High-fat diet-induced obesity compromises the efficacy of disease-modifying therapies in an animal model of multiple sclerosis 3296

Abstract Description Multiple Sclerosis (MS) is a complex neuroinflammatory disease caused by genetic and environmental factors. Obesity has emerged as a significant risk factor that exacerbates the severity of MS. We and others have shown that high-fat diet-induced obesity (DIO) worsens the severity of Experimental autoimmune encephalomyelitis (EAE), an animal model of MS. However, it remains unclear whether DIO compromises the efficacy of disease-modifying therapies (DMTs) such as Copaxone. To investigate this, obesity was induced in C57BL/6J (B6) mice by feeding a high-fat-diet (HFD) for eight weeks. Subsequently, EAE was induced using MOG35-55/CFA/PTX, and Copaxone (20 µg) was administered subcutaneously to DIO mice and normal chow (NC) fed lean mice every alternate day, starting on day nine post-EAE. Although Copaxone treatment reduces EAE in NC fed lean mice, it fails to ameliorate EAE severity in DIO mice, highlighting a potential obesity-driven impairment in treatment response that may be linked to metabolic and immune dysregulation. Altogether, our findings reveal that DIO exacerbates EAE severity and compromises the therapeutic efficacy of the MS DMT Copaxone. These insights underscore the critical need for future studies to unravel the underlying mechanisms driving this impaired response, paving the way for innovative, targeted treatments for obese MS patients. Funding Sources This work was supported by the National Institute of Allergy and Infectious Diseases Grant 1RO1AI137075 (to A.K.M.), Veteran Affairs Merit Award 1I01CX002212 and I01BX006112 (to A.K.M.), a gift from P. Heppelmann and M. Wacek (A.K.M.) and the University of Iowa Fraternal Order of Eagles Diabetes Research Center pilot grant (A.K.M.). Topic Categories Basic Autoimmunity (BA)