Effect of hypothalamic orexin-A on the regulation of hepatic inflammatory and insulin signaling after cerebral ischemia

[Speaker] Shinichi Harada:1
[Co-author] Shogo Tokuyama:1
1:Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Japan

 [Aim] The communication system between brain and peripheral tissues through the autonomic nervous system is important for maintaining glucose and energy metabolism. We have reported that hypothalamic orexin-A (OXA)-induced activation of vagus nerve recovers the development of post-ischemic glucose intolerance and mediates a neuroprotective effect. Cerebral ischemia induces hepatic inflammatory factors and influences to the development of hepatic insulin resistance by activating sympathetic nerves. However, it is not enough to understand whether OXA regulates these mechanisms through activation of vagus nerve. In this study, we demonstrated that the involvement of OXA-induced activation of vagus nerve in the regulation of hepatic inflammatory factors and hepatic insulin signaling by cerebral ischemia.
[Methods] Focal cerebral ischemic model construction was performed by 2 h of middle cerebral artery occlusion (MCAO) in ddY male mice. Hepatic vagotomy model was inducted by selectively transection of hepatic branch of the vagus nerve. Neuronal damage was estimated by histological and behavioral analyses. Orexin-A (5 pmol/mouse) was intra-hypothalamic administrated immediately after reperfusion. Measurement of each mRNA and protein levels used qRT-PCR and western blots.
[Results] The level of hypothalamic orexin-A, detected by immunohistochemictry, was decreased on day 1 after MCAO. Intra-hypothalamic administration of orexin-A significantly suppressed the development of post-ischemic glucose intolerance on day 1 and development of neuronal damage on day 3. The MCAO-induced decrease in hepatic insulin receptors and increase in hepatic gluconeogenic enzymes were suppressed by OXA administration. Additionally, MCAO-induced increase in c-Jun N-terminal kinase (JNK; one of understream of inflammatory signaling) and serine-phosphorylated insulin receptor substrate on day 1 was recovered to control levels by OXA. These effects were canceled by hepatic vagotomy. MCAO-induced increases in hepatic F4/80, tumor necrosis factor-α, and interleukin-1β on day 1 after MCAO were reversed by OXA administration. These effects were abolished by hepatic vagotomy.
[Discussion] These results suggest that OXA-induced activation of vagus nerve regulates the post-ischemic elevation of hepatic inflammatory factors, and which may be influenced by a part of OXA-mediated pathway after ischemic glucose intolerance.
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