Early-Life Overnutrition Reprograms Metabolism and Immunity to Promote Sex-Biased CNS Autoimmunity 2333917

Abstract Introduction Multiple sclerosis (MS) is a chronic autoimmune disease with a strong female bias and no curative therapy. MS incidence has increased too rapidly to be explained by genetics alone, implicating environmental factors. Childhood and adolescent obesity are established risk factors for MS, particularly in females. However, how early-life overnutrition programs metabolism and immunity to influence CNS autoimmunity remains poorly defined. Methods To model early-life overnutrition without dietary confounders, we employed postnatal overfeeding (PNO) via litter size reduction in C57BL/6 mice. Long-term metabolic phenotyping was performed using indirect calorimetry and glucose tolerance testing. Baseline immune phenotypes were assessed by flow cytometry, cytokine production following T cell stimulation, and genetic disruption of type I interferon signaling. CNS autoimmunity was evaluated using experimental autoimmune encephalomyelitis (EAE), including active disease induction and adoptive transfer approaches. Results PNO resulted in durable increases in body weight, visceral adiposity, and induced long-term metabolic reprogramming, including increased oxygen consumption and mid-life glucose intolerance. Female, but not male, PNO mice exhibited altered immune homeostasis, characterized by increased thymus and spleen size and enhanced IFN-γ production by CD4+ T cells. This Th1 bias persisted in T cell-specific IFNAR1-deficient mice, indicating independence from type I interferon signaling. Consistent with these changes, PNO selectively exacerbated EAE severity in females, while male PNO mice showed no disease enhancement despite increased adiposity. Conclusion Together, these findings demonstrate that early-life overnutrition durably reprograms metabolic and immune states in a sex-dependent manner and selectively enhances susceptibility to CNS autoimmunity in females. Ongoing studies aim to define the mechanisms by which metabolic programming affects immune development to drive sex-biased autoimmune disease. Funding Source Canadian Institutes of Health Research (CIHR) Topic Categories Basic Autoimmunity (BA)