{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T11:20:21Z","timestamp":1783077621320,"version":"3.54.6"},"reference-count":39,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T00:00:00Z","timestamp":1713312000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["K08CA245188"],"award-info":[{"award-number":["K08CA245188"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R37CA280692"],"award-info":[{"award-number":["R37CA280692"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA264133"],"award-info":[{"award-number":["R01CA264133"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006668","name":"Oregon Health and Science University","doi-asserted-by":"publisher","award":["P30 CA069533"],"award-info":[{"award-number":["P30 CA069533"]}],"id":[{"id":"10.13039\/100006668","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006668","name":"Oregon Health and Science University","doi-asserted-by":"publisher","award":["P30 CA069533 13S5"],"award-info":[{"award-number":["P30 CA069533 13S5"]}],"id":[{"id":"10.13039\/100006668","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":[[2024,6]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n Patients with pancreatic ductal adenocarcinoma (PDAC) often suffer from cachexia, a wasting syndrome that significantly reduces both quality of life and survival. Although advanced cachexia is associated with inflammatory signalling and elevated muscle catabolism, the early events driving wasting are poorly defined. During periods of nutritional scarcity, the body relies on hepatic ketogenesis to generate ketone bodies, and lipid metabolism via ketogenesis is thought to protect muscle from catabolizing during nutritional scarcity.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We developed an orthotopic mouse model of early PDAC cachexia in 12\u2010week\u2010old C57BL\/6J mice. Murine pancreatic cancer cells (KPC) were orthotopically implanted into the pancreas of wild\u2010type, IL\u20106\n \u2212\/\u2212<\/jats:sup>\n , and hepatocyte STAT3\n \u2212\/\u2212<\/jats:sup>\n male and female mice. Mice were subject to fasting, 50% food restriction, ad libitum feeding or ketogenic diet interventions. We measured longitudinal body composition by EchoMRI, body mass and food intake. At the endpoint, we measured tissue mass, tissue gene expression by quantitative real\u2010time polymerase chain reaction, whole\u2010body calorimetry, circulating hormone levels, faecal protein and lipid content, hepatic lipid content and ketogenic response to medium\u2010chain fatty acid bolus. We assessed muscle atrophy in vivo and C2C12 myotube atrophy in vitro.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Pre\u2010cachectic PDAC mice did not preserve gastrocnemius muscle mass during 3\u2010day food restriction (\u221213.1\u00a0\u00b1\u00a07.7% relative to food\u2010restricted sham,\n P<\/jats:italic>\n \u00a0=\u00a00.0117) and displayed impaired fatty acid oxidation during fasting, resulting in a hypoketotic state (ketogenic response to octanoate bolus, \u221283.0\u00a0\u00b1\u00a017.3%,\n P<\/jats:italic>\n \u00a0=\u00a00.0328;\n Hmgcs2<\/jats:italic>\n expression, \u221228.3\u00a0\u00b1\u00a07.6%,\n P<\/jats:italic>\n \u00a0=\u00a00.0004). PDAC human patients display impaired fasting ketones (\u221246.9\u00a0\u00b1\u00a07.1%,\n P<\/jats:italic>\n \u00a0<\u00a00.0001) and elevated circulating interleukin\u20106 (IL\u20106) (12.4\u00a0\u00b1\u00a016.5\u2010fold increase,\n P<\/jats:italic>\n \u00a0=\u00a00.0001). IL\u20106\n \u2212\/\u2212<\/jats:sup>\n PDAC mice had improved muscle mass (+35.0\u00a0\u00b1\u00a03.9%,\n P<\/jats:italic>\n \u00a0=\u00a00.0031) and ketogenic response (+129.4\u00a0\u00b1\u00a044.4%,\n P<\/jats:italic>\n \u00a0=\u00a00.0033) relative to wild\u2010type PDAC mice. Hepatocyte\u2010specific signal transducer and activator of transcription 3 (STAT3) deletion prevented muscle loss (+9.3\u00a0\u00b1\u00a04.0%,\n P<\/jats:italic>\n \u00a0=\u00a00.009) and improved fasting ketone levels (+52.0\u00a0\u00b1\u00a043.3%,\n P<\/jats:italic>\n \u00a0=\u00a00.018) in PDAC mice. Without affecting tumour growth, a carbohydrate\u2010free diet improved tibialis anterior myofibre diameter (+16.5\u00a0\u00b1\u00a03.5%,\n P<\/jats:italic>\n \u00a0=\u00a00.0089), circulating ketone bodies (+333.0\u00a0\u00b1\u00a0117.6%,\n P<\/jats:italic>\n \u00a0<\u00a00.0001) and\n Hmgcs2<\/jats:italic>\n expression (+106.5\u00a0\u00b1\u00a036.1%,\n P<\/jats:italic>\n \u00a0<\u00a00.0001) in PDAC mice. Ketone supplementation protected muscle against PDAC\u2010induced atrophy in vitro (+111.0\u00a0\u00b1\u00a017.6%,\n P<\/jats:italic>\n \u00a0<\u00a00.0001 myofibre diameter).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n In early PDAC cachexia, muscle vulnerability to wasting is dependent on inflammation\u2010driven metabolic reprogramming in the liver. PDAC suppresses lipid \u03b2\u2010oxidation and impairs ketogenesis in the liver, which is reversed in genetically modified mouse models deficient in IL\u20106\/STAT3 signalling or through ketogenic diet supplementation. This work establishes a direct link between skeletal muscle homeostasis and hepatic metabolism. Dietary and anti\u2010inflammatory interventions that restore ketogenesis may be a viable preventative approach for pre\u2010cachectic patients with pancreatic cancer.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.13466","type":"journal-article","created":{"date-parts":[[2024,4,18]],"date-time":"2024-04-18T00:43:25Z","timestamp":1713401005000},"page":"975-988","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Hepatic signal transducer and activator of transcription\u20103 signalling drives early\u2010stage pancreatic cancer cachexia via suppressed ketogenesis"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2706-9652","authenticated-orcid":false,"given":"Paige C.","family":"Arneson\u2010Wissink","sequence":"first","affiliation":[{"name":"Brenden\u2010Colson Center for Pancreatic Care Oregon Health & Science University Portland OR 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