{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T11:37:56Z","timestamp":1790941076235,"version":"4.1.0"},"reference-count":74,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2026,6]]},"abstract":"\n Abstract<\/jats:title>\n \n Thermoregulation is essential for survival in homeothermic animals. Vagal sensory nerves are well known to detect visceral signals and regulate feeding and metabolic functions, but their role in thermoregulation remains poorly understood. Cholecystokinin (CCK), a gut hormone released postprandially, activates vagal sensory nerves via CCK\u2010A receptors (CCK\u2010AR). Although exogenous CCK has been reported to induce thermogenesis in intrascapular brown adipose tissue (iBAT), whether this effect depends on vagal pathways and specific central circuits remains incompletely understood. Here, we assessed the thermogenic effect of\n i.p.<\/jats:sc>\n administered CCK\u20108 and investigated the underlying autonomic reflex pathways.\n i.p.<\/jats:sc>\n CCK\u20108 transiently and dose\u2010dependently increased rectal temperature and oxygen consumption without changing locomotor activity. This response was significantly attenuated by pharmacological blockade of CCK\u2010AR, subdiaphragmatic vagotomy or knockdown of CCK\u2010AR primarily targeting vagal sensory neurons. In addition, CCK\u20108 activated sympathetic nerve activity via vagal afferents. CCK\u20108\u2010induced thermogenesis was blunted by iBAT sympathectomy or \u03b23\u2010adrenergic receptor blockade. Furthermore,\n i.p.<\/jats:sc>\n CCK\u20108 activated oxytocin neurons in the paraventricular nucleus of the hypothalamus (PVH\n OXT<\/jats:sup>\n ). Chemogenetic inhibition of PVH\n OXT<\/jats:sup>\n neurons or oxytocin receptor expressing neurons in the rostral medullary raphe attenuated the thermogenic response. These findings suggest that CCK\u2010induced thermogenesis involves functional neural components, including the afferent input (CCK\u2010AR\u2010expressing vagal afferents), the central integrative hub (PVH\n OXT<\/jats:sup>\n neurons and OXTR signalling), and the efferent output (iBAT sympathetic nerves). This study further suggests that CCK\u2010AR\u2010expressing vagal sensory neurons may contribute to thermoregulation under physiological conditions in which CCK is endogenously released.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n Vagal sensory nerves, which connect the gut and the brain, play a key role in regulating meal\u2010related physiology; however, their role in thermoregulation remains incompletely understood.<\/jats:p>\n <\/jats:list-item>\n \n \n This study reveals that\n i.p.<\/jats:sc>\n cholecystokinin (CCK)\u2010induced thermogenesis involves functional neural components, including the afferent input (CCK\u2010A receptor\u2010expressing vagal afferents), the central integrative hub (hypothalamic oxytocin neurons in the paraventricular nucleus and oxytocin receptor\u2010expressing neurons in the rostral medullary raphe) and the efferent output (sympathetic nerves innervating intrascapular brown adipose tissue).\n <\/jats:p>\n <\/jats:list-item>\n \n This newly identified gut\u2013brain\u2013fat axis may contribute to part of diet\u2010induced thermogenesis, and its impairment could be involved in the development of metabolic disorders such as obesity.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp290717","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T01:00:31Z","timestamp":1778634031000},"page":"4651-4677","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Peripheral cholecystokinin promotes thermogenesis via vagal afferent signalling, hypothalamic oxytocin and sympathetic outflow to brown adipose tissue"],"prefix":"10.1113","volume":"604","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9643-5807","authenticated-orcid":false,"given":"Yuta","family":"Masuda","sequence":"first","affiliation":[{"name":"Laboratory of Animal Functional Science, Graduate School of Life and Environmental Sciences Kyoto Prefectural University Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miyuki","family":"Kawase","sequence":"additional","affiliation":[{"name":"Laboratory of Animal Functional Science, Graduate School of Life and Environmental Sciences Kyoto Prefectural University Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rika","family":"Kitano","sequence":"additional","affiliation":[{"name":"Laboratory of Animal Functional Science, Graduate School of Life and Environmental Sciences Kyoto Prefectural University Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kento","family":"Ohbayashi","sequence":"additional","affiliation":[{"name":"Laboratory of Animal Functional Science, Graduate School of Life and Environmental Sciences Kyoto Prefectural University Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6208-0590","authenticated-orcid":false,"given":"Toshiki","family":"Yabe\u2010Wada","sequence":"additional","affiliation":[{"name":"Department of Immunology Kanazawa Medical University Uchinada Ishikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Inoue","sequence":"additional","affiliation":[{"name":"Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative Kanazawa University Kanazawa Ishikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1620-7167","authenticated-orcid":false,"given":"Mamoru","family":"Tanida","sequence":"additional","affiliation":[{"name":"Department of Physiology II Kanazawa Medical University Uchinada Ishikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0655-4384","authenticated-orcid":false,"given":"Yusaku","family":"Iwasaki","sequence":"additional","affiliation":[{"name":"Laboratory of Animal Functional Science, Graduate School of Life and Environmental Sciences Kyoto Prefectural University Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"e_1_2_3_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00335-023-10010-7"},{"key":"e_1_2_3_3_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2102-21.2022"},{"key":"e_1_2_3_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0700293104"},{"key":"e_1_2_3_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.10.031"},{"key":"e_1_2_3_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M006246200"},{"key":"e_1_2_3_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ijo.2010.182"},{"key":"e_1_2_3_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2025.103058"},{"key":"e_1_2_3_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2003.08.036"},{"issue":"12","key":"e_1_2_3_10_1","article-title":"Duodenal lipid sensing activates vagal afferents to regulate non\u2010shivering brown fat thermogenesis in rats","volume":"7","author":"Blouet C.","year":"2012","journal-title":"Public Library of Science ONE"},{"key":"e_1_2_3_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.05.002"},{"key":"e_1_2_3_12_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00015.2003"},{"key":"e_1_2_3_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2009.07.005"},{"key":"e_1_2_3_14_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2002.35954"},{"key":"e_1_2_3_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/MED.0b013e32834eb77d"},{"key":"e_1_2_3_16_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00014.2005"},{"key":"e_1_2_3_17_1","volume-title":"The mouse brain in stereotaxic coordinates","author":"Franklin K. B. J.","year":"2007"},{"key":"e_1_2_3_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0361-9230(87)90026-8"},{"key":"e_1_2_3_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111380"},{"key":"e_1_2_3_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113305"},{"key":"e_1_2_3_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(93)91070-X"},{"key":"e_1_2_3_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2387-5"},{"key":"e_1_2_3_23_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.75718"},{"key":"e_1_2_3_24_1","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0423-21.2022"},{"key":"e_1_2_3_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2019.09.039"},{"key":"e_1_2_3_26_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00344.2014"},{"key":"e_1_2_3_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.npep.2012.08.009"},{"key":"e_1_2_3_28_1","doi-asserted-by":"publisher","DOI":"10.1538\/expanim.55.137"},{"key":"e_1_2_3_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1838(94)00145-A"},{"key":"e_1_2_3_30_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00223.2021"},{"key":"e_1_2_3_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0005-2736(98)00232-6"},{"key":"e_1_2_3_32_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00035.2011"},{"key":"e_1_2_3_33_1","doi-asserted-by":"publisher","DOI":"10.2337\/db15-0973"},{"key":"e_1_2_3_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.04.096"},{"key":"e_1_2_3_35_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00313.2001"},{"key":"e_1_2_3_36_1","doi-asserted-by":"publisher","DOI":"10.1142\/S0129065717500162"},{"key":"e_1_2_3_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05266-z"},{"key":"e_1_2_3_38_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2015.4315"},{"key":"e_1_2_3_39_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.1995.269.3.G319"},{"key":"e_1_2_3_40_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.91007.2008"},{"key":"e_1_2_3_41_1","doi-asserted-by":"publisher","DOI":"10.1080\/23328940.2016.1257407"},{"key":"e_1_2_3_42_1","first-page":"199","article-title":"Satiation and stress\u2010induced hypophagia: Examining the role of hindbrain neurons expressing prolactin\u2010releasing peptide or glucagon\u2010like peptide 1","volume":"6","author":"Maniscalco J. W.","year":"2012","journal-title":"Frontiers in Neuroscience"},{"key":"e_1_2_3_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2023.12.014"},{"key":"e_1_2_3_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/cph4.70010"},{"key":"e_1_2_3_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.02.005"},{"key":"e_1_2_3_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(97)00865-2"},{"key":"e_1_2_3_47_1","first-page":"R46","article-title":"Blockade of type A, not type B, CCK receptors attenuates satiety actions of exogenous and endogenous CCK","volume":"262","author":"Moran T. H.","year":"1992","journal-title":"American Journal of Physiology"},{"key":"e_1_2_3_48_1","doi-asserted-by":"publisher","DOI":"10.2741\/3677"},{"key":"e_1_2_3_49_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1219-04.2004"},{"key":"e_1_2_3_50_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-11-04600.2002"},{"key":"e_1_2_3_51_1","doi-asserted-by":"publisher","DOI":"10.1111\/apha.70148"},{"key":"e_1_2_3_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(92)90635-M"},{"key":"e_1_2_3_53_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1973.53.1.159"},{"key":"e_1_2_3_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2012.189"},{"key":"e_1_2_3_55_1","first-page":"G242","article-title":"Cholecystokinin inhibits gastric motility and emptying via a capsaicin\u2010sensitive vagal pathway in rats","volume":"255","author":"Raybould H. E.","year":"1988","journal-title":"American Journal of Physiology"},{"key":"e_1_2_3_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2010.03.059"},{"key":"e_1_2_3_57_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI43703"},{"key":"e_1_2_3_58_1","doi-asserted-by":"publisher","DOI":"10.1186\/s10020-022-00590-6"},{"key":"e_1_2_3_59_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00050.2002"},{"key":"e_1_2_3_60_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.1998.275.1.R63"},{"key":"e_1_2_3_61_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0150882"},{"key":"e_1_2_3_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.04.008"},{"key":"e_1_2_3_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2199-7"},{"key":"e_1_2_3_64_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00126.2025"},{"key":"e_1_2_3_65_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00275.2004"},{"key":"e_1_2_3_66_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0077221"},{"key":"e_1_2_3_67_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.122058"},{"key":"e_1_2_3_68_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0045167"},{"key":"e_1_2_3_69_1","doi-asserted-by":"publisher","DOI":"10.1210\/js.2017-00136"},{"key":"e_1_2_3_70_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00168.2025"},{"key":"e_1_2_3_71_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0285589"},{"key":"e_1_2_3_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2018.10.009"},{"key":"e_1_2_3_73_1","doi-asserted-by":"publisher","DOI":"10.1037\/h0037210"},{"key":"e_1_2_3_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.12.036"},{"key":"e_1_2_3_75_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00669"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP290717","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP290717","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP290717","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T12:41:25Z","timestamp":1781527285000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP290717"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,12]]},"references-count":74,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1113\/JP290717"],"URL":"https:\/\/doi.org\/10.1113\/jp290717","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,12]]},"assertion":[{"value":"2025-12-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}