Abstract 5550: C-reactive Protein (CRP) Causes Insulin Resistance in Mice Through Fc γ RIIB-mediated Inhibition of Insulin Signaling

Abstract

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 Fc γ receptor IIB (Fc γ RIIB). 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 μ g/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 Fc γ RIIB was determined in littermates from matings of TG-CRP with Fc γ RIIB −/− mice. CRP was <1 μ g/mL in mice lacking CRP transgene and 13±2 and 10±3 μ g/ml in Fc γ RIIB +/+ TG-CRP and Fc γ RIIB −/− ;TG-CRP, respectively. Compared to Fc γ RIIB +/+ , fasting insulin was markedly increased in Fc γ RIIB +/+ ;TG-CRP; in contrast, it was normal in Fc γ RIIB −/− ;TG-CRP. Whereas Fc γ RIIB +/+ ;TG-CRP were insulin resistant, Fc γ RIIB −/− ;TG-CRP were not. Immunohistochemistry with anti-mouse Fc γ RIIB/Fc γ RIII Ab in Fc γ RIII −/− mice detected Fc γ RIIB protein in skeletal muscle microvascular endothelium, whereas endothelium in Fc γ RIIB −/− was negative. Fc γ RIIB 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 Fc γ RIIB that is most likely in endothelium. Future therapies targeting Fc γ RIIB may potentially normalize both the endothelial dysfunction and insulin resistance characteristic of obesity and other chronic inflammatory conditions.