Depot-specific Acetylation Profiles of Adipose Tissues-therapeutic Targets for Metabolically Unhealthy Obesity

Overview

Journal Diabetol Metab Syndr

Publisher Biomed Central

Date 2025 Jan 29

PMID 39881347

Authors

Haoyue Guo

Zhiyi Zhang

Juntao Yang

Jiangfeng Liu

Hongwei Lin

Ningbei Yin

Affiliations

Soon will be listed here.

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.

References

Andres M, Garcia-Gomis D, Ponte I, Suau P, Roque A . Histone H1 Post-Translational Modifications: Update and Future Perspectives. Int J Mol Sci. 2020; 21(16). PMC: 7460583. DOI: 10.3390/ijms21165941. View

Perez-Perez R, Ortega-Delgado F, Garcia-Santos E, Lopez J, Camafeita E, Ricart W . Differential proteomics of omental and subcutaneous adipose tissue reflects their unalike biochemical and metabolic properties. J Proteome Res. 2009; 8(4):1682-93. DOI: 10.1021/pr800942k. View

Dagpo T, Nolan C, Delghingaro-Augusto V . Exploring Therapeutic Targets to Reverse or Prevent the Transition from Metabolically Healthy to Unhealthy Obesity. Cells. 2020; 9(7). PMC: 7407965. DOI: 10.3390/cells9071596. View

Pasarica M, Gowronska-Kozak B, Burk D, Remedios I, Hymel D, Gimble J . Adipose tissue collagen VI in obesity. J Clin Endocrinol Metab. 2009; 94(12):5155-62. PMC: 2819828. DOI: 10.1210/jc.2009-0947. View

Liu Y, Yang H, Liu X, Gu H, Li Y, Sun C . Protein acetylation: a novel modus of obesity regulation. J Mol Med (Berl). 2021; 99(9):1221-1235. DOI: 10.1007/s00109-021-02082-2. View

Otsuka T, Kan H, Mason T, Nair L, Laurencin C . Overexpression of NDST1 Attenuates Fibrotic Response in Murine Adipose-Derived Stem Cells. Stem Cells Dev. 2022; 31(23-24):787-798. PMC: 9836701. DOI: 10.1089/scd.2022.0053. View

Fruman D, Chiu H, Hopkins B, Bagrodia S, Cantley L, Abraham R . The PI3K Pathway in Human Disease. Cell. 2017; 170(4):605-635. PMC: 5726441. DOI: 10.1016/j.cell.2017.07.029. View

Ibrahim M . Subcutaneous and visceral adipose tissue: structural and functional differences. Obes Rev. 2009; 11(1):11-8. DOI: 10.1111/j.1467-789X.2009.00623.x. View

Zhou Y, Peng J, Jiang S . Role of histone acetyltransferases and histone deacetylases in adipocyte differentiation and adipogenesis. Eur J Cell Biol. 2014; 93(4):170-7. DOI: 10.1016/j.ejcb.2014.03.001. View

10.

van den Born J, Pikas D, Pisa B, Eriksson I, Kjellen L, Berden J . Antibody-based assay for N-deacetylase activity of heparan sulfate/heparin N-deacetylase/N-sulfotransferase (NDST): novel characteristics of NDST-1 and -2. Glycobiology. 2003; 13(1):1-10. DOI: 10.1093/glycob/cwg011. View

11.

Khan T, Muise E, Iyengar P, Wang Z, Chandalia M, Abate N . Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol Cell Biol. 2008; 29(6):1575-91. PMC: 2648231. DOI: 10.1128/MCB.01300-08. View

12.

Murri M, Insenser M, Bernal-Lopez M, Perez-Martinez P, Escobar-Morreale H, Tinahones F . Proteomic analysis of visceral adipose tissue in pre-obese patients with type 2 diabetes. Mol Cell Endocrinol. 2013; 376(1-2):99-106. DOI: 10.1016/j.mce.2013.06.010. View

13.

Cypess A . Reassessing Human Adipose Tissue. N Engl J Med. 2022; 386(8):768-779. DOI: 10.1056/NEJMra2032804. View

14.

Hruska P, Kucera J, Kuruczova D, Buzga M, Pekar M, Holeczy P . Unraveling adipose tissue proteomic landscapes in severe obesity: insights into metabolic complications and potential biomarkers. Am J Physiol Endocrinol Metab. 2023; 325(5):E562-E580. PMC: 10864023. DOI: 10.1152/ajpendo.00153.2023. View

15.

Malodobra-Mazur M, Cierzniak A, Myszczyszyn A, Kaliszewski K, Dobosz T . Histone modifications influence the insulin-signaling genes and are related to insulin resistance in human adipocytes. Int J Biochem Cell Biol. 2021; 137:106031. DOI: 10.1016/j.biocel.2021.106031. View

16.

Nakajima I, Muroya S, Chikuni K . Extracellular matrix development during differentiation into adipocytes with a unique increase in type V and VI collagen. Biol Cell. 2002; 94(3):197-203. DOI: 10.1016/s0248-4900(02)01189-9. View

17.

Chen T, Ma J, Liu Y, Chen Z, Xiao N, Lu Y . iProX in 2021: connecting proteomics data sharing with big data. Nucleic Acids Res. 2021; 50(D1):D1522-D1527. PMC: 8728291. DOI: 10.1093/nar/gkab1081. View

18.

Mariman E, Wang P . Adipocyte extracellular matrix composition, dynamics and role in obesity. Cell Mol Life Sci. 2010; 67(8):1277-92. PMC: 2839497. DOI: 10.1007/s00018-010-0263-4. View

19.

Krupka S, Hoffmann A, Jasaszwili M, Dietrich A, Guiu-Jurado E, Kloting N . Consequences of COVID-19 on Adipose Tissue Signatures. Int J Mol Sci. 2024; 25(5). PMC: 10932458. DOI: 10.3390/ijms25052908. View

20.

Alfadda A, Masood A, Al-Naami M, Chaurand P, Benabdelkamel H . A Proteomics Based Approach Reveals Differential Regulation of Visceral Adipose Tissue Proteins between Metabolically Healthy and Unhealthy Obese Patients. Mol Cells. 2017; 40(9):685-695. PMC: 5638776. DOI: 10.14348/molcells.2017.0073. View