| Autor: |
Peterson KR; Department of Pharmacology, Vanderbilt University School of Medicine , Nashville, Tennessee., Gutierrez DA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine , Nashville, Tennessee.; Investigational Biology, Merck Exploratory Science Center , Cambridge, Massachusetts., Kikuchi T; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine , Nashville, Tennessee., Anderson-Baucum EK; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine , Nashville, Tennessee., Winn NC; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine , Nashville, Tennessee., Shuey MM; Department of Genetic Medicine, Vanderbilt University Medical Center , Nashville, Tennessee., Bolus WR; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine , Nashville, Tennessee., McGuinness OP; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine , Nashville, Tennessee., Hasty AH; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine , Nashville, Tennessee.; Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee. |
| Abstrakt: |
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 cont ) and spontaneously C5-deficient (C5 def , B10.D2- Hc 0 H2 d H2 - T18 c /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 def 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 def mice demonstrated severe glucose intolerance and systemic insulin resistance, as well as impaired insulin signaling in liver and AT. C5 def 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 0 H2 d H2 - T18 c /oSnJ model. Irrespective of the genetic defect, adenoviral delivery of C5 improved insulin sensitivity in both C5 cont and C5 def mice, indicating an insulin-sensitizing function of C5. |
