GLP-1 Receptor Agonists Ameliorate Obesity-Driven EAE Severity in HLA Class II Transgenic Mice 2265661

Abstract

Abstract Introduction Multiple sclerosis (MS) is a chronic neuroinflammatory disease driven by genetic and environmental factors. Obesity and gut microbiota dysbiosis are emerging as key modifiable risk factors that exacerbate MS severity. The HLA-DR2.DQ6 haplotype within the HLA class II locus confers strong susceptibility to both MS and obesity. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as liraglutide are FDA-approved anti-obesity drugs with immunomodulatory potential. This study examines whether GLP-1R activation mitigates obesity-driven EAE severity by restoring gut-immune-brain homeostasis in HLA-DR2.DQ6 class-II transgenic (Tg) mice, a preclinical model of MS. Methods HLA-DR2.DQ6 Tg mice were fed a normal chow (NC) or high-fat diet (HFD) for 8 weeks, followed by liraglutide (0.2 mg/kg, S.C.) or vehicle treatment for 3 weeks. Fecal samples were collected for microbiome profiling. EAE was induced with MOG35-55/CFA/PTX, and clinical scores were monitored (0-5 scale). On day 31 post immunization, splenocytes were stimulated (PMA/ionomycin) and analyzed by flow cytometry for pro-inflammatory CD4+ T cells. Results Liraglutide treatment significantly reduced body weight in HFD-fed mice (HFD vs. HFD + Liraglutide, p < 0.0001) but had no significant effect in NC-fed controls (NC vs. NC + Liraglutide, p = 0.088). Moreover, liraglutide markedly ameliorated disease severity in HFD-induced obese HLA-DR2.DQ6 Tg mice with EAE. Notably, liraglutide administration alleviated obesity-associated gut microbiota dysbiosis and reduced the frequency of pro-inflammatory cytokine-producing effector CD4+ T cells. Conclusion Together, these findings suggest that GLP-1RAs reprogram the gut-immune-brain axis and act as dual-acting metabolic and immunomodulatory agents that restore gut microbial balance and reduce EAE severity in HLA-DR2.DQ6 Tg mice, offering a promising strategy to mitigate obesity-exacerbated MS and related neuroinflammatory diseases. Funding Source National Multiple Sclerosis Society (NMSS) #: RG-2407-43720, U.S. Department of Defense (DoD)# HT94252510562, University of Iowa Carver College of Medicine for the Startup Fund Topic Categories Therapeutic Approaches to Autoimmunity (THER)