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dc.contributor.authorJeong, Jae Hoonen
dc.contributor.authorLee, Dong Kunen
dc.contributor.authorBlouet, Clemenceen
dc.contributor.authorRuiz, Henry Hen
dc.contributor.authorBuettner, Christophen
dc.contributor.authorChua, Streamson Jren
dc.contributor.authorSchwartz, Gary Jen
dc.contributor.authorJo, Young-Hwanen
dc.date.accessioned2015-05-27T16:03:39Z
dc.date.available2015-05-27T16:03:39Z
dc.date.issued2015-04-11en
dc.identifier.citationMolecular Metabolism Volume 4, Issue 6, June 2015, Pages 483–492. doi:10.1016/j.molmet.2015.03.006en
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/248034
dc.description.abstractObjective: Brown adipose tissue (BAT) thermogenesis is critical in maintaining body temperature. The dorsomedial hypothalamus (DMH) integrates cutaneous thermosensory signals and regulates adaptive thermogenesis. Here, we study the function and synaptic connectivity of input from DMH cholinergic neurons to sympathetic premotor neurons in the raphe pallidus (Rpa). Methods: In order to selectively manipulate DMH cholinergic neuron activity, we generated transgenic mice expressing channelrhodopsin fused to yellow fluorescent protein (YFP) in cholinergic neurons (choline acetyltransferase (ChAT)-Cre::ChR2-YFP) with the Cre-LoxP technique. In addition, we used an adeno-associated virus carrying the Cre recombinase gene to delete the floxed Chat gene in the DMH. Physiological studies in response to optogenetic stimulation of DMH cholinergic neurons were combined with gene expression and immunocytochemical analyses. Results: A subset of DMH neurons are ChAT-immunopositive neurons. The activity of these neurons is elevated by warm ambient temperature. A phenotype-specific neuronal tracing shows that DMH cholinergic neurons directly project to serotonergic neurons in the Rpa. Optical stimulation of DMH cholinergic neurons decreases BAT activity, which is associated with reduced body core temperature. Furthermore, elevated DMH cholinergic neuron activity decreases the expression of BAT uncoupling protein 1 (Ucp1) and peroxisome proliferator-activated receptor γ coactivator 1 α (Pgc1α) mRNAs, markers of BAT activity. Injection of M2-selective muscarinic receptor antagonists into the 4th ventricle abolishes the effect of optical stimulation. Single cell qRT-PCR analysis of retrogradely identified BAT-projecting neurons in the Rpa shows that all M2 receptor-expressing neurons contain tryptophan hydroxylase 2. In animals lacking the Chat gene in the DMH, exposure to warm temperature reduces neither BAT Ucp1 nor Pgc1α mRNA expression. Conclusion: DMH cholinergic neurons directly send efferent signals to sympathetic premotor neurons in the Rpa. Elevated cholinergic input to this area reduces BAT activity through activation of M2 mAChRs on serotonergic neurons. Therefore, the direct DMHACh–Rpa5-HT pathway may mediate physiological heat-defense responses to elevated environmental temperature.
dc.description.sponsorshipWe thank Althea Cavanaugh and Licheng Wu for technical supports. This work was supported by NIDDK (RO1DK092246) to Y.-H.J. and New York obesity nutrition research center to J.H.J.
dc.languageEnglishen
dc.language.isoenen
dc.publisherElsevier
dc.rightsAttribution 2.0 UK: England & Wales*
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/uk/*
dc.subjectAcetylcholineen
dc.subjectMuscarinicen
dc.subjectNicotinicen
dc.subjectNeuronal tracingen
dc.subjectSerotoninen
dc.subjectHypothalamusen
dc.titleCholinergic neurons in the dorsomedial hypothalamus regulate mouse brown adipose tissue metabolismen
dc.typeArticle
dc.description.versionThis is the final published version. It first appeared at http://www.sciencedirect.com/science/article/pii/S2212877815000617.en
prism.endingPage492
prism.publicationDate2015en
prism.publicationNameMolecular Metabolismen
prism.startingPage483
prism.volume4en
dcterms.dateAccepted2015-03-31en
rioxxterms.versionofrecord10.1016/j.molmet.2015.03.006en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-04-11en
dc.contributor.orcidBlouet, Clemence [0000-0002-1752-1270]
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMedical Research Council (MC_UU_12012/5/B)


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Attribution 2.0 UK: England & Wales
Except where otherwise noted, this item's licence is described as Attribution 2.0 UK: England & Wales