Abstract 549: Adiponectin Modulation of Macrophage Inflammatory and Metabolic Properties is Regulated by Macrophage Polarization Status and Adiponectin Receptor Expression

Abstract

Adiponectin, an adipose-derived adipokine, exerts metabolic, anti-inflammatory and anti-atherogenic effects to ameliorate metabolic syndrome, diabetes and cardiovascular disease. Monocytes/macrophages play a crucial pathogenic role in these inflammatory and metabolic disorders. We identified that macrophage polarization profoundly alters their adiponectin receptor expression and functional responses to adiponectin. We addressed the hypothesis that macrophage activation status which affects adiponectin receptor expression leads to differential adiponectin-mediated inflammatory and metabolic response. Mouse bone marrow macrophages, differentiated into either classically-activated (IFN-γ and LPS) macrophages (M1) or alternatively-activated (IL-10) macrophages (M2), were treated with adiponectin. Our studies revealed that M1 activation substantially suppressed while M2 activation had only a modest effect on the macrophage adiponectin receptor expression. The macrophage activation status also produced contrasting adiponectin effects. Adiponectin significantly increased TNF-α expression in M1 macrophages but had no effect M2 macrophages. In contrast, adiponectin significantly increased anti-inflammatory cytokine, IL-10 in M2 macrophages but had no effect in M1 macrophages. We investigated the adiponectin effect on genes regulating macrophage cholesterol efflux, fatty acid and cholesterol metabolism. Interestingly, adiponectin increased CD36 expression in M1 macrophages but not in M2 macrophages. Similarly, adiponectin increased cholesterol efflux receptor, ABCA1 only in M1 macrophages with no effect in M2 macrophages. Measurement of metabolic gene expression revealed that adiponectin induced HMGCoA reductase levels in M1 macrophages and this effect was absent in M2 macrophages. FAS expression was unaffected by adiponectin in M1 or M2 macrophages. In conclusion, these studies provide important evidence that adiponectin modulation of macrophage inflammatory and atherogenic properties is differentially controlled by macrophage activation status which profoundly affects their pathogenic role in inflammatory and metabolic cardiovascular disease.