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C5 control (C5<jats:sub>cont<\/jats:sub>) and spontaneously C5-deficient (C5<jats:sub>def<\/jats:sub>, B10.D2- Hc<jats:sup>0<\/jats:sup>H2<jats:sup>d<\/jats:sup>H2- T18<jats:sup>c<\/jats:sup>\/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. C5<jats:sub>def<\/jats:sub>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, C5<jats:sub>def<\/jats:sub>mice demonstrated severe glucose intolerance and systemic insulin resistance, as well as impaired insulin signaling in liver and AT. C5<jats:sub>def<\/jats:sub>mice also exhibited decreased expression of insulin receptor (INSR) gene and protein, as well as improper processing of pro-INSR. 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-bp deletion in the Insr gene in the B10.D2- Hc<jats:sup>0<\/jats:sup>H2<jats:sup>d<\/jats:sup>H2- T18<jats:sup>c<\/jats:sup>\/oSnJ model. Irrespective of the genetic defect, adenoviral delivery of C5 improved insulin sensitivity in both C5<jats:sub>cont<\/jats:sub>and C5<jats:sub>def<\/jats:sub>mice, indicating an insulin-sensitizing function of C5.<\/jats:p>","DOI":"10.1152\/ajpendo.00042.2019","type":"journal-article","created":{"date-parts":[[2019,5,14]],"date-time":"2019-05-14T18:20:19Z","timestamp":1557858019000},"page":"E200-E211","source":"Crossref","is-referenced-by-count":1,"title":["Impaired insulin signaling in the B10.D2-<i>Hc<sup>0<\/sup>H2<sup>d<\/sup>H2<\/i>-<i>T18<sup>c<\/sup><\/i>\/oSnJ mouse model of complement factor 5 deficiency"],"prefix":"10.1152","volume":"317","author":[{"given":"Kristin R.","family":"Peterson","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dario A.","family":"Gutierrez","sequence":"additional","affiliation":[{"name":"Department of 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