Obesity takes its toll on visceral pain: High-fat diet induces toll-like receptor 4-dependent visceral hypersensitivity

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dc.contributor.authorTramullas, Mónica
dc.contributor.authorFinger, Beate C.
dc.contributor.authorDinan, Timothy G.
dc.contributor.authorCryan, John F.
dc.contributor.funderScience Foundation Ireland
dc.contributor.funderHealth Research Board
dc.contributor.funderSeventh Framework Programme
dc.date.accessioned2017-06-21T11:01:26Z
dc.date.available2017-06-21T11:01:26Z
dc.date.issued2016-05-09
dc.description.abstractExposure to high-fat diet induces both, peripheral and central alterations in TLR4 expression. Moreover, functional TLR4 is required for the development of high-fat diet-induced obesity. Recently, central alterations in TLR4 expression have been associated with the modulation of visceral pain. However, it remains unknown whether there is a functional interaction between the role of TLR4 in diet-induced obesity and in visceral pain. In the present study we investigated the impact of long-term exposure to high-fat diet on visceral pain perception and on the levels of TLR4 and Cd11b (a microglial cell marker) protein expression in the prefrontal cortex (PFC) and hippocampus. Peripheral alterations in TLR4 were assessed following the stimulation of spleenocytes with the TLR4-agonist LPS. Finally, we evaluated the effect of blocking TLR4 on visceral nociception, by administering TAK-242, a selective TLR4-antagonist. Our results demonstrated that exposure to high-fat diet induced visceral hypersensitivity. In parallel, enhanced TLR4 expression and microglia activation were found in brain areas related to visceral pain, the PFC and the hippocampus. Likewise, peripheral TLR4 activity was increased following long-term exposure to high-fat diet, resulting in an increased level of pro-inflammatory cytokines. Finally, TLR4 blockage counteracted the hyperalgesic phenotype present in mice fed on high-fat diet. Our data reveal a role for TLR4 in visceral pain modulation in a model of diet-induced obesity, and point to TLR4 as a potential therapeutic target for the development of drugs to treat visceral hypersensitivity present in pathologies associated to fat diet consumption.en
dc.description.sponsorshipScience Foundation Ireland (APC Microbiome Grant Number SFI/12/RC/2273); Health Research Board of Ireland (Grant Numbers HRA_POR/2011/23; HRA_POR/2012/32)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleide0155367
dc.identifier.citationTramullas, M., Finger, B. C., Dinan, T. G. and Cryan, J. F. (2016) 'Obesity takes its toll on visceral pain: High-fat diet induces toll-like receptor 4-dependent visceral hypersensitivity', PLoS ONE, 11(5), e0155367 (15pp). doi: 10.1371/journal.pone.0155367en
dc.identifier.doi10.1371/journal.pone.0155367
dc.identifier.endpage15
dc.identifier.issn1932-6203
dc.identifier.issued5
dc.identifier.journaltitlePLoS ONEen
dc.identifier.startpage1
dc.identifier.urihttps://hdl.handle.net/10468/4134
dc.identifier.volume11
dc.language.isoenen
dc.publisherPLoSen
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP1::KBBE/613979/EU/Microbiome Influence on Energy balance and Brain Development-Function Put into Action to Tackle Diet-related Diseases and Behavior./MYNEWGUT
dc.relation.urihttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155367
dc.rights© 2016, Tramullas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are crediteden
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectDieten
dc.subjectToll-like receptorsen
dc.subjectObesityen
dc.subjectHypersensitivityen
dc.subjectMouse modelsen
dc.subjectPrefrontal cortexen
dc.subjectHippocampusen
dc.subjectSpleenen
dc.titleObesity takes its toll on visceral pain: High-fat diet induces toll-like receptor 4-dependent visceral hypersensitivityen
dc.typeArticle (peer-reviewed)en
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