Sex differences in response to obesity and caloric restriction on cognition and hippocampal markers of autophagic-lysosomal pathway function

Abstract Obesity rates in the U.S. continue to increase, with nearly 50% of the population being either obese or morbidly obese. Obesity, along with female sex, are leading risk factors for sporadic Alzheimer’s Disease (AD). Animal and clinical studies both indicate that autophagy-lysosomal pathway (ALP) dysfunction is among the earliest known cellular systems to become perturbed in AD, preceding cognitive decline, yet little is known about how obesity and sex affects these cellular functions in an AD susceptible brain region, like the hippocampus. We hypothesized that obesity would negatively affect key markers of ALP in the hippocampus, effects would vary based on sex, and that caloric restriction would counteract obesity effects. Female and male mice were placed on an obesogenic diet for 10 months, at which point half were switched to caloric restriction. Cognitive function in female mice responded differently to caloric restriction based on whether they were on a normal or obesogenic diet; male cognition was only mildly affected by obesity or caloric restriction. Significant male-specific changes occurred in cellular markers of autophagy, including pAkt, pRPS6, Slc38a9, Atg7, and Atg12. In contrast females experienced changes due to diet/caloric restriction predominately in lysosomal markers including TFE3, folliculin, folliculin interacting protein 2, and pAMPK. Results support that hippocampal ALP is a target of obesity and that sex shapes molecular responses to dietary manipulation, while supporting the need to pivot beyond late-stage pathological markers and focus on earlier etiological events of AD that begin decades prior to cognitive decline.