Sex differences in response to obesity and caloric restriction on cognition and hippocampal measures of autophagic-lysosomal transcripts and signaling pathways

BACKGROUND: 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) necessitating the need to better understand how these variables impact cellular function independent of age or genetic mutations.

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 the hippocampus, a brain region uniquely susceptible to the negative effects of obesity.

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.

METHODS: Female and male mice were placed on an obesogenic diet for 10 months, at which point half were switched to caloric restriction for three months, followed by cognitive testing in the Morris watermaze.

Hippocampus was analyzed by western blot and qPCR.

RESULTS: 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 caloric restriction and not obesity.

Significant male-specific changes occurred in cellular markers of autophagy, including obesity increasing pAkt, Slc38a9, and Atg12, while caloric restriction reduced pRPS6 and increased Atg7.

In contrast females experienced changes due to diet/caloric restriction predominately in lysosomal markers including increased TFE3, FLCN, FNIP2, and pAMPK.

CONCLUSIONS: Results support that hippocampal ALP is a target of obesity and that sex shapes molecular responses, while providing insight into how dietary manipulations affect learning and memory based on sex.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12868-023-00840-1.