The effects of ketogenic diet on brain gene expressions in type 2 diabetes background

Aims: Type 2 diabetes mellitus (T2DM) is considered as a risk of neurodegenerative diseases (NDDs). The ketogenic diet (KD) has significant beneficial effects on glycemic control and may act effectively against NDDs. However, the mechanism by which KD is protective against NDDs is still unknown. In the current study, we aimed to explore a possible interaction of KDs on brain functions by determining the effects of KDs on transcriptional changes of brains in the background of T2DM. Methods: Male db/db mice were fed with KD or normal diet from 9 weeks to 6 months of age, and whole brains were sampled for mRNA-seq analysis. Gene Ontology functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes signaling pathway enrichment analysis were conducted to identify the functions of differentially expressed genes. Proteasomal activities were assessed using biochemical methods. Results: The KD showed significantly beneficial effects on glycemic control and body weight in db/db mice (P < 0.05). Moreover, KD altered gene expressions in multiple pathways including energy metabolism, biosynthesis, and inflammatory responses in the brain of db/db mice. KD improved in db/db mouse brains the proteasome degradation system, the primary quality control machinery whose defects are involved in most NDDs. Conclusions: This study suggests that the KD supplement may activate the expression of genes associated with multiple signaling pathway that are closely involved in NDDs. Our results deepen understanding of the molecular mechanisms underlying the improvement of NDDs with KD intervention and may contribute to the development of promising new therapeutic strategies to NDDs.