Effects of maternal high-fat diet on brain transcriptome of weaned offspring and high-fat diet fed-adult offspring

Abstract

Maternal high-fat diet (HFD) consumption is known to affect the development of offspring, and its effect may persist until adulthood. However, most of the relevant studies have been conducted at one specific developmental stage of offspring. Therefore, this study investigated the effects of maternal HFD consumption on offspring brain on postnatal day (PD) 21, right after weaning, and PD105, when adult offspring were fed HFD for 12 weeks post-weaning. Five-week-old female C57BL/6 mice were provided with low-fat diet (LFD, 10% calories from fat) or high-fat diet (HFD, 45% calories from fat) before and during pregnancy, and during lactation period. Two of male offspring per dam were sacrificed on PD21, and the other two male offspring per dam were fed with HFD for 12 weeks until the sacrifice on PD105. Whole brain transcriptomes of offspring were analyzed using microarray. There were 25 differentially expressed genes (DEGs, Benjamini P-value < 0.05) in the comparison between HFD21 and LFD21 (HFD21/LFD21) and 5 DEGs in HFD105/LFD105. Among 5 DEGs of HFD105/LFD105, 3 genes were involved in brain serotonin system (Tph2, Slc6a4) and showed significantly higher expressions in HFD105 compared to LFD105. However, levels of serotonin, its metabolite (5-hydroxyindoleacetic acid) and its precursor (tryptophan) in the whole brain were not different between LFD105 and HFD105. Also, mRNA level of Cartpt, a gene encoding neuropeptide, cocaine- and amphetamine-regulated transcript peptide, was higher in HFD105 compared to LFD105, which may be due to the activation of its transcription factor, cAMP response element binding protein by AMP-activated protein kinase. Such higher gene expressions of Tph2, Slc6a4 and Cartpt in HFD105 compared to LFD105 were revealed to be affected by maternal oxidative stress indicated by serum level of thiobarbituric acid reactive substances. On the other hand, there were unique 377 DEGs in HFD105/HFD21, which were associated with immune response. Especially, upregulated genes were mostly involved in gene ontology terms indicating chemokine-mediated inflammation. However, protein levels of phosphorylated c-Jun N-terminal kinases, hyperphosphorylated tau and amyloid-β, which are the markers of neuropathogenesis, showed no differences by maternal diet in PD105 offspring. In conclusion, maternal HFD consumption induced upregulation of genes involved in brain serotonin system and neuropeptide in adult offspring which were fed HFD for 12 weeks, but not in weaned offspring. Also, as weaned offspring were fed HFD for 12 weeks, maternal HFD induced higher gene expressions of chemokine-mediated inflammation, which were not induced in offspring from LFD-fed dams.