Palmitic acid causes insulin resistance in granulosa cells via activation of JNK

in Journal of Molecular Endocrinology

Correspondence should be addressed to S Zhao: shidouzhao@sdu.edu.cn

*(L Xu and W Wang contributed equally to this work)

Restricted access

Obesity is a worldwide health problem with rising incidence and results in reproductive difficulties. Elevated saturated free fatty acids (FFAs) in obesity can cause insulin resistance (IR) in peripheral tissues. The high intra-follicular saturated FFAs may also account for IR in ovarian granulosa cells (GCs). In the present study, we investigated the relationship between saturated FFAs and IR in GCs by the use of palmitic acid (PA). We demonstrated that the glucose uptake in cultured GCs and lactate accumulation in the culture medium were stimulated by insulin, but the effects of insulin were attenuated by PA treatment. Besides, insulin-induced phosphorylation of Akt was reduced by PA in a dose- and time-dependent manner. Furthermore, PA increased phosphorylation of JNK and JNK blockage rescued the phosphorylation of Akt which was downregulated by PA. These findings highlighted the negative effect of PA on GCs metabolism and may partially account for the obesity-related reproductive disorders.

 

      Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 2170 2079 197
Full Text Views 134 130 0
PDF Downloads 43 38 0
  • AardemaHVosPLLolicatoFRoelenBAKnijnHMVaandragerABHelmsJBGadellaBM 2011 Oleic acid prevents detrimental effects of saturated fatty acids on bovine oocyte developmental competence. Biology of Reproduction 85 6269. (https://doi.org/10.1095/biolreprod.110.088815)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • AguirreVUchidaTYenushLDavisRWhiteMF 2000 The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). Journal of Biological Chemistry 275 90479054. (https://doi.org/10.1074/jbc.275.12.9047)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • AkamineEHMarcalACCamporezJPHoshidaMSCaperutoLCBevilacquaECarvalhoCR 2010 Obesity induced by high-fat diet promotes insulin resistance in the ovary. Journal of Endocrinology 206 6574. (https://doi.org/10.1677/JOE-09-0461)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • BarberTMMcCarthyMIWassJAHFranksS 2006 Obesity and polycystic ovary syndrome. Clinical Endocrinology 65 137145. (https://doi.org/10.1111/j.1365-2265.2006.02587.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BiYWuWShiJLiangHYinWChenYTangSCaoSCaiMShenS 2014 Role for sterol regulatory element binding protein-1c activation in mediating skeletal muscle insulin resistance via repression of rat insulin receptor substrate-1 transcription. Diabetologia 57 592602. (https://doi.org/10.1007/s00125-013-3136-1)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BodenG 1997 Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 46 310. (https://doi.org/10.2337/diab.46.1.3)

  • BodenG 1998 Free fatty acids (FFA), a link between obesity and insulin resistance. Frontiers in Bioscience 3 d169d175. (https://doi.org/10.2741/A272)

  • BodenG 2008 Obesity and free fatty acids. Endocrinology and Metabolism Clinics of North America 37 635646. (https://doi.org/10.1016/j.ecl.2008.06.007)

  • BodenGCheungPSteinTPKresgeKMozzoliM 2002 FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis. American Journal of Physiology: Endocrinology and Metabolism 283 E12E19. (https://doi.org/10.1152/ajpendo.00429.2001)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • BruceCRFebbraioMA 2007 It’s what you do with the fat that matters! Nature Medicine 13 11371138. (https://doi.org/10.1038/nm1007-1137)

  • CrujeirasABCasanuevaFF 2015 Obesity and the reproductive system disorders: epigenetics as a potential bridge. Human Reproduction Update 21 249261. (https://doi.org/10.1093/humupd/dmu060)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Diamanti-KandarakisEChatzigeorgiouAPapageorgiouEKoundourasDKoutsilierisM 2016 Advanced glycation end-products and insulin signaling in granulosa cells. Experimental Biology and Medicine 241 14381445. (https://doi.org/10.1177/1535370215584937)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • DupontJScaramuzziRJ 2016 Insulin signalling and glucose transport in the ovary and ovarian function during the ovarian cycle. Biochemical Journal 473 14831501. (https://doi.org/10.1042/BCJ20160124)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • FanHYLiuZShimadaMSterneckEJohnsonPFHedrickSMRichardsJS 2009 MAPK3/1 (ERK1/2) in ovarian granulosa cells are essential for female fertility. Science 324 938941. (https://doi.org/10.1126/science.1171396)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • FedorcsakPStorengRDalePOTanboTAbyholmT 2000 Impaired insulin action on granulosa-lutein cells in women with polycystic ovary syndrome and insulin resistance. Gynecological Endocrinology 14 327336. (https://doi.org/10.3109/09513590009167701)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • GaoZHwangDBatailleFLefevreMYorkDQuonMJYeJ 2002 Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. Journal of Biological Chemistry 277 4811548121. (https://doi.org/10.1074/jbc.M209459200)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Hage HassanRPacheco de SousaACMahfouzRHainaultIBlachnio-ZabielskaABourronOKoskasFGorskiJFerrePFoufelleF 2016 Sustained action of ceramide on the insulin signaling pathway in muscle cells: implication of the double-stranded RNA-activated protein kinase. Journal of Biological Chemistry 291 30193029. (https://doi.org/10.1074/jbc.M115.686949)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • HirosumiJTuncmanGChangLGorgunCZUysalKTMaedaKKarinMHotamisligilGS 2002 A central role for JNK in obesity and insulin resistance. Nature 420 333336. (https://doi.org/10.1038/nature01137)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • HotamisligilGS 1999 The role of TNFalpha and TNF receptors in obesity and insulin resistance. Journal of Internal Medicine 245 621625. (https://doi.org/10.1046/j.1365-2796.1999.00490.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • JangSYuLRAbdelmegeedMAGaoYBanerjeeASongBJ 2015 Critical role of c-jun N-terminal protein kinase in promoting mitochondrial dysfunction and acute liver injury. Redox Biology 6 552564. (https://doi.org/10.1016/j.redox.2015.09.040)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • KimJKFillmoreJJChenYYuCMooreIKPypaertMLutzEPKakoYVelez-CarrascoWGoldbergIJ 2001 Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. PNAS 98 75227527. (https://doi.org/10.1073/pnas.121164498)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • KodamanPHBehrmanHR 1999 Hormone-regulated and glucose-sensitive transport of dehydroascorbic acid in immature rat granulosa cells. Endocrinology 140 36593665. (https://doi.org/10.1210/endo.140.8.6938)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LieBLLeungELeungPCAuerspergN 1996 Long-term growth and steroidogenic potential of human granulosa-lutein cells immortalized with SV40 large T antigen. Molecular and Cellular Endocrinology 120 169176. (https://doi.org/10.1016/0303-7207(96)03835-X)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LinYFridstromMHillensjoT 1997 Insulin stimulation of lactate accumulation in isolated human granulosa-luteal cells: a comparison between normal and polycystic ovaries. Human Reproduction 12 24692472. (https://doi.org/10.1093/humrep/12.11.2469)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • MalhiHBronkSFWerneburgNWGoresGJ 2006 Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. Journal of Biological Chemistry 281 1209312101. (https://doi.org/10.1074/jbc.M510660200)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • MitchellAFantasiaHC 2016 Understanding the effect of obesity on fertility among reproductive-age women. Nursing for Women’s Health 20 368376. (https://doi.org/10.1016/j.nwh.2016.07.001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • MitchellMArmstrongDTRobkerRLNormanRJ 2005 Adipokines: implications for female fertility and obesity. Reproduction 130 583597. (https://doi.org/10.1530/rep.1.00521)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • MuYMYanaseTNishiYTanakaASaitoMJinCHMukasaCOkabeTNomuraMGotoK 2001 Saturated FFAs, palmitic acid and stearic acid, induce apoptosis in human granulosa cells. Endocrinology 142 35903597. (https://doi.org/10.1210/endo.142.8.8293)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • NakamuraSTakamuraTMatsuzawa-NagataNTakayamaHMisuHNodaHNabemotoSKuritaSOtaTAndoH 2009 Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive oxygen species produced by mitochondria. Journal of Biological Chemistry 284 1480914818. (https://doi.org/10.1074/jbc.M901488200)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • NguyenMTSatohHFavelyukisSBabendureJLImamuraTSbodioJIZalevskyJDahiyatBIChiNWOlefskyJM 2005 JNK and tumor necrosis factor-alpha mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. Journal of Biological Chemistry 280 3536135371. (https://doi.org/10.1074/jbc.M504611200)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • NishiYYanaseTMuYObaKIchinoISaitoMNomuraMMukasaCOkabeTGotoK 2001 Establishment and characterization of a steroidogenic human granulosa-like tumor cell line, KGN, that expresses functional follicle-stimulating hormone receptor. Endocrinology 142 437445. (https://doi.org/10.1210/endo.142.1.7862)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • NiuZLinNGuRSunYFengY 2014 Associations between insulin resistance, free fatty acids, and oocyte quality in polycystic ovary syndrome during in vitro fertilization. Journal of Clinical Endocrinology and Metabolism 99 E2269E2276. (https://doi.org/10.1210/jc.2013-3942)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • OzcanUCaoQYilmazELeeAHIwakoshiNNOzdelenETuncmanGGorgunCGlimcherLHHotamisligilGS 2004 Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306 457461. (https://doi.org/10.1126/science.1103160)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • PasqualiRPelusiCGenghiniSCacciariMGambineriA 2003 Obesity and reproductive disorders in women. Human Reproduction Update 9 359372. (https://doi.org/10.1093/humupd/dmg024)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • PurcellSHChiMMLanzendorfSMoleyKH 2012 Insulin-stimulated glucose uptake occurs in specialized cells within the cumulus oocyte complex. Endocrinology 153 24442454. (https://doi.org/10.1210/en.2011-1974)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • RicchiMOdoardiMRCarulliLAnzivinoCBallestriSPinettiAFantoniLIMarraFBertolottiMBanniS 2009 Differential effect of oleic and palmitic acid on lipid accumulation and apoptosis in cultured hepatocytes. Journal of Gastroenterology and Hepatology 24 830840. (https://doi.org/10.1111/j.1440-1746.2008.05733.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • RiceSChristoforidisNGaddCNikolaouDSeyaniLDonaldsonAMargaraRHardyKFranksS 2005 Impaired insulin-dependent glucose metabolism in granulosa-lutein cells from anovulatory women with polycystic ovaries. Human Reproduction 20 373381. (https://doi.org/10.1093/humrep/deh609)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • RiceSPellattLJBryanSJWhiteheadSAMasonHD 2011 Action of metformin on the insulin-signaling pathway and on glucose transport in human granulosa cells. Journal of Clinical Endocrinology and Metabolism 96 E427E435. (https://doi.org/10.1210/jc.2010-2060)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • RopelleERPauliJRCintraDEda SilvaASDe SouzaCTGuadagniniDCarvalhoBMCaricilliAMKatashimaCKCarvalho-FilhoMA 2013 Targeted disruption of inducible nitric oxide synthase protects against aging, S-nitrosation, and insulin resistance in muscle of male mice. Diabetes 62 466470. (https://doi.org/10.2337/db12-0339)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • RuddockMWSteinALandakerEParkJCookseyRCMcClainDPattiME 2008 Saturated fatty acids inhibit hepatic insulin action by modulating insulin receptor expression and post-receptor signalling. Journal of Biochemistry 144 599607. (https://doi.org/10.1093/jb/mvn105)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ShahDKMissmerSABerryKFRacowskyCGinsburgES 2011 Effect of obesity on oocyte and embryo quality in women undergoing in vitro fertilization. Obstetrics and Gynecology 118 6370. (https://doi.org/10.1097/AOG.0b013e31821fd360)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • SolinasGNauglerWGalimiFLeeMSKarinM 2006 Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. PNAS 103 1645416459. (https://doi.org/10.1073/pnas.0607626103)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • StebbinsJLDeSKMachleidtTBecattiniBVazquezJKuntzenCChenLHCellittiJFRiel-MehanMEmdadiA 2008 Identification of a new JNK inhibitor targeting the JNK-JIP interaction site. PNAS 105 1680916813. (https://doi.org/10.1073/pnas.0805677105)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • StumvollMGoldsteinBJvan HaeftenTW 2005 Type 2 diabetes: principles of pathogenesis and therapy. Lancet 365 13331346. (https://doi.org/10.1016/S0140-6736(05)61032-X)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • SugiuraKPendolaFLEppigJJ 2005 Oocyte control of metabolic cooperativity between oocytes and companion granulosa cells: energy metabolism. Developmental Biology 279 2030. (https://doi.org/10.1016/j.ydbio.2004.11.027)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • TaniguchiCMEmanuelliBKahnCR 2006 Critical nodes in signalling pathways: insights into insulin action. Nature Reviews: Molecular Cell Biology 7 8596. (https://doi.org/10.1038/nrm1837)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • UysalKTWiesbrockSMMarinoMWHotamisligilGS 1997 Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389 610614. (https://doi.org/10.1038/39335)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ValckxSDArias-AlvarezMDe PauwIFievezVVlaeminckBFransenEBolsPELeroyJL 2014 Fatty acid composition of the follicular fluid of normal weight, overweight and obese women undergoing assisted reproductive treatment: a descriptive cross-sectional study. Reproductive Biology and Endocrinology 12 13. (https://doi.org/10.1186/1477-7827-12-13)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • VanholderTLeroyJLSoomAVOpsomerGMaesDCorynMde KruifA 2005 Effect of non-esterified fatty acids on bovine granulosa cell steroidogenesis and proliferation in vitro. Animal Reproduction Science 87 3344. (https://doi.org/10.1016/j.anireprosci.2004.09.006)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • WuXKZhouSYLiuJXPollanenPSallinenKMakinenMErkkolaR 2003 Selective ovary resistance to insulin signaling in women with polycystic ovary syndrome. Fertility and Sterility 80 954965. (https://doi.org/10.1016/S0015-0282(03)01007-0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • WuLLRussellDLNormanRJRobkerRL 2012 Endoplasmic reticulum (ER) stress in cumulus-oocyte complexes impairs pentraxin-3 secretion, mitochondrial membrane potential (DeltaPsi m), and embryo development. Molecular Endocrinology 26 562573. (https://doi.org/10.1210/me.2011-1362)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • XieYLPanYEChangCJTangPCHuangYFWalzemRLChenSE 2012 Palmitic acid in chicken granulosa cell death-lipotoxic mechanisms mediate reproductive inefficacy of broiler breeder hens. Theriogenology 78 19171928. (https://doi.org/10.1016/j.theriogenology.2012.07.004)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • YangXWuLLChuraLRLiangXLaneMNormanRJRobkerRL 2012 Exposure to lipid-rich follicular fluid is associated with endoplasmic reticulum stress and impaired oocyte maturation in cumulus-oocyte complexes. Fertility and Sterility 97 14381443. (https://doi.org/10.1016/j.fertnstert.2012.02.034)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ZeydaMStulnigTM 2009 Obesity, inflammation, and insulin resistance--a mini-review. Gerontology 55 379386. (https://doi.org/10.1159/000212758)

  • ZhangCNiuWWangZWangXXiaG 2012 The effect of gonadotropin on glucose transport and apoptosis in rat ovary. PLoS One 7 e42406. (https://doi.org/10.1371/journal.pone.0042406)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ZhaoSXuHCuiYWangWQinYYouLChanWYSunYChenZJ 2016 Metabolic actions of insulin in ovarian granulosa cells were unaffected by hyperandrogenism. Endocrine 53 823830. (https://doi.org/10.1007/s12020-016-0949-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation