Endocrine Abstracts

Activation of complement factor 5 (C5) produces the anaphylatoxin C5a and the proinflammatory cytolytic complex C5b-9. Recent studies have shown that C5a receptor (C5aR) deficiency leads to improved systemic and white adipose tissue (WAT) insulin sensitivity. This phenotype is considered to be due to the potent inflammatory potential of signalling through C5aR; however, the pleiotropic functions of C5 in inflammation and metabolism remain to be elucidated. We investigated the effect of C5 itself on systemic glucose tolerance and insulin sensitivity and found C5 to play a critical role in metabolic health. To determine the metabolic phenotype of C5 deficiency, we performed glucose tolerance tests and hyperinsulinaemic euglycaemic clamps using C5 deficient (C5D) and C5 sufficient (C5S) mice. Surprisingly, we found that C5D mice developed severe glucose intolerance and insulin resistance compared to C5S controls. Glucose uptake in muscle and WAT was lower in C5D mice. Conversely, C5S mice injected with C5a adenovirus showed improved insulin sensitivity and increased glucose uptake in muscle and WAT. We next sought to determine the mechanism for insulin resistance in C5D mice. We showed that expression and glycosylation of insulin receptor (InsR) was impaired in the liver, muscle, and WAT of C5D mice. Consequently, AKT phosphorylation following insulin stimulation was decreased in the liver of C5D mice. Insulin resistance in C5D mice was independent of obesity, inflammation, and leukocyte infiltration into WAT or liver. We tested the effect of C5 siRNA on HepG2 liver cells, which resulted in decreased total InsR protein levels and decreased insulin-stimulated AKT phosphorylation. Cumulatively, these results reveal a novel function of C5 on glucose tolerance and insulin sensitivity via InsR processing that is independent of immune cell infiltration, inflammation, and/or obesity.

Disclosure: This project was supported by a Mouse Metabolic Phenotyping Center MICROmouse award to AHH (5U24 DK076169).