Immunometabolism and the role of complement factor 5 in insulin action
Peterson, Kristin Rose
Adipose tissue (AT) is a dynamic endocrine organ that contributes to metabolic health. Proper function of resident immune cells is vital to AT function, and thus the pro-inflammatory AT environment during obesity contributes to disease. Brown AT functions differently than white AT, and burns energy through thermogenesis rather than storing lipid. This Dissertation discusses what is known about immune cells in white AT, discoveries our lab has made in regards to the prevalence of immune cells in brown AT, and then focuses on a potential role for complement factor 5 (C5) in insulin action. C5 control (C5cont) and C5 deficient (C5def) mice were placed on low and high fat diets to investigate their inflammatory and metabolic phenotypes. C5def mice gained less weight while fed a high fat diet; accompanied by reduced AT inflammation, liver mass, and liver triglyceride content. Despite these beneficial metabolic effects, C5def mice demonstrated severe glucose intolerance and systemic insulin resistance (IR), as well as impaired insulin signaling in liver and AT. C5def mice also exhibited decreased Insr expression, improper processing of pro-INSR, and decreased INSR-β protein. This was not due to the C5 deficiency itself as other C5 deficient models did not recapitulate the INSR processing defect; rather, in addition to the mutation in the C5 gene, whole genome sequencing revealed an intronic 31 base-pair deletion in the Insr gene in the C5def mice. Irrespective of the genetic defect, adenoviral delivery of C5 improved insulin sensitivity in both C5cont and C5def mice, indicating an insulin sensitizing function of C5.