Up-Regulation of the Complement System in Subcutaneous Adipocytes from Nonobese, Hypertriglyceridemic Subjects Is Associated with Adipocyte Insulin Resistance

• Published in: The journal of clinical endocrinology and metabolism Vol. 97; no. 12; pp. 4742 - 4752
• Main Authors: van Greevenbroek, M. M. J., Ghosh, S., van der Kallen, C. J. H., Brouwers, M. C. G. J., Schalkwijk, C. G., Stehouwer, C. D. A.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Oxford University Press 01.12.2012; Endocrine Society
• Subjects: Adipocytes; Adipocytes - immunology; Adipocytes - metabolism; Adipocytes - physiology; Adipose tissue; Adult; Biological and medical sciences; Body fat; Case-Control Studies; Complement system; Complement System Proteins - genetics; Complement System Proteins - metabolism; Complement System Proteins - physiology; Diabetes mellitus (non-insulin dependent); Disease resistance; Dyslipidemia; Endocrine Research; Endocrinopathies; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Profiling; Gene set enrichment analysis; Humans; Hyperlipidemia; Hypertriglyceridemia; Hypertriglyceridemia - complications; Hypertriglyceridemia - genetics; Hypertriglyceridemia - immunology; Hypertriglyceridemia - metabolism; Insulin resistance; Insulin Resistance - immunology; Insulin Resistance - physiology; Macrophages; Male; Medical sciences; Metabolic disorders; Metabolic syndrome; Microarray Analysis; Middle Aged; Models, Biological; Molecular modelling; Obesity; Obesity - metabolism; Signal Transduction - genetics; Subcutaneous Fat - immunology; Subcutaneous Fat - metabolism; Subcutaneous Fat - physiology; Transcriptomes; Triglycerides; Up-regulation; Up-Regulation - genetics; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Endocrinopathy; Human; Adipocyte; Obesity; Pancreatic hormone; Nutrition; Subcutaneous; Nutrition disorder; Metabolic diseases; Complement; Insulin; Target tissue resistance; Regulation(control); Association; Insulin resistance; Endocrinology; Nutritional status
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2012-2539

Dysfunctional adipose tissue plays an important role in the etiology of the metabolic syndrome, type 2 diabetes, and dyslipidemia. However, the molecular mechanisms underlying adipocyte dysfunction are incompletely understood.Aim:The aim of the study was to identify differentially regulated pathways in sc adipocytes of dyslipidemic subjects.Methods:Whole-genome expression profiling was conducted on sc adipocytes from a discovery group of nine marginally overweight subjects with familial combined hyperlipidemia (FCHL) and nine controls of comparable body sizes as well as two independent confirmation groups. In this study, FCHL served as a model of familial insulin resistance and dyslipidemia, in the absence of frank obesity.Results:Functional analyses and gene set enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes or a custom pathway database identified the complement system and complement regulators as one of the top up-regulated pathways in FCHL [false discovery rate (FDR) < 1E-30]. Higher adipocyte complement expression in FCHL was confirmed in the appropriate confirmation group. Higher complement gene expression was associated with lower adipocyte insulin receptor substrate-1 expression as marker of adipocyte insulin resistance, independent of age, sex, or disease status, and this association was corroborated in the two confirmation groups. Additionally, complement gene expression was associated with triglycerides in the discovery set and with triglycerides and/or waist circumference in the confirmation groups. Complement pathway up-regulation did not appear to be driven by hypertriglyceridemia because a 40% pharmacological reduction in triglycerides did not affect complement expression.Conclusions:These findings point to an up-regulation of a complement-related transcriptome in sc adipocytes under metabolically stressed conditions, even in the absence of overt obesity. Such up-regulation may subsequently influence downstream processes, including macrophage infiltration into adipose tissue and adipocyte insulin resistance.