Effects of obesity in multiple sclerosis pathogenesis: oligodendrocyte development, myelination and glia reactivity

Abstract

Multiple sclerosis (MS) is a chronic autoimmune neurodegenerative disease characterized by the dissemination of focal inflammatory and demyelinating lesions throughout the central nervous system. Emerging evidence has reported a positive relationship between obesity at early stages of life with increased risk of MS development, while studies in animal models demonstrated worsened disease progression and severity in non-obese mice fed with high-fat diet (HFD). Although several therapeutic strategies have been approved for MS treatment, no current available therapy can promote remyelination, despite the several clinical trials developed over the years. Therefore, the aim of this work is to investigate the impact of obesity in MS pathogenesis, focusing on demyelination and oligodendrocyte differentiation, which might contribute to the identification of new targets that could be used for the development of novel therapies to promote remyelination in MS patients. Hence, we induced the MS animal model, the experimental autoimmune encephalomyelitis (EAE), in female C57BL/6 mice previously fed either with a standard or HFD. Our results demonstrated that obesity favours EAE disease progression and severity. Accordingly, obese EAE-induced mice displayed enhanced peripheral inflammation, contributing, at least in part, to increased demyelination at the chronic phase. Furthermore, it was possible to observe, in obese EAE-mice, elevated glial density, specifically microglia at both stages of disease, as well as increased microglia activation, while its phagocytic capacity decreased with disease progression. Obese EAE-induced mice also showed an increased inflammatory milieu within the spinal cord at the peak of disease. Moreover, our results showed that obesity might impair oligodendrocyte precursor cells (OPCs) differentiation into mature oligodendrocytes, while simultaneously induce OPCs apoptosis at the peak of disease. Overall, these results provide valuable insights into how obesity-related mechanisms might impact MS disease, although future research will be needed to further translate these findings into the development of new therapeutic approaches.