recombinant acylation stimulating protein administration to c3？？ mice increases insulin resistance via adipocyte inflammatory mechanisms酰化刺激蛋白重组政府c3 老鼠增加胰岛素抵抗通过脂肪细胞炎症机制.pdfVIP

Recombinant Acylation Stimulating Protein Administration to C32/ 2 Mice Increases Insulin Resistance via Adipocyte Inflammatory Mechanisms Mercedes Nancy Munkonda, Marc Lapointe, Pierre Miegueu, Christian Roy, Danny Gauvreau, Denis Richard, Katherine Cianflone* ´ ´ ´ Centre de Recherche Institut Universitaire de Cardiologie Pneumologie de Quebec, Universite Laval, Quebec, Canada Abstract Background: Complement 3 (C3), a key component of the innate immune system, is involved in early inflammatory responses. Acylation stimulating protein (ASP; aka C3adesArg), a C3 cleavage product, is produced in adipose tissue and stimulates lipid storage. We hypothesized that, depending on the diet, chronic ASP administration in C32/ 2 mice would affect lipid metabolism and insulin sensitivity via an adaptive adipose tissue inflammatory response. Methodology/Principal Findings: C32/ 2 mice on normal low fat diet (ND) or high fat diet (HFD) were chronically administered recombinant ASP (rASP) for 25 days via an osmotic mini-pump. While there was no effect on food intake, there was a decrease in activity, with a relative increase in adipose tissue weight on ND, and a shift in adipocyte size distribution. While rASP administration to C32/ 2 mice on a ND increased insulin sensitivity, on a HFD, rASP administration had the opposite effect. Specifically, rASP administration in C32/ 2 HFD mice resulted in decreased gene expression of IRS1, GLUT4, SREBF1 and NFkB in muscle, and decreased C5L2 but increased JNK, CD36, CD11c, CCR2 and NFkB gene expression in adipose tissue as well as increased secretion of proinflammatory cytokines (Rantes, KC, MCP-1, IL-6 and G-CSF). In adipose tissue, although IRS1 and GLUT4