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. 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.

研究目的：2型糖尿病（Type 2 diabetes mellitus, T2DM）被认为是神经退行性疾病（neurodegenerative diseases, NDDs）的风险因素。生酮饮食（ketogenic diet, KD）对血糖控制具有显著益处，且可能对神经退行性疾病发挥有效防护作用，但其防护神经退行性疾病的具体机制目前仍未阐明。本研究旨在探究生酮饮食对脑功能的潜在调控效应，通过分析生酮饮食对2型糖尿病背景下小鼠大脑转录组变化的影响展开相关研究。
实验方法：选取雄性db/db小鼠，自9周龄至6月龄期间分别喂食生酮饮食或正常饮食，随后采集全脑组织进行mRNA测序（mRNA-seq）分析。采用基因本体论（Gene Ontology, GO）功能富集分析与京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）信号通路富集分析，以鉴定差异表达基因的功能。同时通过生化方法检测蛋白酶体活性。
实验结果：生酮饮食可显著改善db/db小鼠的血糖控制状况与体重水平（P < 0.05）。此外，生酮饮食可改变db/db小鼠大脑中多条通路的基因表达谱，涵盖能量代谢、生物合成以及炎症反应相关通路。生酮饮食可修复db/db小鼠大脑中的蛋白酶体降解系统——该系统是细胞主要的质量控制机制，其功能缺陷与绝大多数神经退行性疾病的发生发展密切相关。
研究结论：本研究表明，生酮饮食干预可激活与多条神经退行性疾病相关信号通路相关的基因表达。本研究结果加深了对生酮饮食改善神经退行性疾病的分子机制的理解，或可为神经退行性疾病的新型治疗策略开发提供理论依据。
选取雄性db/db小鼠，自9周龄至6月龄期间分别喂食生酮饮食或正常饮食，随后采集全脑组织进行mRNA测序（mRNA-seq）分析。采用基因本体论（Gene Ontology, GO）功能富集分析与京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）信号通路富集分析，以鉴定差异表达基因的功能。同时通过生化方法检测蛋白酶体活性。