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.

authors

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 MC

doi

10.1073/pnas.0802864106

subject

Has Abstract

pub_date

2009-03-03 00:00:00

pages

3354-9

issue

9

eissn

0027-8424

issn

1091-6490

pii

0802864106

journal_volume

106

pub_type

杂志文章
  • Rivers across the Siberian Arctic unearth the patterns of carbon release from thawing permafrost.

    abstract::Climate warming is expected to mobilize northern permafrost and peat organic carbon (PP-C), yet magnitudes and system specifics of even current releases are poorly constrained. While part of the PP-C will degrade at point of thaw to CO2 and CH4 to directly amplify global warming, another part will enter the fluvial ne...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1811797116

    authors: Wild B,Andersson A,Bröder L,Vonk J,Hugelius G,McClelland JW,Song W,Raymond PA,Gustafsson Ö

    更新日期:2019-05-21 00:00:00

  • Differential amplification of specific areas of phage T4 genome as revealed by hybridization to cloned genetic segments.

    abstract::Under various conditions, specific genetic areas of the phage T4 DNA molecule are preferentially and repeatedly replicated, resulting in the amplification of these areas. These areas are found to lie in the vicinity of the known origins of DNA replication. ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.77.9.5064

    authors: Kozinski AW,Ling SK,Hutchinson N,Halpern ME,Mattson T

    更新日期:1980-09-01 00:00:00

  • Pelizaeus-Merzbacher disease: a valine to phenylalanine point mutation in a putative extracellular loop of myelin proteolipid.

    abstract::In the central nervous system, myelin proteolipid protein isoforms (PLP and DM20) play an essential structural role in myelination. It has been shown in several species that myelination is impaired by molecular defects resulting from single base mutations in the PLP gene. We have used DNA amplification by polymerase c...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.88.17.7562

    authors: Pham-Dinh D,Popot JL,Boespflug-Tanguy O,Landrieu P,Deleuze JF,Boué J,Jollès P,Dautigny A

    更新日期:1991-09-01 00:00:00

  • Flow of information in the light-triggered cyclic nucleotide cascade of vision.

    abstract::Photolyzed rhodopsin catalyzes the exchange of GTP for FDP bound to a protein in retinal rod outer segments. We previously proposed that the GTP complex of this protein regulates the cyclic GMP phosphodiesterase and that it may be the first amplified intermediate in visual excitation [Fung, B. K.-K. & Stryer, L. (1980...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.78.1.152

    authors: Fung BK,Hurley JB,Stryer L

    更新日期:1981-01-01 00:00:00

  • CD1d-Restricted pathways in hepatocytes control local natural killer T cell homeostasis and hepatic inflammation.

    abstract::Invariant natural killer T (iNKT) cells recognize lipid antigens presented by CD1d and play a central role in regulating immunity and inflammation in peripheral tissues. However, the mechanisms which govern iNKT cell homeostasis after thymic emigration are incompletely understood. Here we demonstrate that microsomal t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1701428114

    authors: Zeissig S,Peuker K,Iyer S,Gensollen T,Dougan SK,Olszak T,Kaser A,Blumberg RS

    更新日期:2017-09-26 00:00:00

  • Expression of the insulin-like growth factor II gene in the choroid plexus and the leptomeninges of the adult rat central nervous system.

    abstract::The rat insulin-like growth factor II gene, encoding a fetal somatomedin, expresses a multitranscript family in embryonic/fetal tissues and in the adult brain and spinal cord. By performing in situ hybridization on tissue sections of adult brain and spinal cord, we have found that these transcripts are not expressed i...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.85.1.141

    authors: Stylianopoulou F,Herbert J,Soares MB,Efstratiadis A

    更新日期:1988-01-01 00:00:00

  • Regulation of blood flow in activated human brain by cytosolic NADH/NAD+ ratio.

    abstract::It has been known for more than a century that increases in neuronal activity in the brain are reliably accompanied by changes in local blood flow. More recently it has been appreciated that these blood flow increases are accompanied by increases in glycolysis that are much greater than the increases in oxidative phos...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0510632103

    authors: Vlassenko AG,Rundle MM,Raichle ME,Mintun MA

    更新日期:2006-02-07 00:00:00

  • Emergence of neural encoding of auditory objects while listening to competing speakers.

    abstract::A visual scene is perceived in terms of visual objects. Similar ideas have been proposed for the analogous case of auditory scene analysis, although their hypothesized neural underpinnings have not yet been established. Here, we address this question by recording from subjects selectively listening to one of two compe...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1205381109

    authors: Ding N,Simon JZ

    更新日期:2012-07-17 00:00:00

  • Autophagy protects C. elegans against necrosis during Pseudomonas aeruginosa infection.

    abstract::Autophagy, a conserved pathway that delivers intracellular materials into lysosomes for degradation, is involved in development, aging, and a variety of diseases. Accumulating evidence demonstrates that autophagy plays a protective role against infectious diseases by diminishing intracellular pathogens, including bact...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1405032111

    authors: Zou CG,Ma YC,Dai LL,Zhang KQ

    更新日期:2014-08-26 00:00:00

  • Insulin receptors in beta-cells are critical for islet compensatory growth response to insulin resistance.

    abstract::Insulin and insulin-like growth factor 1 (IGF1) are ubiquitous growth factors that regulate proliferation in most mammalian tissues including pancreatic islets. To explore the specificity of insulin receptors in compensatory beta-cell growth, we examined two models of insulin resistance. In the first model, we used li...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0608703104

    authors: Okada T,Liew CW,Hu J,Hinault C,Michael MD,Krtzfeldt J,Yin C,Holzenberger M,Stoffel M,Kulkarni RN

    更新日期:2007-05-22 00:00:00

  • Climatic change and wetland desiccation cause amphibian decline in Yellowstone National Park.

    abstract::Amphibians are a bellwether for environmental degradation, even in natural ecosystems such as Yellowstone National Park in the western United States, where species have been actively protected longer than anywhere else on Earth. We document that recent climatic warming and resultant wetland desiccation are causing sev...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0809090105

    authors: McMenamin SK,Hadly EA,Wright CK

    更新日期:2008-11-04 00:00:00

  • Surface exposure to sunlight stimulates CO2 release from permafrost soil carbon in the Arctic.

    abstract::Recent climate change has increased arctic soil temperatures and thawed large areas of permafrost, allowing for microbial respiration of previously frozen C. Furthermore, soil destabilization from melting ice has caused an increase in thermokarst failures that expose buried C and release dissolved organic C (DOC) to s...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1214104110

    authors: Cory RM,Crump BC,Dobkowski JA,Kling GW

    更新日期:2013-02-26 00:00:00

  • The 3D NOESY-[(1)H,(15)N,(1)H]-ZQ-TROSY NMR experiment with diagonal peak suppression.

    abstract::In our 3D NOESY-[(1)H,(15)N,(1)H]-ZQ-TROSY experiment, the TROSY principle (transverse relaxation-optimized spectroscopy) is used in three-dimensional (3D) (15)N-resolved nuclear Overhauser enhancement spectroscopy (NOESY), which enables resonance assignments by sequential nuclear Overhauser effects and the collection...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.96.17.9607

    authors: Pervushin KV,Wider G,Riek R,Wüthrich K

    更新日期:1999-08-17 00:00:00

  • Probing counterion modulated repulsion and attraction between nucleic acid duplexes in solution.

    abstract::Understanding biological and physical processes involving nucleic acids, such as the binding of proteins to DNA and RNA, DNA condensation, and RNA folding, requires an understanding of the ion atmosphere that surrounds nucleic acids. We have used a simple model DNA system to determine how the ion atmosphere modulates ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0404448102

    authors: Bai Y,Das R,Millett IS,Herschlag D,Doniach S

    更新日期:2005-01-25 00:00:00

  • Discovery and characterization of an epithelial-specific galectin in the endometrium that forms crystals in the trophectoderm.

    abstract::Secretions of the uterus support survival and growth of the conceptus (embryo/fetus and associated membranes) during pregnancy. Galectin-15, also known as OVGAL11 and a previously uncharacterized member of the galectin family of secreted beta-galactoside lectins containing a conserved carbohydrate recognition domain a...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0402669101

    authors: Gray CA,Adelson DL,Bazer FW,Burghardt RC,Meeusen EN,Spencer TE

    更新日期:2004-05-25 00:00:00

  • Regulation of human monocyte adherence by granulocyte-macrophage colony-stimulating factor.

    abstract::Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) was found to increase the adherence of purified peripheral blood monocytes to plastic surfaces and to monolayers of human umbilical vein endothelial cells. With plastic surfaces as a model 9-hr culture with GM-CSF was necessary for enhancement...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.86.18.7169

    authors: Gamble JR,Elliott MJ,Jaipargas E,Lopez AF,Vadas MA

    更新日期:1989-09-01 00:00:00

  • De novo generation of a transmissible spongiform encephalopathy by mouse transgenesis.

    abstract::Most transmissible spongiform encephalopathies arise either spontaneously or by infection. Mutations of PRNP, which encodes the prion protein, PrP, segregate with phenotypically similar diseases. Here we report that moderate overexpression in transgenic mice of mPrP(170N,174T), a mouse PrP with two point mutations tha...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0810680105

    authors: Sigurdson CJ,Nilsson KP,Hornemann S,Heikenwalder M,Manco G,Schwarz P,Ott D,Rülicke T,Liberski PP,Julius C,Falsig J,Stitz L,Wüthrich K,Aguzzi A

    更新日期:2009-01-06 00:00:00

  • Production of a tissue-like structure by contraction of collagen lattices by human fibroblasts of different proliferative potential in vitro.

    abstract::Fibroblasts can condense a hydrated collagen lattice to a tissue-like structure 1/28th the area of the starting gel in 24 hr. The rate of the process can be regulated by varying the protein content of the lattice, the cell number, or the concentration of an inhibitor such as Colcemid. Fibroblasts of high population do...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.76.3.1274

    authors: Bell E,Ivarsson B,Merrill C

    更新日期:1979-03-01 00:00:00

  • Pronounced zonal heterogeneity in Eocene southern high-latitude sea surface temperatures.

    abstract::Paleoclimate studies suggest that increased global warmth during the Eocene epoch was greatly amplified at high latitudes, a state that climate models cannot fully reproduce. However, proxy estimates of Eocene near-Antarctic sea surface temperatures (SSTs) have produced widely divergent results at similar latitudes, w...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1321441111

    authors: Douglas PM,Affek HP,Ivany LC,Houben AJ,Sijp WP,Sluijs A,Schouten S,Pagani M

    更新日期:2014-05-06 00:00:00

  • Illegitimate Cre-dependent chromosome rearrangements in transgenic mouse spermatids.

    abstract::The bacteriophage P1 Cre/loxP system has become a powerful tool for in vivo manipulation of the genomes of transgenic mice. Although in vitro studies have shown that Cre can catalyze recombination between cryptic "pseudo-loxP" sites in mammalian genomes, to date there have been no reports of loxP-site infidelity in tr...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.240471297

    authors: Schmidt EE,Taylor DS,Prigge JR,Barnett S,Capecchi MR

    更新日期:2000-12-05 00:00:00

  • Two-dimensional infrared spectra reveal relaxation of the nonnucleoside inhibitor TMC278 complexed with HIV-1 reverse transcriptase.

    abstract::The two nitrile groups at the wings of the nonnucleoside HIV-1 reverse transcriptase (RT) inhibitor TMC278 are both identified in high-sensitivity 2D IR spectroscopy experiments of the HIV-1 RT/TMC278 complex. The vibrational spectra indicate that the two arms of the inhibitor sense quite different environments within...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0709320104

    authors: Fang C,Bauman JD,Das K,Remorino A,Arnold E,Hochstrasser RM

    更新日期:2008-02-05 00:00:00

  • The impact of rising CO2 and acclimation on the response of US forests to global warming.

    abstract::The response of forests to climate change depends in part on whether the photosynthetic benefit from increased atmospheric CO2 (∆Ca = future minus historic CO2) compensates for increased physiological stresses from higher temperature (∆T). We predicted the outcome of these competing responses by using optimization the...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1913072116

    authors: Sperry JS,Venturas MD,Todd HN,Trugman AT,Anderegg WRL,Wang Y,Tai X

    更新日期:2019-12-17 00:00:00

  • Emergent trade-offs and selection for outbreak frequency in spatial epidemics.

    abstract::Nonspatial theory on pathogen evolution generally predicts selection for maximal number of secondary infections, constrained only by supposed physiological trade-offs between pathogen infectiousness and virulence. Spread of diseases in human populations can, however, exhibit large scale patterns, underlining the need ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0405682101

    authors: van Ballegooijen WM,Boerlijst MC

    更新日期:2004-12-28 00:00:00

  • Systemic surfaceome profiling identifies target antigens for immune-based therapy in subtypes of advanced prostate cancer.

    abstract::Prostate cancer is a heterogeneous disease composed of divergent molecular and histologic subtypes, including prostate adenocarcinoma (PrAd) and neuroendocrine prostate cancer (NEPC). While PrAd is the major histology in prostate cancer, NEPC can evolve from PrAd as a mechanism of treatment resistance that involves a ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1802354115

    authors: Lee JK,Bangayan NJ,Chai T,Smith BA,Pariva TE,Yun S,Vashisht A,Zhang Q,Park JW,Corey E,Huang J,Graeber TG,Wohlschlegel J,Witte ON

    更新日期:2018-05-08 00:00:00

  • Synthesis and characterization of a nanocrystalline diamond aerogel.

    abstract::Aerogel materials have myriad scientific and technological applications due to their large intrinsic surface areas and ultralow densities. However, creating a nanodiamond aerogel matrix has remained an outstanding and intriguing challenge. Here we report the high-pressure, high-temperature synthesis of a diamond aerog...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1010600108

    authors: Pauzauskie PJ,Crowhurst JC,Worsley MA,Laurence TA,Kilcoyne AL,Wang Y,Willey TM,Visbeck KS,Fakra SC,Evans WJ,Zaug JM,Satcher JH Jr

    更新日期:2011-05-24 00:00:00

  • PKA and GAB2 play central roles in the FSH signaling pathway to PI3K and AKT in ovarian granulosa cells.

    abstract::Controlled maturation of ovarian follicles is necessary for fertility. Follicles are restrained at an immature stage until stimulated by FSH secreted by pituitary gonadotropes. FSH acts on granulosa cells within the immature follicle to inhibit apoptosis, promote proliferation, stimulate production of steroid and prot...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1205661109

    authors: Hunzicker-Dunn ME,Lopez-Biladeau B,Law NC,Fiedler SE,Carr DW,Maizels ET

    更新日期:2012-10-30 00:00:00

  • Noncanonical Wnt signaling mediates androgen-dependent tumor growth in a mouse model of prostate cancer.

    abstract::Prostate cancer development is associated with hyperactive androgen signaling. However, the molecular link between androgen receptor (AR) function and humoral factors remains elusive. A prostate cancer mouse model was generated by selectively mutating the AR threonine 877 into alanine in prostatic epithelial cells thr...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1014850108

    authors: Takahashi S,Watanabe T,Okada M,Inoue K,Ueda T,Takada I,Watabe T,Yamamoto Y,Fukuda T,Nakamura T,Akimoto C,Fujimura T,Hoshino M,Imai Y,Metzger D,Miyazono K,Minami Y,Chambon P,Kitamura T,Matsumoto T,Kato S

    更新日期:2011-03-22 00:00:00

  • A high-resolution landscape of mutations in the BCL6 super-enhancer in normal human B cells.

    abstract::The super-enhancers (SEs) of lineage-specific genes in B cells are off-target sites of somatic hypermutation. However, the inability to detect sufficient numbers of mutations in normal human B cells has precluded the generation of a high-resolution mutational landscape of SEs. Here we captured and sequenced 12 B cell ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1914163116

    authors: Shen JC,Kamath-Loeb AS,Kohrn BF,Loeb KR,Preston BD,Loeb LA

    更新日期:2019-12-03 00:00:00

  • Induction of complete and molecular remissions in acute myeloid leukemia by Wilms' tumor 1 antigen-targeted dendritic cell vaccination.

    abstract::Active immunization using tumor antigen-loaded dendritic cells holds promise for the adjuvant treatment of cancer to eradicate or control residual disease, but so far, most dendritic cell trials have been performed in end-stage cancer patients with high tumor loads. Here, in a phase I/II trial, we investigated the eff...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1008051107

    authors: Van Tendeloo VF,Van de Velde A,Van Driessche A,Cools N,Anguille S,Ladell K,Gostick E,Vermeulen K,Pieters K,Nijs G,Stein B,Smits EL,Schroyens WA,Gadisseur AP,Vrelust I,Jorens PG,Goossens H,de Vries IJ,Price DA,Oji Y

    更新日期:2010-08-03 00:00:00

  • Protein p53 and inducer-mediated erythroleukemia cell commitment to terminal cell division.

    abstract::Inducer-mediated murine erythroleukemia cell (MELC) differentiation provides a model for examining factors determining terminal cell differentiation. The nuclear protein, p53, has been implicated as a potential determinant of cell cycle progression and cell differentiation. In this study p53 content and synthesis, dur...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.80.19.5919

    authors: Shen DW,Real FX,DeLeo AB,Old LJ,Marks PA,Rifkind RA

    更新日期:1983-10-01 00:00:00