Abstract 15277: Interplay Between CD40-TRAF2/3/5 and CD40-TRAF6 Interactions in Diet Induced Obesity
Introduction: We have recently shown that blocking and genetic deletion of CD40L alleviates adipose tissue inflammation and metabolic manifestations of obesity. Here we hypothesize that loss of CD40 and specific CD40-TRAF signaling pathways is responsible for the observed phenotype.
Methods: CD40+/+, CD40-/-, or CD40-/- mice that contained a CD40 transgene with or without mutations at the CD40-TRAF2/3/5, CD40-TRAF6 or CD40-TRAF2/3/5/6 binding site were fed a chow or high fat diet (HFD) for 18-20 weeks (N=9-12 mice per genotype and diet), and metabolic and inflammatory parameters were evaluated.
Results: CD40-/- mice on a HFD exhibited a higher body weight, food intake and liver weight compared to CD40+/+ mice. In addition, CD40-/- mice were insulin resistant, glucose intolerant and displayed adipose tissue (AT) inflammation with high numbers of CD3+, CD8+ T cells and low numbers of Tregs. Compared to CD40-Twt mice (+77%), HFD fed CD40-T2/3/5/6-/- mice had the highest weight gain (+93%), while CD40-T6-/- mice gained less weight (+70%), although having the highest food intake. Liver weights of CD40-T2/3/5/6-/- mice were higher and showed aggravated hepatic steatosis compared to the other CD40-TRAF mice. All mice displayed clear signs of glucose intolerance and insulin resistance after a HFD with CD40-T2/3/5/6-/- mice displaying 100% insulin resistance. FACS of the epididymal AT revealed that CD40-T2/3/5/6-/- mice had a pro-inflammatory T cell profile characterized by a high number of CD3+, CD8+, and CD4+ helper T cells and a low number of Tregs whereas CD40-T6-/- mice had a similar T cell profile as the CD40-Twt mice. The CD40-T2/3/5-/- mice presented an intermediate metabolic and inflammatory phenotype.
Conclusions: CD40 deficiency, in contrast to CD40L deficiency, leads to aggravated inflammation in AT and promotes metabolic manifestations of obesity. Genetic ablation of CD40-T2/3/5 and CD40-T2/3/5/6 signaling, but not CD40-T6 signaling, mimics the phenotype of CD40-/- mice. We therefore conclude that only the CD40-T6, not the CD40-T2/3/5 signaling pathway is responsible for the progression of diet induced obesity. These data suggest that obesity and its co-morbidities can be managed by controlling the pro-inflammatory CD40L/CD40/TRAF6 axis.
- © 2011 by American Heart Association, Inc.