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Maternal nutrient intake influences the health of the offspring via microenvironmental systems in digestion and absorption. Maternal high fructose diet (HFD) impairs hippocampus-dependent memory in adult female rat offspring. However, the underlying mechanisms remain largely unclear. Maternal HFD causes microbiota dysbiosis. In this study, we find that the plasma level of butyrate, a major metabolite of microbiota, is significantly decreased in the adult female maternal HFD offspring. In these rats, GPR43, a butyrate receptor was downregulated in the hippocampus. Moreover, the expressions of mitochondrial transcription factor A (TFAM), and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) were downregulated in the hippocampus. The decreases of these functional proteins were reversed by fructooligosaccharides (FOS, a probiotic) treatment in adulthood. Astrocytes are critical for energy metabolism in the brain. Primary astrocyte culture from female maternal HFD offspring indicated that GPR43 and the mitochondrial biogenesis were significantly suppressed, which was reversed by supplemental butyrate incubation. The oxygen consumption rate (OCR) was reduced in the HFD group and rescued by butyrate. Intriguingly, the nuclear histone deacetylase 4 (HDAC4) was enhanced in the HFD group, suggesting an inhibitory role of butyrate on histone deacetylase activity. Inhibition of HDAC4 effectively restored the OCR, bioenergetics, and biogenesis of mitochondria. Together, these results suggested that the impaired butyrate signaling by maternal HFD could underlie the reduced mitochondrial functions in the hippocampus via HDAC4-mediated epigenetic changes. [ABSTRACT FROM AUTHOR]

High fructose ingestion enhances mortality which has been linked to autonomic dysregulation. However, the underlying mechanisms are still largely unknown. In the present study, we demonstrated that 3 months of high fructose diet (HFD) ingestion induced mortality in 18-week-old Wistar Kyoto rats (WKY) during anesthesia. Concurrently, the low frequency (LF) and the high frequency (HF) elements of the power spectral analyses of SBP were increased. Of note, the decreased ratio of LF and HF (LF/HF), an index of sympathetic and parasympathetic balance, suggested an autonomic imbalance. In the rostral ventrolateral medulla (RVLM), a center of sympathetic outflow, the levels of presynaptic (synaptophysin) and postsynaptic (postsynaptic density protein 95 and phospho-Ca2+/calmodulin-dependent protein kinase II) proteins were increased. The down-regulation of insulin receptor β and insulin receptor substrate 1 suggested the status of insulin desensitization. Moreover, the up-regulation of AMP-activated protein kinase and sirtuin 1 suggested the enhancement of energy sensing to activate autophagy. Simultaneously, the accumulations of Beclin-1, ATG12 and LC3B were increased in RVLM. Pioglitazone (PIO), an insulin sensitizer, effectively relieved the accumulation of Beclin-1 and ATG12 as well as the synaptic proteins synchronized with the reverses of insulin and energy sensing signals. Moreover, the autonomic dysregulation and anesthesia-associated mortality were intervened. Together, these results suggested that the HFD-induced, anesthesia-associated mortality rate was related to the autonomic abnormality derived from the RVLM synaptic alteration, which is strongly related to insulin desensitization-associated autophagy. PIO intervened the HFD-induced mortality via reversal of the above-mentioned molecules. [ABSTRACT FROM AUTHOR]

The mechanisms beneath the initiation of neuroinflammation are still inconclusive. Growing evidence proposes the maternal effect on the development of neuroinflammation. In this study, we evaluated the upstream regulators and the indices of neuroinflammation in the hippocampi of female offspring at 3 months old. The accumulation of nuclear factor-κB (NF-κB, 65 kDa), a cytokine-encoding transcription factor, was increased in microglia. The enhanced microglial activation was detected in CA1, CA3 and dentate gyrus (DG) HFD group with upregulation of CD11b and ionized calcium binding adaptor molecule 1 (Iba-1). Moreover, proinflammatory cytokines (including TNFα, IL-1β and IL-6) were significantly increased in HFD group. Peroxisome proliferator-activated receptors γ (PPARγ) is a transcription factor involved in the suppression of NF-κB expression and in encoding endogenous antioxidants (such as catalase and glutathione peroxidases). On the contrary, the expression of nuclear PPARγ was suppressed in hippocampal neurons of the HFD group. In addition, the expressions of glutathione peroxidase 1 (GPx1) was suppressed in HFD group. Oral application with pioglitazone, a PPARγ agonist, effectively ceased the neuroinflammation and reversed the expression of antioxidants in HFD group. Together, these results for the first time demonstrated that maternal HFD triggered the waxing and waning of NF-κB and PPARγ may initiate neuroinflammation in the hippocampus of adult female offspring. Our findings further suggest that PPARγ could be the feasible targets to reprogram the hippocampal impairment induced by maternal HFD. [ABSTRACT FROM AUTHOR]