The C3a anaphylatoxin receptor is a key mediator of insulin resistance and functions by modulating adipose tissue macrophage infiltration and activation.
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.
Mamane
Yaël
Y
Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada. yael_mamane@merck.com
Chung Chan
Chi
C
Lavallee
Genevieve
G
Morin
Nicolas
N
Xu
Li-Jing
LJ
Huang
JingQi
J
Gordon
Robert
R
Thomas
Winston
W
Lamb
John
J
Schadt
Eric E
EE
Kennedy
Brian P
BP
Mancini
Joseph A
JA
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*
D004041:Dietary Fats; D007004:Hypoglycemic Agents; D007328:Insulin; D011951:Receptors, Complement; C085567:complement C3a receptor