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

Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3354-9. doi: 10.1073/pnas.0802864106. Epub 2009 Feb 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animal Feed
  • Animals
  • Disease Progression
  • Exocrine Pancreatic Insufficiency / chemically induced
  • Exocrine Pancreatic Insufficiency / metabolism
  • Exocrine Pancreatic Insufficiency / pathology
  • Fatty Acids / metabolism*
  • Fatty Acids / pharmacology
  • Inflammation / genetics
  • Inflammation / metabolism
  • Insulin Resistance
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Obesity / metabolism*
  • Oxidation-Reduction
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Time Factors
  • ras Proteins / metabolism


  • Fatty Acids
  • Receptors, Tumor Necrosis Factor, Type I
  • ras Proteins