Influence of Ketogenic Diet Lipid Composition on Anxiety-Like Behavior and Neurometabolic Profile in Healthy Rats

Ketogenic diets (KDs) modulate brain function, but how their fatty acid composition impacts behavior remains poorly understood. Male Wistar rats were fed a control diet (CD, n = 6), a classic ketogenic diet (CKD, n = 6) rich in saturated fatty acids (SAFAs), or a modified ketogenic diet (MKD, n = 6) enriched with polyunsaturated fatty acids (PUFAs) and DHA. After 100 days, both KDs induced similar ketosis and increased brain glucose metabolism (¹⁸F-FDG PET/CT), while reducing some cerebral pro-inflammatory cytokines (IL-1β, IL-6) and oxidized LDL. Notably, the CKD group exhibited an anxiety-like phenotype in the Elevated Plus Maze versus controls, significantly reducing open arm entries [1.58(0.60) vs. 5.08(1.03); p = 0.025], increasing closed arm time [3.33 min(0.22) vs. 1.70 min(0.19); p = 0.001], and elevating the Anxiety Index [0.92(0.04) vs. 0.70(0.07); p = 0.048], which correlated with SAFA incorporation in the frontal lobe. In contrast, the MKD group did not induce this anxiety-like effect, maintaining behavioral parameters comparable to the CD group, while showing an intense incorporation of omega-3 fatty acids and DHA in the hippocampus. These findings demonstrate that the behavioral divergence between KDs occurred despite shared reductions in the specific neuroinflammatory and oxidative markers evaluated. Overall, our results suggest that the dietary fatty acid profile, rather than the magnitude of systemic ketosis level, plays a critical role in modulating behavioral outcomes under ketogenic conditions.