Low-grade inflammation and insulin resistance independently explain substantial parts of the association between body fat and serum C3: The CODAM study

ObjectiveTo investigate the role of low-grade inflammation and insulin resistance (HOMA2-IR) in adiposity-related increases in serum complement factor 3 (C3). Although C3 has been linked to type 2 diabetes and cardiovascular diseases, and C3 levels are closely related to body fat, the underlying mechanisms explaining this association are still unknown.MethodsAdiposity measures (including BMI, waist circumference (WC), sagittal diameter and several skinfolds), HOMA2-IR and markers of inflammation (hs-CRP, IL-6, SAA, haptoglobin, ceruloplasmin, sICAM-1) were determined in 532 individuals (62% men, mean age 59 ± 6.9 yrs) from the Cohort on Diabetes and Atherosclerosis Maastricht study. Markers of inflammation were standardized and compiled into an averaged inflammation score. Cross-sectional associations between adiposity measures and C3 and the mediating role of low-grade inflammation and/or HOMA2-IR herein were analysed with multiple linear regression models.ResultsAdiposity measurements were significantly associated with C3 levels, with the strongest (adjusted) associations found for WC (β = 0.383; 95%CI 0.302-0.464) and sagittal diameter (β = 0.412; 95%CI 0.333-0.490). Further adjustment for inflammation and HOMA2-IR attenuated these associations to β = 0.115 (95%CI 0.030-0.200) and β = 0.163 (95%CI 0.082-0.244) respectively. Multiple mediation analyses showed that inflammation [β = 0.090 (95%CI 0.060-0.126)] and HOMA2-IR [β = 0.179 (95%CI 0.128-0.236)] each explained, independently of one another, a significant portion of the association between WC and C3 (23% and 47%, respectively). Similar mediation by inflammation (19-27%) and HOMA2-IR (37-56%) was found for other adiposity measures.ConclusionSystemic low-grade inflammation and insulin resistance may represent two independent pathways by which body fat leads to elevated C3 levels.