{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:15:37Z","timestamp":1788344137192,"version":"build-2803163510"},"reference-count":40,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100002135","name":"Hirshberg Foundation for Pancreatic Cancer Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002135","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018071","name":"Knight Cancer Institute, Oregon Health and Science University","doi-asserted-by":"publisher","award":["P30 CA069533"],"award-info":[{"award-number":["P30 CA069533"]}],"id":[{"id":"10.13039\/100018071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018071","name":"Knight Cancer Institute, Oregon Health and Science University","doi-asserted-by":"publisher","award":["P30 CA069533 13S5"],"award-info":[{"award-number":["P30 CA069533 13S5"]}],"id":[{"id":"10.13039\/100018071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["S10OD034224"],"award-info":[{"award-number":["S10OD034224"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cachexia is defined by chronic loss of fat and muscle, is a frequent complication of pancreatic ductal adenocarcinoma (PDAC) and negatively impacts patient outcomes. Nutritional supplementation cannot fully reverse tissue wasting, and the mechanisms underlying this phenotype are unclear. This work aims to define the relative contributions of catabolism and anabolism to adipose wasting in PDAC\u2010bearing mice. Human antigen R (HuR) is an RNA\u2010binding protein recently shown to suppress adipogenesis. We hypothesize that fat wasting results from a loss of adipose anabolism driven by increased HuR activity in adipocytes of PDAC\u2010bearing mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Adult C57BL\/6J mice received orthotopic PDAC cell (\n                      <jats:italic>Kras<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>G12D<\/jats:italic>\n                      <\/jats:sup>\n                      ;\n                      <jats:italic>p53<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>R172H\/+<\/jats:italic>\n                      <\/jats:sup>\n                      ;\n                      <jats:italic>Pdx1\u2010cre<\/jats:italic>\n                      ) (PDAC) or PBS (sham) injections. Mice exhibiting moderate cachexia (9\u2009days after injection) were fasted for 24\u2009h, or fasted 24\u2009h and refed 24\u2009h before euthanasia. A separate cohort of PDAC mice were treated with an established HuR inhibitor (KH\u20103, 100\u2009mg\/kg) and subjected to the fast\/refeed paradigm. We analysed body mass, gross fat pad mass and adipose tissue mRNA expression. We quantified lipolytic rate as the normalized quantity of glycerol released from 3T3\u2010L1 adipocytes in\u00a0vitro and gonadal fat pads (gWAT) ex\u00a0vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      3T3\u2010L1 adipocytes treated with PDAC cell conditioned media (CM) had lower expression of lipolysis and lipogenesis genes than control cells and did not display elevated lipolysis as measured by liberated glycerol. PDAC gWAT cultured ex\u00a0vivo displayed decreased lipolysis compared to sham gWAT (\u221254.7%). PDAC and sham mice lost equivalent fat mass after a 24\u2009h fast; however, PDAC mice could not restore inguinal fat pads (iWAT) (\u221240.5%) or gWAT (\u221231.8%) mass after refeeding. RNAseq revealed 572 differentially expressed genes in gWAT from PDAC compared to sham mice. Downregulated genes (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009126) were associated with adipogenesis (adj\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.05), and expression of adipogenesis master regulators\n                      <jats:italic>Pparg<\/jats:italic>\n                      and\n                      <jats:italic>Cebpa<\/jats:italic>\n                      were reduced in gWAT from PDAC mice. Immunohistochemistry revealed increased HuR staining in gWAT (+74.9%) and iWAT (+41.2%) from PDAC mice. Inhibiting HuR binding restored lipogenesis in refed animals with a concomitant increase in iWAT mass (+131.7%).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our work highlights deficient adipose anabolism as a driver of reduced lipid content in 3T3\u2010L1 adipocytes treated with PDAC conditioned media and PDAC mice. The small molecule KH\u20103, which disrupts HuR binding, restored adipose anabolism in PDAC mice. This highlights HuR as a potentially targetable regulatory node for adipose anabolism in cancer cachexia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70253","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T07:53:32Z","timestamp":1773906812000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Impaired Adipose Anabolism in Pancreatic Cancer Cachexia Is Reversed by HuR Inhibition"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2706-9652","authenticated-orcid":false,"given":"Paige\u00a0C.","family":"Arneson\u2010Wissink","sequence":"first","affiliation":[{"name":"Brenden\u2010Colson Center for Pancreatic Care Oregon Health &amp; Science University  Portland Oregon USA"},{"name":"Department of Radiation Medicine Oregon Health &amp; Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Pelz","sequence":"additional","affiliation":[{"name":"Brenden\u2010Colson Center for Pancreatic Care Oregon Health &amp; Science University  Portland Oregon USA"},{"name":"Department of Surgery Oregon Health &amp; Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beth","family":"Worley","sequence":"additional","affiliation":[{"name":"Brenden\u2010Colson Center for Pancreatic Care Oregon Health &amp; Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"Mendez","sequence":"additional","affiliation":[{"name":"Brenden\u2010Colson Center for Pancreatic Care Oregon Health &amp; Science University  Portland Oregon USA"},{"name":"Department of Radiation Medicine Oregon Health &amp; Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Pham","sequence":"additional","affiliation":[{"name":"Brenden\u2010Colson Center for Pancreatic Care Oregon Health &amp; Science University  Portland Oregon USA"},{"name":"Department of Radiation Medicine Oregon Health &amp; Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parham","family":"Diba","sequence":"additional","affiliation":[{"name":"Brenden\u2010Colson Center for Pancreatic Care Oregon Health &amp; Science University  Portland Oregon USA"},{"name":"Department of Radiation Medicine Oregon Health &amp; Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter\u00a0R.","family":"Levasseur","sequence":"additional","affiliation":[{"name":"Brenden\u2010Colson Center for Pancreatic Care Oregon Health &amp; Science University  Portland Oregon USA"},{"name":"Department of Radiation Medicine Oregon Health &amp; Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"McCarthy","sequence":"additional","affiliation":[{"name":"Brenden\u2010Colson Center for Pancreatic Care Oregon Health &amp; Science University  Portland Oregon USA"},{"name":"Department of Surgery Oregon Health &amp; Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Chitsazan","sequence":"additional","affiliation":[{"name":"Cancer Early Detection Advanced Research Center Oregon Health &amp; Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan\u00a0R.","family":"Brody","sequence":"additional","affiliation":[{"name":"Brenden\u2010Colson Center for Pancreatic Care Oregon Health &amp; Science University  Portland Oregon USA"},{"name":"Department of Surgery Oregon Health &amp; Science University  Portland Oregon USA"},{"name":"Department of Cell, Developmental, and Cancer Biology Oregon Health &amp; Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4690-4948","authenticated-orcid":false,"given":"Aaron\u00a0J.","family":"Grossberg","sequence":"additional","affiliation":[{"name":"Brenden\u2010Colson Center for Pancreatic Care Oregon Health &amp; 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