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R-spondin3 (Rspo3), a bioactive protein promoting the Wnt signaling pathway, regulates metabolic features especially around hepatic central veins. However, the functional impact of hepatic metabolic zonation, regulated by the Rspo3\/Wnt signaling pathway, on whole-body metabolism homeostasis remains poorly understood. In this study, we analyze the local functions of Rspo3 in the liver and the remote actions of hepatic Rspo3 on other organs of the body by using murine models. Rspo3 expression analysis shows that Rspo3 expression patterns are spatiotemporally controlled in the murine liver such that it locates in the pericentral zones and converges after feeding, and the dynamics of these processes are disturbed in obesity. We find that viral-mediated induction of Rspo3 in hepatic tissue of obesity improves insulin resistance and prevents body weight gain by restoring attenuated organ insulin sensitivities, reducing adipose tissue enlargement and reversing overstimulated adaptive thermogenesis. Denervation of the hepatic vagus suppresses these remote effects, derived from hepatic Rspo3 induction, toward adipose tissues and skeletal muscle, suggesting that signals are transduced via the neuronal communication consisting of afferent vagal and efferent sympathetic nerves. Furthermore, the non-neuronal inter-organ communication up-regulating muscle lipid utilization is partially responsible for the ameliorations of both fatty liver development and reduced skeletal muscle quality in obesity. In contrast, hepatic Rspo3 suppression through Cre-LoxP-mediated recombination system exacerbates diabetes due to glucose intolerance and insulin resistance, promotes fatty liver development and decreases skeletal muscle quality, resulting in obesity. Taken together, our study results reveal that modulation of hepatic Rspo3 contributes to maintaining systemic glucose metabolism and body composition via a newly identified inter-organ communication mechanism.<\/jats:p>","DOI":"10.1371\/journal.pbio.3002955","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T18:41:28Z","timestamp":1737744088000},"page":"e3002955","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Rspo3-mediated metabolic liver zonation regulates systemic glucose metabolism and body mass in mice"],"prefix":"10.1371","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9362-9232","authenticated-orcid":true,"given":"Kenji","family":"Uno","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Uchino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Sayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Edo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyoko","family":"Uno-Eder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Morita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshio","family":"Ishikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miho","family":"Koizumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Honda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Katagiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhisa","family":"Tsukamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,1,24]]},"reference":[{"issue":"2","key":"pbio.3002955.ref001","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.devcel.2010.01.011","article-title":"Organogenesis and development of the liver","volume":"18","author":"K Si-Tayeb","year":"2010","journal-title":"Dev Cell"},{"issue":"3","key":"pbio.3002955.ref002","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/0163-7258(92)90055-5","article-title":"Metabolic zonation of the liver: regulation and implications for liver function","volume":"53","author":"R. 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