The Gender-Dependent Effects of Carbohydrate Sources and Quantity on Caspase-1 Activity in the Central Nervous System of Mice

Research Background

With the global intensification of aging, the incidence of cognitive impairments and dementia is rapidly increasing, with Alzheimer’s disease being the most common form of senile dementia. Studies have shown that metabolic dysfunctions like diabetes are associated with an increased risk of cognitive decline. Chronic inflammation, oxidative stress, and activation of immune cells are key factors, all of which are closely related to diet. Previous research has indicated that sex hormones can regulate metabolism and immune processes. Based on this, Rasa Valiauga and the team hypothesize that long-term dietary changes may affect nervous system function by regulating the activity of inflammasomes, and that this phenotype could be gender-dependent.

Study Origin

This study was conducted jointly by Rasa Valiauga, Sarah Talley, Mark Khemmani, and others, with findings published in the Journal of Neuroinflammation (2024, Volume 21:151).

Research Objectives and Methods

Researchers selected 5-week-old male and female transgenic mice expressing a caspase-1 bioluminescent reporter gene for monitoring in vivo activity. All mice underwent cranial window surgery and were fed a control diet (65% complex carbohydrates, 15% fat) and a high glycemic index diet (65% carbohydrates from sucrose, 15% fat), or a ketogenic diet (1% complex carbohydrates, 79% fat) from the age of 6 to 26 weeks. The study involved glucose tolerance tests on the mice, quantification of bioluminescence emitted by the brain using an IVIS in vivo imaging system, detection of serum cytokine levels with cytokine bead arrays, examination of the gut microbiome in mouse feces by 16S ribosomal RNA gene amplicon sequencing, as well as the evaluation of diet-related integrative behaviors.

Research Findings

The ketogenic diet led to an increase in body weight and a decrease in glucose tolerance in both male and female mice. Caspase-1 biosensor activity was enhanced by the high glycemic index diet in male mice, while in female mice, it was the ketogenic diet that increased sensor activity. These changes were associated with increased levels of inflammatory cytokines in serum and the occurrence of anxious behavior in the tested mice. Gut microbiome compositions showed significant differences between diets; however, the researchers found no clear link between diet, glucose tolerance, or caspase-1 signaling.

Conclusion and Significance

The study demonstrates that dietary composition, particularly the source and amount of carbohydrates, has a gender-specific effect on the activation of inflammasomes and behavior in the central nervous system. Male mice showed increased anxiety behavior. Further research is needed to determine whether this phenotype is related to changes in the gut microbiota.

Highlights of This Study

The study is innovative in researching the gender-dependent effects of diet on mice, and it employs a unique research method—the use of a caspase-1 biosensor to monitor inflammasome activity in the mouse brain—and explores the association between gut microbiota and behavior.