Complement Factor H Is Expressed in Adipose Tissue in Association With Insulin Resistance

10 páginas, 5 figuras, 5 tablas -- PAGS nros. 200-209OBJECTIVE Activation of the alternative pathway of the complement system, in which factor H (fH; complement fH [CFH]) is a key regulatory component, has been suggested as a link between obesity and metabolic disorders. Our objective was to study the associations between circulating and adipose tissue gene expressions of CFH and complement factor B (fB; CFB) with obesity and insulin resistance. RESEARCH DESIGN AND METHODS Circulating fH and fB were determined by enzyme-linked immunosorbent assay in 398 subjects. CFH and CFB gene expressions were evaluated in 76 adipose tissue samples, in isolated adipocytes, and in stromovascular cells (SVC) (n = 13). The effects of weight loss and rosiglitazone were investigated in independent cohorts. RESULTS Both circulating fH and fB were associated positively with BMI, waist circumference, triglycerides, and inflammatory parameters and negatively with insulin sensitivity and HDL cholesterol. For the first time, CFH gene expression was detected in human adipose tissue (significantly increased in subcutaneous compared with omental fat). CFH gene expression in omental fat was significantly associated with insulin resistance. In contrast, CFB gene expression was significantly increased in omental fat but also in association with fasting glucose and triglycerides. The SVC fraction was responsible for these differences, although isolated adipocytes also expressed fB and fH at low levels. Both weight loss and rosiglitazone led to significantly decreased circulating fB and fH levels. CONCLUSIONS Increased circulating fH and fB concentrations in subjects with altered glucose tolerance could reflect increased SVC-induced activation of the alternative pathway of complement in omental adipose tissue linked to insulin resistance and metabolic disturbances.Obesity is closely associated with a cluster of metabolic diseases, such as dyslipidemia, hypertension, insulin resistance, type 2 diabetes, and atherosclerosis (1). Adipose tissue is well known for its essential role as an energy storage depot and for secreting adipokines that influence sites as diverse as brain, liver, muscle, β-cells, gonads, lymphoid organs, and systemic vasculature (2,3). Expression analysis of macrophage and nonmacrophage cell populations isolated from adipose tissue demonstrates that adipose tissue macrophages are responsible for most of the proinflammatory cytokines (4). In recent years, it has become evident that alterations in the function of the innate immune system are intrinsically linked to metabolic pathways in humans (5–8). The complement system is a major component of the innate immune system, defending the host against pathogens, coordinating various events during inflammation, and bridging innate and adaptive immune responses. Complement deficiency and abnormalities in the regulation of the complement system lead to increased susceptibility to infection and chronic inflammatory diseases (9,10,11). Factor H (fH) is a relatively abundant plasma glycoprotein that is essential to maintain complement homeostasis and to restrict the action of complement to activating surfaces. fH acts as a cofactor for factor I–mediated cleavage of C3b (the active fragment of the third component of complement C3), accelerates the dissociation of the alternative pathway C3 convertases (a bimolecular enzymatic complex formed by active fragments of C3 and factor B [fB]), and competes with fB for binding to C3b. fH regulates complement both in fluid phase and on cellular surfaces (12–16). It has been suggested that activation of the alternative pathway of the complement system could be a link between obesity and metabolic disorders (17–21). Moreover, fB and factor D (fD, adipsin) are produced by adipose tissue where they likely influence formation of the alternative pathway component C3 convertase and the production of the anaphylatoxin C3a and its carboxypeptidase B-anaphylatoxic–inactivated derivative C3adesArg (acylation-stimulating protein [ASP]). Both ASP/C3adesArg and C3a interact with the receptor C5L2 to effectively stimulate triglyceride synthesis in cultured adipocytes (22). C3 knockout (C3KO) mice are obligatorily ASP deficient and present lipid abnormalities (23). In humans, ASP levels are increased in obesity, type 2 diabetes, and in individuals at risk of arterial disease, including those with hypertension, type 2 diabetes, dyslipidemia, and coronary artery disease, whereas exercise or weight loss decreases ASP levels (24,25). These data suggest a relationship between these conditions and activation of the alternative pathway of complement. There is also a correlation between increased C3 concentration and decreased insulin action (26,27). Levels of C3 and fB were higher in subjects with insulin resistance and other features of the metabolic syndrome (28,29).Given these interactions among activation of the alternative pathway of complement, metabolic disturbances, and a chronic low-level inflammatory state, we designed experiments to study the associations among circulating fH, fB, insulin resistance, lipid parameters, and inflammatory markers. We found that circulating fH and fB are strongly associated with obesity. For that reason, we also studied whether adipose tissue could constitute a source of circulating fH and fBThis work was partially supported by research grants from the Ministerio de Educación y Ciencia (SAF2008-02073). CIBEROBN Fisiopatología de la Obesidad y Nutrición is an initiative from the Instituto de Salud Carlos III from SpainPeer reviewe