1. Upregulation of Early and Downregulation of Terminal Pathway Complement Genes in Subcutaneous Adipose Tissue and Adipocytes in Acquired Obesity
- Author
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Sanna Kaye, A. Inkeri Lokki, Anna Hanttu, Eija Nissilä, Sini Heinonen, Antti Hakkarainen, Jesper Lundbom, Nina Lundbom, Lilli Saarinen, Olli Tynninen, Maheswary Muniandy, Aila Rissanen, Jaakko Kaprio, Seppo Meri, Kirsi H. Pietiläinen, Diabetes and Obesity Research Program, Research Programs Unit, Immunobiology Research Program, Department of Medical and Clinical Genetics, Department of Bacteriology and Immunology, Medicum, Clinicum, Helsinki University Hospital Area, Immunomics, HUS Medical Imaging Center, Department of Diagnostics and Therapeutics, University of Helsinki, Genome-Scale Biology (GSB) Research Program, HUSLAB, Department of Pathology, Department of Public Health, Department of Psychiatry, HUS Psychiatry, Institute for Molecular Medicine Finland, Seppo Meri / Principal Investigator, HUS Abdominal Center, Kirsi Hannele Pietiläinen / Principal Investigator, Endokrinologian yksikkö, Epigenetics of Complex Diseases and Traits, and Genetic Epidemiology
- Subjects
0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,EXPRESSION ,medicine.medical_specialty ,obesity ,Adipose tissue macrophages ,Immunology ,Adipose tissue ,Adipokine ,030209 endocrinology & metabolism ,Inflammation ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,monozygotic twins ,INFLAMMATION ,Internal medicine ,medicine ,Immunology and Allergy ,twin study ,C3 ,complement system ,Original Research ,2. Zero hunger ,INSULIN-RESISTANCE ,biology ,RECEPTOR ,medicine.disease ,Complement system ,Insulin receptor ,030104 developmental biology ,Endocrinology ,3121 General medicine, internal medicine and other clinical medicine ,biology.protein ,Alternative complement pathway ,RISK-FACTORS ,gene expression ,3111 Biomedicine ,medicine.symptom ,lcsh:RC581-607 ,MACROPHAGE POLARIZATION ,SYSTEM ,C1Q - Abstract
Inflammation is an important mediator of obesity-related complications such as the metabolic syndrome but its causes and mechanisms are unknown. As the complement system is a key mediator of inflammation, we studied whether it is activated in acquired obesity in subcutaneous adipose tissue and isolated adipocytes. We used a special study design of genetically matched controls of lean and heavy groups, rare monozygotic twin pairs discordant for BMI (n=26, within-pair difference (in body mass index, kg/m2with as much as 18 kg mean weight. Additionally, 14 BMI-concordant (kg/m2) served as a reference group. The detailed measurements included body composition (DEXA), fat distribution (MRI), glucose, insulin, adipokines, C3a and SC5b-9 levels and the expression of complement and insulin signaling pathway-related genes in adipose tissue and adipocytes. In both adipose tissue and isolated adipocytes, the classical and alternative pathway genes were upregulated, and the terminal pathway genes downregulated in the heavier co-twins of the BMI-discordant pairs. The up-regulated genes included C1q, C1s, C2, ficolin-1, factor H, receptors for C3a and C5a (C5aR1) and the iC3b receptor (CR3). While the terminal pathway components C5 and C6 were downregulated, its inhibitor clusterin was upregulated. Complement gene up-regulation in adipose tissue and adipocytes correlated positively with adiposity and hyperinsulinemia, and negatively with the expression of insulin signaling related genes. Plasma C3a, but not SC5b-9, levels were elevated in the heavier co-twins. There were no differences between the co-twins in BMI-concordant pairs. Obesity is associated with increased expression of the early, but not late, complement pathway components and of key receptors. The twins with acquired obesity have therefore an inflated inflammatory activity in the adipose tissue. The results suggest that complement is likely involved in orchestrating clearance of apoptotic debris and inflammation in the adipose tissue.
- Published
- 2017