Hepatic signal transducer and activator of transcription‐3 signalling drives early‐stage pancreatic cancer cachexia via suppressed ketogenesis

Autor: Paige C. Arneson‐Wissink, Heike Mendez, Katherine Pelz, Jessica Dickie, Alexandra Q. Bartlett, Beth L. Worley, Stephanie M. Krasnow, Robert Eil, Aaron J. Grossberg
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Journal of Cachexia, Sarcopenia and Muscle, Vol 15, Iss 3, Pp 975-988 (2024)
Druh dokumentu: article
ISSN: 2190-6009
2190-5991
DOI: 10.1002/jcsm.13466
Popis: Abstract Background 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. Methods We developed an orthotopic mouse model of early PDAC cachexia in 12‐week‐old C57BL/6J mice. Murine pancreatic cancer cells (KPC) were orthotopically implanted into the pancreas of wild‐type, IL‐6−/−, and hepatocyte STAT3−/− 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‐time polymerase chain reaction, whole‐body calorimetry, circulating hormone levels, faecal protein and lipid content, hepatic lipid content and ketogenic response to medium‐chain fatty acid bolus. We assessed muscle atrophy in vivo and C2C12 myotube atrophy in vitro. Results Pre‐cachectic PDAC mice did not preserve gastrocnemius muscle mass during 3‐day food restriction (−13.1 ± 7.7% relative to food‐restricted sham, P = 0.0117) and displayed impaired fatty acid oxidation during fasting, resulting in a hypoketotic state (ketogenic response to octanoate bolus, −83.0 ± 17.3%, P = 0.0328; Hmgcs2 expression, −28.3 ± 7.6%, P = 0.0004). PDAC human patients display impaired fasting ketones (−46.9 ± 7.1%, P
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