Abstract:
: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 TNFalpha in obesity-mediated enhancement of PanIN lesions. Interestingly, however, despite increased TNFalpha 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.
journal_name
Proc Natl Acad Sci U S Aauthors
Khasawneh J,Schulz MD,Walch A,Rozman J,Hrabe de Angelis M,Klingenspor M,Buck A,Schwaiger M,Saur D,Schmid RM,Klöppel G,Sipos B,Greten FR,Arkan MCdoi
10.1073/pnas.0802864106subject
Has Abstractpub_date
2009-03-03 00:00:00pages
3354-9issue
9eissn
0027-8424issn
1091-6490pii
0802864106journal_volume
106pub_type
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