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- Title
The C3a Anaphylatoxin Receptor Is a Key Mediator of Insulin Resistance and Functions by Modulating Adipose Tissue Macrophage Infiltration and Activation.
- Authors
Mamane, Yaël; Chi Chung Chan; Lavallee, Genevieve; Morin, Nicolas; Li-Jing Xu; JingQi Huang; Gordon, Robert; Thomas, Winston; Lamb, John; Schadt, Eric E.; Kennedy, Brian P.; Mancini, Joseph A.
- 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. RESEARCH DESIGN AND 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. Diabetes 58:2006-2017, 2009
- Subjects
IMMUNOLOGY of inflammation; CELL receptors; INSULIN resistance; MACROPHAGE activation; ADIPOSE tissues; DIABETES; FAT cells; CYTOKINES
- Publication
Diabetes, 2009, Vol 58, Issue 9, p2006
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db09-0323