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 (AT) and isolated adipocytes. We used a special study design of genetically matched controls of lean and heavy groups, rare monozygotic twin pairs discordant for body mass index (BMI) [n = 26, within-pair difference (Δ) in body mass index, BMI >3 kg/m2] with as much as 18 kg mean Δweight. Additionally, 14 BMI-concordant (BMI <3 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 AT and adipocytes. In both AT 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 upregulated 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 upregulation in AT 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 AT. The results suggest that complement is likely involved in orchestrating clearance of apoptotic debris and inflammation in the AT.
Highlights
The complement system has a pivotal role in obesity
The expression of a broad spectrum of complement genes was analyzed in adipose tissue (AT) and isolated adipocytes in young adult MZ twins, most of whom were free from obesity-related co-morbidities
Within body mass index (BMI)-concordant pairs, the co-twins’ gene-expression profiles were similar suggesting that the overall expression levels of complement genes are largely familial, and probably controlled by genetic or shared environmental factors
Summary
The complement system has a pivotal role in obesity. While it is an important innate immune defense system against microbes and part of the body’s clearance system, it can regulate the level of inflammation in the adipose tissue (AT) and have metabolic effects. Complement is a key innate sensor between viable and non-viable cells. It recognizes and opsonizes both foreign targets, like microbes, and exposed or damaged endogenous structures, and promotes their clearance by macrophages. The complement system comprises up to 50 proteins that are synthesized by several tissues including the liver and various cell types of AT (adipocytes, macrophages, and vascular cells) [1,2,3]. Many links exist between the complement system and AT, but overall, the meaning and relevance of these links are mostly unclear
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