SUN-673 - Obesity-Associated Leptin Resistance Exacerbates Neuroinflammation in Experimental Autoimmune Encephalomyelitis

Background: The neuroendocrine and immune systems interact bidirectionally through shared ligands and receptors during inflammation. Leptin, a non-glycosylated peptide hormone secreted by adipose tissue and primarily known for regulating appetite and energy balance, is increasingly recognized as an immune modulator, with its receptor widely expressed on immune cells. In diet-induced obesity (DIO), chronic hyperleptinemia leads to leptin resistance, characterized by elevated circulating leptin and impaired central signaling. However, the role of leptin in neuroinflammation under leptin-resistant condition is not fully understood.

Objectives: This study aimed to evaluate the role of leptin in neuroinflammation under leptin-sensitive and leptin-resistant conditions using the murine experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), to assess whether conditional adipose-derived leptin knockout improves disease outcomes.

Methods: Wild-type (WT) C57BL/6 mice were fed high-fat diet for 12–16 weeks to induce DIO-associated leptin resistance or standard chow. Conditional leptin ablation was induced with two weeks of doxycycline. Circulating leptin reduction confirmed by ELISA. Both leptin-reduced and leptin-sufficient mice were immunized with Myelin Oligodendrocyte Glycoprotein (MOG)₃₅-₅₅ emulsified in Complete Freund’s Adjuvant (CFA), followed by intraperitoneal administration of pertussis toxin (PTX) to induce EAE. Disease severity were monitored daily. Flow cytometry of harvested CNS tissue was performed to characterize immune-cell composition across groups.

Results: Compared with leptin-reduced mice, leptin-sufficient littermates exhibited a higher risk of developing clinical disease and more severe neurological impairment. This effect was more pronounced in the context of DIO-induced leptin resistance. Similar results were obtained with a neutralizing anti-leptin antibody. On day 18 post-immunization, two mice per leptin-reduced and leptin-sufficient (WT) group with comparable clinical scores were euthanized. Flow cytometric analysis of brain tissue revealed significantly increased frequencies of infiltrating immune cell populations in WT mice, including CD3⁺ T cells (CD4⁺ and CD8⁺), CD11b⁺ myeloid cells, neutrophils, antigen-presenting myeloid cells, and disease-associated myeloid populations, compared with leptin-deficient animals, despite equivalent clinical severity and disease stage.

Conclusions: Elevated leptin in obesity exacerbates neuroinflammation and reduces leptin’s neuroprotective effects. Higher leptin levels, particularly during leptin resistance, enhance CNS immune-cell infiltration, increasing EAE onset and severity. Targeting leptin signaling in obese patients may represent a promising therapeutic strategy for autoimmune neuroinflammatory diseases.

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