Atorvastatin Exerts Context-Dependent Metabolic and Beneficial Effects on Behavior and Apoptotic Signaling in a Cafeteria Diet-Induced Metabolic Dysfunction Model.

The growing prevalence of obesity has been associated with metabolic and neurobiological alterations that compromise brain integrity and behavior. Diet-induced obesity, often accompanied by hypercholesterolemia, activates apoptotic signaling pathways in the central nervous system, contributing to cognitive and behavioral impairments. This study evaluated the effects of atorvastatin on behavioral performance and apoptotic signaling pathways in the hippocampus and cerebral cortex of rats subjected to a hypercaloric cafeteria diet. Male Wistar rats were assigned to four groups: control diet (CTR), control diet plus atorvastatin (ATOR), cafeteria diet (CAF), and cafeteria diet plus atorvastatin (CAF+ATOR), and exposed to the diets for 24 days. Body weight, adiposity, and circulating cholesterol levels were measured to validate the metabolic model. Behavioral assessments included locomotor activity, immobility time, and recognition memory. The expression of pro-caspase-8, pro-caspase-9, and apoptosis-inducing factor (AIF) was quantified in frontal cortex and hippocampus. The cafeteria diet increased adiposity and circulating cholesterol levels, confirming metabolic dysfunction, whereas atorvastatin reduced cholesterol levels and prevented retroperitoneal fat accumulation. In addition, the cafeteria diet altered the expression of apoptosis-related proteins in the hippocampus and cortex, whereas atorvastatin attenuated these changes. Cafeteria-fed rats showed reduced exploratory activity and increased immobility. Spatial memory was impaired by both atorvastatin and the cafeteria diet but preserved in the CAF+ATOR group. Novel object recognition was impaired only in the ATOR group. These findings indicate that atorvastatin exerts context-dependent effects under conditions of diet-induced metabolic dysfunction.