Tracking CSF inflammatory signatures in an ovine model of leptin resistance

Leptin resistance is a key metabolic feature of diet-induced obesity in sheep, with implications for body condition management and reproductive efficiency. However, changes in central inflammatory mediators during its development remain poorly characterized in longitudinal settings. The present study examined dynamic changes in cerebrospinal fluid (CSF) cytokine, chemokine, and microRNA (miRNA) profiles in an ovine model of leptin resistance. Sixteen ovariectomized Polish Longwool ewes were assigned to control (CTRL, n = 5), food-restricted (LEAN, n = 5), and high-energy diet (OBESE, n = 6) groups over a 14-week period. CSF was collected weekly from the third brain ventricle and analysed for 13 cytokines and chemokines by Luminex multiplex immunoassay; five inflammation-related miRNAs were quantified by digital PCR. Obese animals exhibited elevated CSF IL-8, TNF-α, MIP-1α, and IP-10, alongside upregulation of miR-155-5p, miR-21-5p, miR-125b-5p, and miR-223-3p. TNF-α correlated positively with miR-155-5p (r = 0.68, p = 0.015), while IP-10 was inversely associated with miR-146a-5p (r = - 0.61, p = 0.036). Food-restricted animals displayed distinct CSF inflammatory profiles, with IL-1α and IL-6 exceeding obese levels at several time points, indicating that nutritional stress, independent of hyperleptinemia, can drive central inflammatory changes. These findings demonstrate coordinated CSF cytokine and miRNA signatures associated with diet-induced obesity and caloric restriction, supporting longitudinal CSF profiling as an approach for monitoring central neuroimmune dynamics in large-animal models.