Depot-specific acetylation profiles of adipose tissues-therapeutic targets for metabolically unhealthy obesity.

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.