ObjectiveComplement C3 and other components of the alternative pathway are higher in individuals with obesity. Moreover, C3 has been identified as a risk factor for cardiovascular disease. This study investigated whether, and how, a weight‐loss intervention reduced plasma C3, activated C3 (C3a), and factor D and explored potential biological effects of such a reduction.MethodsThe study measured plasma C3, C3a, and factor D by ELISA and measured visceral adipose tissue, subcutaneous adipose tissue, and intrahepatic lipid by magnetic resonance imaging in lean men (n = 25) and men with abdominal obesity (n = 52). The men with obesity were randomized to habitual diet or an 8‐week dietary weight‐loss intervention.ResultsThe intervention significantly reduced C3 (−0.15 g/L [95% CI: −0.23 to −0.07]), but not C3a or factor D. The C3 reduction was mainly explained by reduction in visceral adipose tissue but not subcutaneous adipose tissue or intrahepatic lipid. This reduction in C3 explained a part of the weight‐loss‐induced improvement of markers of endothelial dysfunction, particularly the reduction in soluble endothelial selectin and soluble intercellular adhesion molecule.ConclusionsDiet‐induced weight loss in men with abdominal obesity could be a way to lower plasma C3 and thereby improve endothelial dysfunction. C3 reduction may be part of the mechanism via which diet‐induced weight loss could ameliorate the risk of cardiovascular disease in men with abdominal obesity.

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Background: Arterial stiffness predicts cardiovascular outcomes. The complement system, particularly the alternative complement pathway, has been implicated in cardiovascular diseases. We herein investigated the associations of factor D, the rate-limiting protease of the alternative pathway, and C3, the central complement component, with arterial stiffness. Methods:In 3019 population-based participants (51.9% men, 60.1 AE 8.2 years, 27.7% type 2 diabetes [T2D], oversampled]), we measured carotid-femoral pulse wave velocity (cfPWV), carotid distensibility coefficient (DC) and carotid Young's elastic modulus (YEM), and plasma concentrations of factors D and C3. We conducted multiple linear regression to investigate the association of factors D and C3 (main independent variables, standardized) with cfPWV (primary outcome) and DC and YEM (secondary outcomes), adjusted for potential confounders.Results: Per SD higher factors D and C3, cfPWV was 0.41 m/s [95% confidence interval: 0.34; 0.49] and 0.33 m/ s [0.25; 0.41] greater, respectively. These associations were substantially attenuated when adjusted for age, sex, education, mean arterial pressure, and heart rate (0.08 m/s [0.02; 0.15] and 0.11 m/s [0.05; 0.18], respectively), and were not significant when additionally adjusted for T2D, waist circumference and additional cardiovascular risk factors (0.06 m/s [À0.01; 0.13] and 0.01 m/s [À0.06; 0.09], respectively). Results were comparable for carotid YEM and DC. In persons with T2D, but not in those without, the association between factors D and cfPWV was significant in the fully adjusted model (0.14 m/s, [0.01; 0.27], P ¼ 0.038, P interaction < 0.05). Conclusion:The strong association of plasma factors D and C3 with arterial stiffness in this population-based cohort was not independent of T2D and other metabolic risk factors. Our data suggest that a possible causal pathway starting from alternative complement activation may via hypertension and T2D contribute to greater arterial stiffness.