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However, the role of EphB1 in metabolic regulation and obesity remains poorly understood. This study aims to uncover the role of EphB1 in energy metabolism and provide insights into the underlying mechanisms by which EphB1 regulates obesity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Two <jats:italic>Ephb1<\/jats:italic> mutations identified from a forward genetic screen for obesity\u2010related loci in mice were examined for their effects in gene expression, energy metabolism, and endocrine changes. The impacts of EphB1 on neuropeptide expression and signal transduction were evaluated in both hypothalamic tissues and primary cells. Potential downstream signals were modified in <jats:italic>Ephb1<\/jats:italic> mutants to verify the interaction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>Ephb1<\/jats:italic> mutants develop obesity in adolescence and develop impaired glucose tolerance during adulthood. EphB1 deficiency caused lower body temperature, blunted cold\u2010induced thermogenesis, and decreased locomotor activity, but it did not alter food intake. EphB1 promotes cyclic AMP\u2010responsive\u00a0element\u2010binding protein (CREB) phosphorylation via phosphatidylinositol 3\u2010kinase (PI3K)\/protein kinase B (AKT) signaling in a cell\u2010autonomous manner. EphB1 deficiency leads to reduced expression of corticotropin\u2010releasing hormone (CRH) and thyrotropin\u2010releasing hormone (TRH) in the brain. Intraventricular administration of either TRH or a CRH fragment suppressed obesity in <jats:italic>Ephb1<\/jats:italic> mutants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>EphB1 regulates hypothalamic CRH and TRH expression and promotes energy expenditure in mice.<\/jats:p><\/jats:sec>","DOI":"10.1002\/oby.24275","type":"journal-article","created":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T04:49:31Z","timestamp":1744260571000},"page":"1101-1112","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Disruption of <scp><i>Ephb1<\/i><\/scp> causes reduced hypothalamic <scp>CRH<\/scp> and <scp>TRH<\/scp> expression and obesity in mice"],"prefix":"10.1002","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2356-8048","authenticated-orcid":false,"given":"Simin","family":"Xie","sequence":"first","affiliation":[{"name":"State Key Laboratory of Genetic Engineering and 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Collaborative Innovation Center of Genetics and Development, School of Life Sciences Fudan University  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongyong","family":"Meng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences Fudan University  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Cui","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences Fudan University  Shanghai 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