Upregulation of Early and Downregulation of Terminal Pathway Complement Genes in Subcutaneous Adipose Tissue and Adipocytes in Acquired Obesity

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.

TMT Based Proteomic Analysis of Human Follicular Fluid From Overweight/Obese and Normal-Weight Patients With Polycystic Ovary Syndrome

“…Elevated transcripts encoding cytokines, chemokines as well as immune cell markers in granulosa cells, unbalanced ovarian recruitment of macrophages, decreased dendritic cells, altered T lymphocyte subsets, and leukocyte populations have been reported in PCOS patients and animal models, implying immunological and inflammatory imbalance of the disease (37)(38)(39). Obesity increased the expression of early complement pathway components in subcutaneous adipose tissue (40). Obesity has been reported to upregulate inflammatory adipokines and to induce IR, androgen production, and adipogenesis (41,42).…”

Intracellular complement activation—An alarm raising mechanism?

“…C3adesArg has been suggested to increase triacylglycerol production in the adipocytes by increasing the uptake of free fatty acids [149]. Our recent study compared genetically identical monozygotic twins, where the siblings had an average weight difference of 18 kg [13]. In obese individuals the genes for components of both the classical and the alternative pathway were upregulated in fat tissue and in the isolated adipocytes, while the terminal pathway genes were downregulated.…”

“…The negative regulator MAp44 is primarily expressed in the heart [12]. Adipocytes and fat tissue produce most complement components and, interestingly, the synthesis of components of all the early pathways is increased in obese individuals, while the production of terminal pathway components is decreased [13]. T and B lymphocytes have been shown to produce C3, C5 and an array of complement receptors.…”

Immune activation by nucleic acids: A role in pregnancy complications

“…Obesity itself is associated with a chronic state of mild inflammation as a result of increased TNF levels in adipose tissue 76 as well as complementary gene upregulation. 77 Therefore, during gestation, the placenta is also affected by inflammation due to placental nutrient transporter expression. The role of cell-free nucleic acids has not been deeply examined in this area but certainly it is an important factor as inflammation in general is associated with cfDNA.…”

“…Obese women are predisposed to become diabetic during gestation. Obesity itself is associated with a chronic state of mild inflammation as a result of increased TNF levels in adipose tissue as well as complementary gene upregulation . Therefore, during gestation, the placenta is also affected by inflammation due to placental nutrient transporter expression.…”