Abstract 16026: CD40 is Associated with Obesity in Humans and Stimulation of CD40 Signaling Limits Progression of Pre-Established Metabolic Disease in Mice
Background: Immune and inflammatory cell recruitment critically drives adipose tissue inflammation during the metabolic syndrome. Co-stimulatory cascades such as the CD40L-CD40 dyad effectively modulate immune cell functioning and polarization. We recently showed that CD40-deficiency induced an aggravated inflammatory and metabolic phenotype in mice. Here, we tested the novel therapeutic concept of immune modulation with a stimulating anti-CD40 antibody during diet induced-obesity (DIO).
Methods and Results: To induce the metabolic syndrome C57Bl6 mice were fed a high fat diet (HFD) for 6 weeks. Mice were then randomized to either treatment with an isotype antibody control or the stimulating anti-CD40 antibody FGK45 (n=12 per group) for additional 6 weeks. Activation of CD40 signaling abolished further weight gain during diet-induced obesity (DIO), lowered glucose and insulin plasma levels, and improved insulin resistance as assessed by intraperitoneal insulin-tolerance testing (ITT), suggestive of an improved metabolic phenotype. Immune cell accumulation, such as of M1-polarized macrophages, as well as of pathogenic B- and T-cells was substantially reduced, while protective T-helper subsets were elevated after stimulation with FGK. To further prove a clinical association between metabolic disease and CD40, 183 patients with a high prevalence of the metabolic syndrome were screened for plasma levels of soluble CD40. Expression levels of CD40 tended to be higher in patients with an increasing number of factors for the MS and were significantly elevated in obese patients with a high BMI and high waist circumference. In the tested patient cohort CD40 levels were also associated with the inflammatory marker CRP and the adipokine leptin, suggesting CD40 as a potential link between inflammatory and metabolic disease.
Conclusion: We present the novel finding that activation of CD40 signaling improves adipose tissue inflammation and its metabolic complications in pre-established disease in mice. In line with this concept, levels of soluble CD40 associated with obesity in humans. Positive modulation of the co-stimulatory CD40 pathway might therefore constitute a promising novel therapeutic concept in the fight against metabolic disease.
- © 2012 by American Heart Association, Inc.