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Exercise is beneficial for gut health, but the specific mechanisms remain poorly understood. Intestine\u2010specific apelin receptor (APJ) knockdown (KD) and wild\u2010type male mice were randomly divided into two subgroups, with\/without exercise, to obtain four groups: WT, WT with exercise, APJ KD and APJ KD with exercise. Animals in the exercise groups were subjected to daily treadmill exercise for 3\u00a0weeks. Duodenum was collected at 48\u00a0h after the last bout of exercise. AMP\u2010activated protein kinase (AMPK) \u03b11 KD and wild\u2010type mice were also utilized for investigating the mediatory role of AMPK on exercise\u2010induced duodenal epithelial development. AMPK and peroxisome proliferator\u2010activated receptor \u03b3 coactivator\u20101\u00a0\u03b1 were upregulated by exercise via APJ activation in the intestinal duodenum. Correspondingly, exercise induced permissive histone modifications in the PR domain containing 16 (PRDM16) promoter to activate its expression, which was dependent on APJ activation. In agreement, exercise elevated the expression of mitochondrial oxidative markers. The expression of intestinal epithelial markers was downregulated due to AMPK deficiency, and AMPK signalling facilitated epithelial renewal. These data demonstrate that exercise\u2010induced activation of the APJ\u2013AMPK axis facilitates the homeostasis of the intestinal duodenal epithelium.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15578-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Apelin receptor (APJ) signalling is required for improved epithelial homeostasis of the small intestine in response to exercise.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Exercise intervention activates PRDM16 through inducing histone modifications, enhanced mitochondrial biogenesis and fatty acid metabolism in duodenum.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The morphological development of duodenal villus and crypt is enhanced by the muscle\u2010derived exerkine apelin through the APJ\u2010AMP\u2010activated protein kinase axis.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp284552","type":"journal-article","created":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T07:23:21Z","timestamp":1683530601000},"page":"2371-2389","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Exercise improves homeostasis of the intestinal epithelium by activation of apelin receptor\u2013AMP\u2010activated protein kinase signalling"],"prefix":"10.1113","volume":"601","author":[{"given":"Song Ah","family":"Chae","sequence":"first","affiliation":[{"name":"Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences Washington State University Pullman WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7232-072X","authenticated-orcid":false,"given":"Min","family":"Du","sequence":"additional","affiliation":[{"name":"Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences Washington State University Pullman WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun Seok","family":"Son","sequence":"additional","affiliation":[{"name":"Laboratory of Perinatal Kinesioepigenetics, Department of Obstetrics, Gynecology &amp; 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