Impaired insulin signaling in the B10.D2--/oSnJ mouse model of complement factor 5 deficiency.

Peterson KR, Gutierrez DA, Kikuchi T, Anderson-Baucum EK, Winn NC, Shuey MM, Bolus WR, McGuinness OP, Hasty AH
Am J Physiol Endocrinol Metab. 2019 317 (2): E200-E211

PMID: 31084499 · PMCID: PMC6732470 · DOI:10.1152/ajpendo.00042.2019

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 (C5) and spontaneously C5-deficient (C5, B10.D2--/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 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 mice demonstrated severe glucose intolerance and systemic insulin resistance, as well as impaired insulin signaling in liver and AT. C5 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 gene, whole genome sequencing revealed an intronic 31-bp deletion in the gene in the B10.D2--/oSnJ model. Irrespective of the genetic defect, adenoviral delivery of C5 improved insulin sensitivity in both C5 and C5 mice, indicating an insulin-sensitizing function of C5.

MeSH Terms (17)

Adenoviridae Animals Complement C5 Disease Models, Animal Energy Metabolism Glucose Intolerance Hereditary Complement Deficiency Diseases Insulin Resistance Mice Mice, Inbred AKR Mice, Inbred C57BL Mice, Inbred CBA Mice, Inbred DBA Mice, Inbred NOD Mice, Transgenic Signal Transduction Transduction, Genetic

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