Deletion of complement factor 5 amplifies glucose intolerance in obese male but not female mice.

Complement factor 5 of the innate immune system generates C5a and C5b ligands, which initiate inflammatory and cell lysis events, respectively. C5 activation has been linked with obesity-associated metabolic disorders; however, whether it has a causative role is unclear. We generated a C5 null (C5-/-) mouse using CRISPR-Cas9 gene editing to determine whether loss of C5 improves obesity-linked metabolic dysfunction. Generation of a new mouse model was prompted in part by the observation of off-target gene mutations in commercially available C5-/- lines. Male and female wild type (WT), heterozygous (Het), and C5-/- mice were fed low fat diet (LFD) or high fat diet (HFD) for 22 weeks. Body weight gain did not differ between genotypes on LFD or HFD. In lean animals, male C5-/- mice had similar glucose tolerance compared to WT controls; however, in obese conditions, glucose tolerance was worsened in C5-/- compared to controls. In contrast, female mice did not exhibit differences in glucose tolerance between genotypes under either dietary paradigm. Fasting insulin was not different between genotypes, while diet-induced obese male C5-/- mice had lower fed insulin concentrations compared to WT controls. No differences in adipose tissue inflammation or adipocyte size were identified between groups. Similarly, susceptibility to fatty liver and hepatic inflammation were similar between WT and C5-/- mice. However, the systemic cytokine response to acute endotoxin exposure was decreased in C5-/- mice. Together, these data suggest that loss of C5 worsens glucose tolerance in obese male but not female mice. Additional work is required to pinpoint the mechanisms by which loss of C5 amplifies glucose intolerance in obesity.