Abstract 5550: C-reactive Protein (CRP) Causes Insulin Resistance in Mice Through FcγRIIB-mediated Inhibition of Insulin Signaling
Insulin promotes the cardiovascular protective functions of the endothelium including NO production by activating endothelial NO synthase (eNOS). Insulin activation of eNOS increases skeletal muscle blood flow and thereby augments glucose uptake. C-reactive protein (CRP), which is modestly elevated in chronic inflammatory conditions including obesity, is positively correlated with type 2 diabetes. We recently showed in cultured endothelium that CRP antagonizes insulin signaling to eNOS by inhibiting the phosphorylation of Akt and eNOS, and that this occurs by CRP binding to the inhibitory IgG receptor Fcγ receptor IIB (FcγRIIB). In this study we determined if the antagonism of insulin signaling by CRP causes insulin resistance in mice. We found that CRP transgenic mice (TG-CRP) with CRP levels of 14±8 μg/ml were hyperinsulinemic, hyperglycemic, and hyperleptinemic. In addition, TG-CRP displayed impaired glucose tolerance and impaired insulin tolerance, and skeletal muscle glucose uptake in vivo was attenuated by 57%. There was no difference in energy expenditure or food intake, but TG-CRP weighed 4% less and had 62% greater fat content than controls. The role of FcγRIIB was determined in littermates from matings of TG-CRP with FcγRIIB−/− mice. CRP was <1 μg/mL in mice lacking CRP transgene and 13±2 and 10±3 μg/ml in FcγRIIB+/+ TG-CRP and FcγRIIB−/−;TG-CRP, respectively. Compared to FcγRIIB+/+, fasting insulin was markedly increased in FcγRIIB+/+;TG-CRP; in contrast, it was normal in FcγRIIB−/−;TG-CRP. Whereas FcγRIIB+/+;TG-CRP were insulin resistant, FcγRIIB−/−;TG-CRP were not. Immunohistochemistry with anti-mouse FcγRIIB/FcγRIII Ab in FcγRIII−/− mice detected FcγRIIB protein in skeletal muscle microvascular endothelium, whereas endothelium in FcγRIIB−/− was negative. FcγRIIB protein was not detected in skeletal muscle cells or adipose. These findings indicate that CRP causes insulin resistance in mice that is due to impaired skeletal muscle glucose uptake and is mediated by FcγRIIB that is most likely in endothelium. Future therapies targeting FcγRIIB may potentially normalize both the endothelial dysfunction and insulin resistance characteristic of obesity and other chronic inflammatory conditions.