着关键作用，不同的脂肪库显示出功能差异。本研究旨在探讨MUO患者皮下（SA）和内脏脂肪组织（VA）的独特特征。方法：对4例男性MUO患者的网膜VA和腹腔SA进行配对，并进行四维数据独立采集（4D-DIA）蛋白质组学和赖氨酸乙酰化（Kac）分析。差异表达蛋白和差异修饰的Kac位点被鉴定、量化、整合并进行功能分析。我们的数据集与先前发表的肥胖人群蛋白质组学数据集之间进行了重叠分析。此外，还鉴定了组蛋白及其相关酶上的差异修饰Kac位点。结果：在6201个可量化蛋白和1826个可量化Kac位点中，共鉴定出281个差异表达蛋白和147个差异修饰Kac位点。SA中的上调蛋白和乙酰化蛋白主要富集于细胞外基质（ECM）重塑通路，而VA中的上调蛋白主要富集于能量代谢和疾病相关通路。SA和VA之间的ECM重塑适应性差异主要是由纤联蛋白和整合素介导的，COL6A1、COL6A3和ITGA5在我们的数据集和之前的研究中被鉴定为不同的乙酰化蛋白重叠。MUO中潜在的独特蛋白在炎症过程中富集，并与乙酰化修饰密切相关。组蛋白上的特异性差异乙酰化位点，包括H1.2K63、H1XK90和H3.7K80，在VA中显示乙酰化增加，n -去乙酰化酶/ n -硫转移酶1 （NDST1）被鉴定为相关酶。结论：本研究提供了SA和VA的蛋白质组学和乙酰组学的完整数据集，为探讨MUO的发病机制和潜在的治疗方法奠定了基础。SA具有明显的ECM重塑调节，而VA适应性较差，代谢功能变化更突出。这些差异过程不仅受到蛋白表达水平的影响，更重要的是受到乙酰化修饰的影响。白色脂肪组织（WAT）中乙酰化修饰的调节，特别是对ECM重塑和炎症相关途径中富集的差异Kac位点的调节，可能是MUO的有效干预策略，NDST1成为一个有希望的治疗靶点。试验注册：由于本研究不涉及临床干预，因此不适用。
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Diabetology & Metabolic Syndrome publishes articles on all aspects of the pathophysiology of diabetes and metabolic syndrome.
By publishing original material exploring any area of laboratory, animal or clinical research into diabetes and metabolic syndrome, the journal offers a high-visibility forum for new insights and discussions into the issues of importance to the relevant community.
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