The C3a Anaphylatoxin Receptor Is a Key Mediator of Insulin Resistance and Functions by Modulating Adipose Tissue Macrophage Infiltration and Activation

Abstract

OBJECTIVESignificant 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 METHODSWe 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.RESULTSWe 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.CONCLUSIONSOverall, our results suggest that the C3aR in macrophages, and potentially adipocytes, plays an important role in adipose tissue homeostasis and insulin resistance.

Complement Factor 3 Is Associated With Insulin Resistance and With Incident Type 2 Diabetes Over a 7-Year Follow-up Period: The CODAM Study

“…The anaphylatoxins C3a and C5a, by acting on their respective receptors (48-50), attract and activate leukocytes and increase the synthesis of proinflammatory cytokines Table 3-Analyses of changes in plasma C3 levels with changes IR and glucose tolerance over a 7-year period (n = 394 at baseline and follow-up) by several cell types, including leukocytes and Kupffer cells (8)(9)(10)(11)(12)50,51). Indeed, blocking of anaphylatoxic pathways in C3aR-or C5aR-knockout mice fed a high-fat diet led to decreased adipocyte size, less liver steatosis, less adipose tissue infiltration by macrophages, a reduction in tissue and plasma proinflammatory cytokines, and less systemic IR (48,51), and inhibition of C3a and C5a signaling by blocking their receptors appeared to induce similar effects (50). As such, complement activation and the subsequent local and/or systemic inflammation may actively contribute to the development of IR and T2DM.…”

Identification and validation of genes affecting aortic lesions in mice

“…demonstrated by significant changes in adiposity in C3ar1 -/-mice compared with littermate controls in the absence of significant changes in lipid profiles or weight (8,9), and has also been shown to be a key mediator of insulin resistance, as evidenced by increased insulin sensitivity in C3ar1 -/-mice (14), making it attractive to test its role in atherosclerosis; and (c) a C3ar1 -/-mouse model was readily available. In the current study, C3ar1 was identified as a causal gene for aortic lesion size in females, but not in males.…”

Downsizing a human inflammatory protein to a small molecule with equal potency and functionality

“…C3a is a powerful proinflammatory agent that recruits immune cells to sites of infection (chemotaxis) and induces immune cells to secrete bactericidal agents (via degranulation) as well as inflammatory cytokines 13,14 . Overexpression of C3a/C3aR or sustained activation of its receptor can lead to inflammatory diseases, including allergies 10 , asthma 15 , arthritis 16 , sepsis 17 , lupus 18 , diabetes 19 , psoriasis 20 , nephropathy 21 , ischaemia-reperfusion injury 22 , obesity, and metabolic and cardiovascular dysfunction 23 . C3a also reportedly has antimicrobial 24 and antifungal 25 activities.…”