Given the chemoattractant potential of complement factor 5 (C5) and its increased expression in adipose tissue (AT) of obese mice, we determined whether this protein of the innate immune system impacts insulin action. C5 control (C5cont) and spontaneously C5 deficient (C5def, B10.D2-Hc0 H2d H2-T18c/oSnJ) mice were placed on low and high fat diets to investigate their inflammatory and metabolic phenotypes. Adenoviral delivery was used to evaluate the effects of exogenous C5 on systemic metabolism. C5def mice gained less weight than controls 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, as well as impaired insulin signaling in liver and AT. C5def mice also exhibited decreased expression of insulin receptor gene and protein, as well as improper processing of insulin pro-receptor. These changes were not due to the C5 deficiency alone 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 B10.D2-Hc0 H2d H2-T18c/oSnJ model. 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.

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