title: The C3a anaphylatoxin receptor is a key mediator of insulin resistance and functions by modulating adipose tissue macrophage infiltration and activation.
abstract: OBJECTIVE
  Significant new data suggest that metabolic disorders such as diabetes, obesity, and atherosclerosis all posses an important inflammatory component. Infiltrating macrophages contribute to both tissue-specific and systemic inflammation, which promotes insulin resistance. The complement cascade is involved in the inflammatory cascade initiated by the innate and adaptive immune response. A mouse genomic F2 cross biology was performed and identified several causal genes linked to type 2 diabetes, including the complement pathway.
  
  
  METHODS
  We therefore sought to investigate the effect of a C3a receptor (C3aR) deletion on insulin resistance, obesity, and macrophage function utilizing both the normal-diet (ND) and a diet-induced obesity mouse model.
  
  
  RESULTS
  We demonstrate that high C3aR expression is found in white adipose tissue and increases upon high-fat diet (HFD) feeding. Both adipocytes and macrophages within the white adipose tissue express significant amounts of C3aR. C3aR(-/-) mice on HFD are transiently resistant to diet-induced obesity during an 8-week period. Metabolic profiling suggests that they are also protected from HFD-induced insulin resistance and liver steatosis. C3aR(-/-) mice had improved insulin sensitivity on both ND and HFD as seen by an insulin tolerance test and an oral glucose tolerance test. Adipose tissue analysis revealed a striking decrease in macrophage infiltration with a concomitant reduction in both tissue and plasma proinflammatory cytokine production. Furthermore, C3aR(-/-) macrophages polarized to the M1 phenotype showed a considerable decrease in proinflammatory mediators.
  
  
  CONCLUSIONS
  Overall, our results suggest that the C3aR in macrophages, and potentially adipocytes, plays an important role in adipose tissue homeostasis and insulin resistance.
authors: Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada. yael_mamane@merck.com
authors: Yaël
authors: Y
authors: Mamane
authors: Chi
authors: C
authors: Chung Chan
authors: Genevieve
authors: G
authors: Lavallee
authors: Nicolas
authors: N
authors: Morin
authors: Li-Jing
authors: LJ
authors: Xu
authors: JingQi
authors: J
authors: Huang
authors: Robert
authors: R
authors: Gordon
authors: Winston
authors: W
authors: Thomas
authors: John
authors: J
authors: Lamb
authors: Eric E
authors: EE
authors: Schadt
authors: Brian P
authors: BP
authors: Kennedy
authors: Joseph A
authors: JA
authors: Mancini
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement / Q000276:immunology; D004041:Dietary Fats / Q000494:pharmacology; D006706:Homeostasis / Q000276:immunology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009765:Obesity / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D011951:Receptors, Complement / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
chemical_list: D004041:Dietary Fats; D007004:Hypoglycemic Agents; D007328:Insulin; D011951:Receptors, Complement; C085567:complement C3a receptor