Translational validity of rodent diet-induced obesity models for cognitive impairment in human metabolic disease

Type 2 diabetes and obesity, often modelled in rodents through high-fat diet interventions, are associated with altered brain energy metabolism and cognitive impairments. However, discrepancies between rodent high-fat diet models and human metabolic diseases challenge the translation of findings. This review provides a view on clinical and preclinical studies examining the effects of high-fat diet-induced metabolic dysfunction on brain function, focusing on the limitations of current rodent models, including diet composition, duration, and control diets. It is discussed how these factors influence brain metabolism and cognition, and highlight the need for standardized, longitudinal, and sex-inclusive studies. The present analysis underscores that while studies using high-fat diet-fed rodents provide valuable mechanistic insights, their metabolic profiles do not fully replicate human obesity and type 2 diabetes. These findings emphasize the importance of refining experimental models to better understand diet-induced brain dysfunction and to develop effective interventions.