Abstract
Adipose tissue is increasingly recognized as an endocrine organ playing important pathophysiological roles in metabolic abnormalities, such as obesity, cardiovascular disease, and type 2 diabetes mellitus (T2DM). In particular, visceral adipose tissue (VAT), as opposed to subcutaneous adipose tissue, is closely linked to the pathogenesis of insulin resistance and T2DM. Despite the importance of VAT, its molecular signatures related to the pathogenesis of T2DM have not been systematically explored. Here, we present comprehensive proteomic analysis of VATs in drug-naïve early T2DM patients and subjects with normal glucose tolerance. A total of 4,707 proteins were identified in LC-MS/MS experiments. Among them, 444 increased in abundance in T2DM and 328 decreased. They are involved in T2DM-related processes including inflammatory responses, peroxisome proliferator-activated receptor signaling, oxidative phosphorylation, fatty acid oxidation, and glucose metabolism. Of these proteins, we selected 11 VAT proteins that can represent alteration in early T2DM patients. Among them, up-regulation of FABP4, C1QA, S100A8, and SORBS1 and down-regulation of ACADL and PLIN4 were confirmed in VAT samples of independent early T2DM patients using Western blot. In summary, our profiling provided a comprehensive basis for understanding the link of a protein profile of VAT to early pathogenesis of T2DM.
Highlights
From the ‡Department of Chemistry, Research Institute for Natural Sciences, Korea University, Seoul, 136-701, Republic of Korea; §Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, DGIST, Daegu, 711-873, Republic of Korea; ʈSchool of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang, Kyungbuk, 790-784, Republic of Korea; **Seoul National University Bundang Hospital, Internal Medicine, Endocrinology and Metabolism, Seoul National University College of Medicine, Gumidong 300, Bundang, Seongnam, Gyeonggi-do, 463-707, Republic of Korea; ‡‡Internal Medicine, Endocrinology and Metabolism, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
To select a proteome profile that could represent the collective pathophysiology of visceral adipose tissue (VAT) in type 2 diabetes mellitus (T2DM), we focused on the differentially expressed proteins (DEPs) that were involved in these processes
Visceral fat accumulation is a key feature of chronic metabolic diseases related to lipotoxicity, such as diabetes, metabolic syndrome, obesity, and cardiovascular disease
Summary
Patient Enrollment and Sample Collection—We collected two independent sets of whole VATs from T2DM and healthy subjects who underwent elective abdominal surgery in Seoul National University Bundang Hospital (SNUBH). Construction and Utilization of VAT Master Accurate Mass and Time Tag Database—Information about UMCs with peptide I.D.s from 59 LC-MS/MS data (triplicate LC-MS/MS experiments of 11 samples and 26 LC-MS/MS experiments of OFFGEL fractionations) was compiled into the master accurate mass and time tag (AMT) database (DB) (Oracle Database 10g Enterprise Edition, Release 10.2.0.1.0; Fig. 1A). It is an assembly of AMTs, which are unique peptide sequences whose monoisotopic mass and NET are experimentally determined. The list of primary antibodies for the selected secretory proteins is summarized in supplemental Table S3
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