High fructose diet induces early mortality via autophagy factors accumulation in the rostral ventrolateral medulla as ameliorated by pioglitazone

Abstract

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.