title: Low-grade inflammation and insulin resistance independently explain substantial parts of the association between body fat and serum C3: the CODAM study.
abstract: OBJECTIVE
  To 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.
  
  
  METHODS
  Adiposity 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.
  
  
  RESULTS
  Adiposity 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.
  
  
  CONCLUSIONS
  Systemic low-grade inflammation and insulin resistance may represent two independent pathways by which body fat leads to elevated C3 levels.
authors: Department of Internal Medicine, Catharina Hospital, Eindhoven, The Netherlands. nickwlazlo@gmail.com
authors: Nick
authors: N
authors: Wlazlo
authors: Marleen M J
authors: MM
authors: van Greevenbroek
authors: Isabel
authors: I
authors: Ferreira
authors: Eugene J H M
authors: EJ
authors: Jansen
authors: Edith J M
authors: EJ
authors: Feskens
authors: Carla J H
authors: CJ
authors: van der Kallen
authors: Casper G
authors: CG
authors: Schalkwijk
authors: Bert
authors: B
authors: Bravenboer
authors: Coen D A
authors: CD
authors: Stehouwer
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000368:Aged; D015415:Biomarkers / Q000097:blood; D015992:Body Mass Index; D002318:Cardiovascular Diseases / Q000378:metabolism; D003176:Complement C3 / Q000378:metabolism*; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D055105:Waist Circumference
chemical_list: D015415:Biomarkers; D003176:Complement C3