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

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.

SUBMITTER: Khasawneh J

PROVIDER: S-EPMC2651311 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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

Khasawneh J J Schulz M D MD Walch A A Rozman J J Hrabe de Angelis M M Klingenspor M M Buck A A Schwaiger M M Saur D D Schmid R M RM Klöppel G G Sipos B B Greten F R FR Arkan M C MC

Proceedings of the National Academy of Sciences of the United States of America 20090210 9

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 underl ...[more]

PMID: 19208810

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Project description:BACKGROUND: The oxidation of fatty acids in mitochondria plays an important role in energy metabolism and genetic disorders of this pathway may cause metabolic diseases. Enzyme deficiencies can block the metabolism at defined reactions in the mitochondrion and lead to accumulation of specific substrates causing severe clinical manifestations. Ten of the disorders directly affecting mitochondrial fatty acid oxidation have been well-defined, implicating episodic hypoketotic hypoglycemia provoked by catabolic stress, multiple organ failure, muscle weakness, or hypertrophic cardiomyopathy. Additionally, syndromes of severe maternal illness (HELLP syndrome and AFLP) have been associated with pregnancies carrying a fetus affected by fatty acid oxidation deficiencies. However, little is known about fatty acids kinetics, especially during fasting or exercise when the demand for fatty acid oxidation is increased (catabolic stress). RESULTS: A computational kinetic network of 64 reactions with 91 compounds and 301 parameters was constructed to study dynamic properties of mitochondrial fatty acid beta-oxidation. Various deficiencies of acyl-CoA dehydrogenase were simulated and verified with measured concentrations of indicative metabolites of screened newborns in Middle Europe and South Australia. The simulated accumulation of specific acyl-CoAs according to the investigated enzyme deficiencies are in agreement with experimental data and findings in literature. Investigation of the dynamic properties of the fatty acid beta-oxidation reveals that the formation of acetyl-CoA - substrate for energy production - is highly impaired within the first hours of fasting corresponding to the rapid progress to coma within 1-2 hours. LCAD deficiency exhibits the highest accumulation of fatty acids along with marked increase of these substrates during catabolic stress and the lowest production rate of acetyl-CoA. These findings might confirm gestational loss to be the explanation that no human cases of LCAD deficiency have been described. CONCLUSION: In summary, this work provides a detailed kinetic model of mitochondrial metabolism with specific focus on fatty acid beta-oxidation to simulate and predict the dynamic response of that metabolic network in the context of human disease. Our findings offer insight into the disease process (e.g. rapid progress to coma) and might confirm new explanations (no human cases of LCAD deficiency), which can hardly be obtained from experimental data alone.

Project description:BackgroundObesity is associated with many adverse effects on female fertility. Obese women have a higher likelihood of developing ovulatory dysfunction due to dysregulation of the hypothalamic-pituitary-ovarian axis. However, the effect of obesity on ovarian function during early pregnancy needs to be further assessed.MethodsC57BL6/J mice were given a high-fat diet (HFD) for 12 weeks to induce obesity. An in vitro high-fat model was established by treating the human ovarian granulosa cell line KGN with oleic acid and palmitic acid. Ovarian morphology of obese mice in early pregnancy was assessed by hematoxylin and eosin staining and ovarian function was assessed by enzyme-linked immunosorbent assay, western blotting, and immunohistochemistry. Oil Red O staining and transmission electron microscopy were used to detect fatty acid accumulation. Specific markers relating to the ovarian functional mechanism were assessed by real-time PCR, western blotting, lactate detection, adenosine triphosphate (ATP) detection, biochemical analyses, and enzyme-linked immunosorbent assay.ResultsThe results of this study showed that during early pregnancy, the number of corpus lutea, serum estradiol and progesterone levels, and the expression of the steroid biosynthesis-related protein CYP19A1 (aromatase), CYP11A1 (cholesterol side chain cleavage enzyme), and StAR (steroidogenic acute regulatory protein), were significantly increased in HFD mice. Mice fed an HFD also showed a significant increase in ovarian lipid accumulation on day 7 of pregnancy. Genes involved in fatty acid synthesis (Acsl4 and Elovl5), and fatty acid uptake and transport (Slc27a4), together with the β-oxidation rate-limiting enzyme Cpt1a, were significantly upregulated in HFD mice. Specifically, there was abnormal elevation of ATP and aberrant expression of tricarboxylic acid cycle (TCA)- and electron transport chain (ETC)-related genes in the ovaries of pregnant HFD mice. KGN cells treated with etomoxir targeting β-oxidation of fatty acid showed decreased TCA cycle and ETC related gene expression. The elevation of ATP and estradiol and progesterone levels was reversed.ConclusionsDuring early pregnancy, HFD-induced obesity increases fatty acid β-oxidation, which in turn increases TCA cycle and ETC related gene expression, leading to increased ATP production and ovarian dysfunction.

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

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

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