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Khasawneh, J.* ; Schulz, M.D.* ; Walch, A.K. ; Rozman, J. ; Hrabě de Angelis, M. ; Klingenspor, M.* ; Buck, A.* ; Schwaiger, M.* ; Saur, D.* ; Schmid, R.M.* ; Klöppel, G.* ; Sipos, B.* ; Greten, F.R.* ; Arkan, M.C.*

Inflammation and mitochondrial fatty acid beta-oxidation link obesity to early tumor promotion.

Proc. Natl. Acad. Sci. U.S.A. 106, 3354-3359 (2009)
DOI PMC Verlagsversion bestellen
Obesity is associated with increased risk for developing pancreatic cancer, and it is suggested that insulin resistance provides the missing link. Here we demonstrate that under the context of genetic susceptibility, a high fat diet (HFD) predisposes mice with oncogenic K-ras activation to accelerated pancreatic intraepithelial neoplasm (PanIN) development. Tumor promotion is closely associated with increased inflammation and abrogation of TNFR1 signaling significantly blocks this process underlining a central role for TNF alpha in obesity-mediated enhancement of PanIN lesions. Interestingly, however, despite increased TNF alpha levels, mice remain insulin sensitive. We show that, while aggravating tumor promotion, a HFD exerts dramatic changes in energy metabolism through enhancement of pancreatic exocrine insufficiency, metabolic rates, and expression of genes involved in mitochondrial fatty acid (FA) beta-oxidation that collectively contribute to improved glucose tolerance in these mice. While on one hand these findings provide significant evidence that obesity is linked to tumor promotion in the pancreas, on the other it suggests alterations in inflammatory responses and bioenergetic pathways as the potential underlying cause.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter energy metabolism; cancer; TNF alpha; mitochondria; pancreas; induced insulin-resistance; pancreatic-cancer; necrosis-factor; innate immunity; mouse; cachexia; cohort; cells; risk; mice
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Zeitschrift Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Band: 106, Heft: 9, Seiten: 3354-3359 Artikelnummer: , Supplement: ,
Verlag National Academy of Sciences
Begutachtungsstatus