Abstract 1601: Role of Human C-Reactive Protein in the Development of Adipose Tissue Remodeling and Insulin Resistance
Background: C-reactive protein (CRP) expression is increased with metabolic alterations and is known to induce activation of renin angiotensin system (RAS) and oxidative stress. We sought to clarify the direct effect of human CRP on the development of adipose tissue remodeling and insulin resistance, focusing on RAS and oxidative stress.
Methods and Results: Transgenic mice with human CRP overexpression (CRP-Tg) and their nontransgenic littermates (CON) were fed high-fat diet from 6 weeks of age. After high-fat diet feeding for 12 weeks, oral glucose tolerance and intraperitoneal insulin tolerance tests were performed and then epididymal adipose tissue (EAT) and liver were excised. Body weight and blood pressure 12 weeks after the high-fat diet were comparable between CRP-Tg and CON. CRP-Tg had deteriorated glucose tolerance and insulin sensitivity compared with CON. Expression of adiponectin mRNA in EAT and serum adiponectin levels (11.1±2.7 vs. 16.9±0.9 μg/mL, p<0.01) were lower in CRP-Tg than CON. Expression of angiotensinogen (p<0.01) and angiotensin II type 1A receptor (p<0.05) mRNA in EAT was upregulated in CRP-Tg than CON. EAT mRNA expression of glutathione peroxidase (GPX)1 and GPX3 was lower in CRP-Tg than CON (both p<0.05). Immunohistochemistry of EAT showed 8-Hydroxy-2′-deoxyguanosine was increased in CRP-Tg compared with CON. Infiltration of macrophage and expression of inflammatory cytokines in EAT were comparable between CRP-Tg and CON. Histological analysis of liver showed that hepatocellular ballooning, oil-drops (Oil-Red O stain) and perisinusoidal fibrosis (Masson-Trichrome stain) were prominent in CRP-Tg compared with CON. Serum alanine aminotransferase level (74.5±35.1 vs. 29.0±14.7 IU/L, p<0.01) and hepatic triglyceride content (303.0±43.6 vs. 133.0±72.8 mg/g, p<0.01) were higher in CRP-Tg than CON.
Conclusions: Human-CRP overexpression facilitated the development of insulin resistance and hepatoste-atosis under high-fat diet in association with RAS activation, adiponectin downregulation, and enhanced oxidative stress in adipose tissue. Increased CRP and metabolic alterations may synergistically accelerate adipose tissue remodeling and insulin resistance.