Hepatic branch vagus nerve plays a critical role in the recovery of post-ischemic glucose intolerance and mediates a neuroprotective effect by hypothalamic orexin-A
Authors: Shuichi Koda
Shogo Tokuyama
Yui Yamazaki
Shinichi Harada
Journal: PLoS ONE (2014)
Discipline: Multidisciplinary
Keywords: Orexin-A; glucose metabolism; post-ischemic glucose intolerance; neuronal damage; autonomic nervous system
Affiliations: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan., Asubio Pharma Co., Ltd., Kobe, Japan.

Abstract:  Orexin-A (a neuropeptide in the hypothalamus) plays an important role in many physiological functions, including the regulation of glucose metabolism. We have previously found that the development of post-ischemic glucose intolerance is one of the triggers of ischemic neuronal damage, which is suppressed by hypothalamic orexin-A. Other reports have shown that the communication system between brain and peripheral tissues through the autonomic nervous system (sympathetic, parasympathetic and vagus nerve) is important for maintaining glucose and energy metabolism. The aim of this study was to determine the involvement of the hepatic vagus nerve on hypothalamic orexin-A-mediated suppression of post-ischemic glucose intolerance development and ischemic neuronal damage. Male ddY mice were subjected to middle cerebral artery occlusion (MCAO) for 2 h. Intrahypothalamic orexin-A (5 pmol/mouse) administration significantly suppressed the development of post-ischemic glucose intolerance and neuronal damage on day 1 and 3, respectively after MCAO. MCAO-induced decrease of hepatic insulin receptors and increase of hepatic gluconeogenic enzymes on day 1 after was reversed to control levels by orexin-A. This effect was reversed by intramedullary administration of the orexin-1 receptor antagonist, SB334867, or hepatic vagotomy. In the medulla oblongata, orexin-A induced the co-localization of cholin acetyltransferase (cholinergic neuronal marker used for the vagus nerve) with orexin-1 receptor and c-Fos (activated neural cells marker). These results suggest that the hepatic branch vagus nerve projecting from the medulla oblongata plays an important role in the recovery of post-ischemic glucose intolerance and mediates a neuroprotective effect by hypothalamic orexin-A. 

Retracted: Yes

PubPeer comments:
 2020 retraction. https: journals.plos.org plosone article?id=10.1371 journal.pone.0236818 After this article [1] was published, the corresponding author requested its retraction due to concerns about results reported in Figure 2 and the outcome of an institutional investigation. This work was investigated by the Investigation Committee on Misconduct in Research Activities at Kobe Gakuin University, who found that the results reported in the histograms in Figure 2A-F differed substantially from the raw data in a manner that affected the conclusions of the article. In light of the above concerns, the PLOS ONE Editors retract this article. ST agreed with the retraction. The other authors either could not be reached or did not respond directly to comment on the retraction decision. Reference 1.Harada S, Yamazaki Y, Koda S, Tokuyama S (2014) Hepatic Branch Vagus Nerve Plays a Critical Role in the Recovery of Post-Ischemic Glucose Intolerance and Mediates a Neuroprotective Effect by Hypothalamic Orexin-A. PLoS ONE 9(4): e95433. https: doi.org 10.1371 journal.pone.0095433 pmid:24759941 ,