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The Neuroinflammatory and Neurotoxic Potential of Palmitic Acid Is Mitigated by Oleic Acid in Microglial Cells and Microglial-Neuronal Co-cultures

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Abstract

Neuroinflammation has been implicated in the pathogenesis of neurodegeneration and is now accepted as a common molecular feature underpinning neuronal damage and death. Palmitic acid (PA) may represent one of the links between diet and neuroinflammation. The aims of this study were to assess whether PA induced toxicity in neuronal cells by modulating microglial inflammatory responses and/or by directly targeting neurons. We also determined the potential of oleic acid (OA), a monounsaturated fatty acid, to counteract inflammation and promote neuroprotection. We measured the ability of PA to induce the secretion of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), the induction of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling pathways, as well as the phosphorylation of c-Jun, and the expression of inducible nitric oxide synthase (iNOS). Finally, to determine whether PA exerted an indirect neurotoxic effect on neuronal cells, we employed a microglia-neuron co-culture paradigm where microglial cells communicate with neuronal cells in a paracrine fashion. Herein, we demonstrate that PA induces the activation of the NF-κB signalling pathway and c-Jun phosphorylation in N9 microglia cells, in the absence of increased cytokine secretion. Moreover, our data illustrate that PA exerts an indirect as well as a direct neurotoxic role on neuronal PC12 cells and these effects are partially prevented by OA. These results are important to establish that PA interferes with neuronal homeostasis and suggest that dietary PA, when consumed in excess, may induce neuroinflammation and possibly concurs in the development of neurodegeneration.

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References

  1. Carson MJ, Thrash JC, Walter B (2006) The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival. Clin Neurosci Res 6(5):237–245. https://doi.org/10.1016/j.cnr.2006.09.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Guerreiro S, Privat AL, Bressac L, Toulorge D (2020) CD38 in Neurodegeneration and Neuroinflammation. Cells 9(2). https://doi.org/10.3390/cells9020471

  3. Bader V, Winklhofer KF (2020) Mitochondria at the interface between neurodegeneration and neuroinflammation. Semin Cell Dev Biol 99:163–171. https://doi.org/10.1016/j.semcdb.2019.05.028

    Article  CAS  PubMed  Google Scholar 

  4. Park J, Wetzel I, Marriott I, Dreau D, D'Avanzo C, Kim DY, Tanzi RE, Cho H (2018) A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease. Nat Neurosci 21(7):941–951. https://doi.org/10.1038/s41593-018-0175-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Vivekanantham S, Shah S, Dewji R, Dewji A, Khatri C, Ologunde R (2015) Neuroinflammation in Parkinson’s disease: role in neurodegeneration and tissue repair. Int J Neurosci 125(10):717–725. https://doi.org/10.3109/00207454.2014.982795

    Article  CAS  PubMed  Google Scholar 

  6. Lee S-H, Suk K (2017) Emerging roles of protein kinases in microglia-mediated neuroinflammation. Biochem Pharmacol 146:1–9. https://doi.org/10.1016/j.bcp.2017.06.137

    Article  CAS  PubMed  Google Scholar 

  7. Jha MK, Lee W-H, Suk K (2016) Functional polarization of neuroglia: implications in neuroinflammation and neurological disorders. Biochem Pharmacol 103(Supplement C):1–16. https://doi.org/10.1016/j.bcp.2015.11.003

    Article  CAS  PubMed  Google Scholar 

  8. Minghetti L, Levi G (1998) Microglia as effector cells in brain damage and repair: focus on prostanoids and nitric oxide. Prog Neurobiol 54(1):99–125. https://doi.org/10.1016/s0301-0082(97)00052-x

    Article  CAS  PubMed  Google Scholar 

  9. Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39(6):889–909. https://doi.org/10.1016/S0896-6273(03)00568-3

    Article  CAS  PubMed  Google Scholar 

  10. Shabab T, Khanabdali R, Moghadamtousi SZ, Kadir HA, Mohan G (2017) Neuroinflammation pathways: a general review. Int J Neurosci 127(7):624–633. https://doi.org/10.1080/00207454.2016.1212854

    Article  CAS  PubMed  Google Scholar 

  11. Milanski M, Degasperi G, Coope A, Morari J, Denis R, Cintra DE, Tsukumo DML, Anhe G et al (2009) Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J Neurosci 29(2):359–370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sergi D, Morris AC, Kahn DE, McLean FH, Hay EA, Kubitz P, MacKenzie A, Martinoli MG et al (2020) Palmitic acid triggers inflammatory responses in N42 cultured hypothalamic cells partially via ceramide synthesis but not via TLR4. Nutr Neurosci 23(4):321–334. https://doi.org/10.1080/1028415X.2018.1501533

    Article  CAS  PubMed  Google Scholar 

  13. Sergi D, Williams LM (2020) Potential relationship between dietary long-chain saturated fatty acids and hypothalamic dysfunction in obesity. Nutr Rev 78(4):261–277. https://doi.org/10.1093/nutrit/nuz056

    Article  PubMed  Google Scholar 

  14. Valdearcos M, Robblee MM, Benjamin DI, Nomura DK, Xu AW, Koliwad SK (2014) Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function. Cell Rep 9(6):2124–2138. https://doi.org/10.1016/j.celrep.2014.11.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Weigert C, Brodbeck K, Staiger H, Kausch C, Machicao F, Häring HU, Schleicher ED (2004) Palmitate, but not unsaturated fatty acids, induces the expression of interleukin-6 in human myotubes through proteasome-dependent activation of nuclear factor-κB. J Biol Chem 279(23):23942–23952

    Article  CAS  PubMed  Google Scholar 

  16. Håversen L, Danielsson KN, Fogelstrand L, Wiklund O (2009) Induction of proinflammatory cytokines by long-chain saturated fatty acids in human macrophages. Atherosclerosis 202(2):382–393. https://doi.org/10.1016/j.atherosclerosis.2008.05.033

    Article  CAS  PubMed  Google Scholar 

  17. Bullo M, Casas-Agustench P, Amigo-Correig P, Aranceta J, Salas-Salvado J (2007) Inflammation, obesity and comorbidities: the role of diet. Public Health Nutr 10(10A):1164–1172. https://doi.org/10.1017/S1368980007000663

    Article  PubMed  Google Scholar 

  18. Arnold SE, Arvanitakis Z, Macauley-Rambach SL, Koenig AM, Wang HY, Ahima RS, Craft S, Gandy S et al (2018) Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol 14(3):168–181. https://doi.org/10.1038/nrneurol.2017.185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sergi D, Renaud J, Simola N, Martinoli MG (2019) Diabetes, a contemporary risk for Parkinson’s disease: epidemiological and cellular evidences. Front Aging Neurosci 11:302. https://doi.org/10.3389/fnagi.2019.00302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Duffy CM, Nixon JP, Butterick TA (2016) Orexin A attenuates palmitic acid-induced hypothalamic cell death. Mol Cell Neurosci 75:93–100. https://doi.org/10.1016/j.mcn.2016.07.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gonzalez-Giraldo Y, Garcia-Segura LM, Echeverria V, Barreto GE (2018) Tibolone preserves mitochondrial functionality and cell morphology in astrocytic cells treated with palmitic acid. Mol Neurobiol 55(5):4453–4462. https://doi.org/10.1007/s12035-017-0667-3

    Article  CAS  PubMed  Google Scholar 

  22. Duffy CM, Yuan C, Wisdorf LE, Billington CJ, Kotz CM, Nixon JP, Butterick TA (2015) Role of orexin A signaling in dietary palmitic acid-activated microglial cells. Neurosci Lett 606:140–144. https://doi.org/10.1016/j.neulet.2015.08.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Klein-Platat C, Drai J, Oujaa M, Schlienger J-L, Simon C (2005) Plasma fatty acid composition is associated with the metabolic syndrome and low-grade inflammation in overweight adolescents1–3. Am J Clin Nutr 82(6):1178–1184. https://doi.org/10.1093/ajcn/82.6.1178

    Article  CAS  PubMed  Google Scholar 

  24. Lee JY, Sohn KH, Rhee SH, Hwang D (2001) Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem 276(20):16683–16689

    Article  CAS  PubMed  Google Scholar 

  25. Laine PS, Schwartz EA, Wang Y, Zhang W-Y, Karnik SK, Musi N, Reaven PD (2007) Palmitic acid induces IP-10 expression in human macrophages via NF-κB activation. Biochem Biophys Res Commun 358(1):150–155. https://doi.org/10.1016/j.bbrc.2007.04.092

    Article  CAS  PubMed  Google Scholar 

  26. Little JP, Madeira JM, Klegeris A (2012) The saturated fatty acid palmitate induces human monocytic cell toxicity toward neuronal cells: exploring a possible link between obesity-related metabolic impairments and neuroinflammation. J Alzheimer’s Dis 30(Suppl 2):S179–S183. https://doi.org/10.3233/JAD-2011-111262

    Article  CAS  Google Scholar 

  27. Posey KA, Clegg DJ, Printz RL, Byun J, Morton GJ, Vivekanandan-Giri A, Pennathur S, Baskin DG et al (2009) Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am J Physiol Endocrinol Metab 296(5):E1003–E1012. https://doi.org/10.1152/ajpendo.90377.2008

    Article  CAS  PubMed  Google Scholar 

  28. Melo HM, Santos LE, Ferreira ST (2019) Diet-derived fatty acids, brain inflammation, and mental health. Front Neurosci 13:265. https://doi.org/10.3389/fnins.2019.00265

    Article  PubMed  PubMed Central  Google Scholar 

  29. Gupta S, Knight AG, Gupta S, Keller JN, Bruce-Keller AJ (2012) Saturated long chain fatty acids activate inflammatory signaling in astrocytes. J Neurochem 120(6):1060–1071. https://doi.org/10.1111/j.1471-4159.2012.07660.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang Z, Liu D, Zhang Q, Wang J, Zhan J, Xian X, Du Z, Wang X et al (2014) Palmitic acid affects proliferation and differentiation of neural stem cells in vitro. J Neurosci Res 92(5):574–586. https://doi.org/10.1002/jnr.23342

    Article  CAS  PubMed  Google Scholar 

  31. Kim JY, Lee HJ, Lee SJ, Jung YH, Yoo DY, Hwang IK, Seong JK, Ryu JM et al (2017) Palmitic Acid-BSA enhances Amyloid-beta production through GPR40-mediated dual pathways in neuronal cells: involvement of the Akt/mTOR/HIF-1alpha and Akt/NF-kappaB pathways. Sci Rep 7(1):4335. https://doi.org/10.1038/s41598-017-04175-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Smith QR, Nagura H (2001) Fatty acid uptake and incorporation in brain. J Mol Neurosci 16(2):167–172. https://doi.org/10.1385/JMN:16:2-3:167

    Article  CAS  PubMed  Google Scholar 

  33. Karmi A, Iozzo P, Viljanen A, Hirvonen J, Fielding BA, Virtanen K, Oikonen V, Kemppainen J et al (2010) Increased brain fatty acid uptake in metabolic syndrome. Diabetes 59(9):2171–2177. https://doi.org/10.2337/db09-0138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Palomer X, Pizarro-Delgado J, Barroso E, Vázquez-Carrera M (2018) Palmitic and oleic acid: the yin and yang of fatty acids in type 2 diabetes mellitus. Trends Endocrinol Metab 29(3):178–190. https://doi.org/10.1016/j.tem.2017.11.009

    Article  CAS  PubMed  Google Scholar 

  35. Avallone R, Vitale G, Bertolotti M (2019) Omega-3 fatty acids and neurodegenerative diseases: new evidence in clinical trials. Int J Mol Sci 20(17). https://doi.org/10.3390/ijms20174256

  36. Nocella C, Cammisotto V, Fianchini L, D'Amico A, Novo M, Castellani V, Stefanini L, Violi F et al (2018) Extra virgin olive oil and cardiovascular diseases: benefits for human health. Endocr Metab Immune Disord Drug Targets 18(1):4–13. https://doi.org/10.2174/1871530317666171114121533

    Article  CAS  PubMed  Google Scholar 

  37. Casas R, Estruch R, Sacanella E (2018) The protective effects of extra virgin olive oil on immune-mediated inflammatory responses. Endocr Metab Immune Disord Drug Targets 18(1):23–35. https://doi.org/10.2174/1871530317666171114115632

    Article  CAS  PubMed  Google Scholar 

  38. Sofi F, Abbate R, Gensini GF, Casini A (2010) Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis. Am J Clin Nutr 92(5):1189–1196. https://doi.org/10.3945/ajcn.2010.29673

    Article  CAS  PubMed  Google Scholar 

  39. Guzman DC, Brizuela NO, Herrera MO, Olguin HJ, Garcia EH, Peraza AV, Mejia GB (2016) Oleic acid protects against oxidative stress exacerbated by cytarabine and doxorubicin in rat brain. Anti Cancer Agents Med Chem 16(11):1491–1495. https://doi.org/10.2174/1871520615666160504093652

    Article  CAS  Google Scholar 

  40. Tse EK, Belsham DD (2018) Palmitate induces neuroinflammation, ER stress, and Pomc mRNA expression in hypothalamic mHypoA-POMC/GFP neurons through novel mechanisms that are prevented by oleate. Mol Cell Endocrinol 472:40–49. https://doi.org/10.1016/j.mce.2017.11.017

    Article  CAS  PubMed  Google Scholar 

  41. Amtul Z, Westaway D, Cechetto DF, Rozmahel RF (2011) Oleic acid ameliorates amyloidosis in cellular and mouse models of Alzheimer’s disease. Brain Pathol 21(3):321–329. https://doi.org/10.1111/j.1750-3639.2010.00449.x

    Article  CAS  PubMed  Google Scholar 

  42. Cousin SP, Hügl SR, Wrede CE, Kajio H, Myers JMG, Rhodes CJ (2001) Free fatty acid-induced inhibition of glucose and insulin-like growth factor i-induced deoxyribonucleic acid synthesis in the pancreatic β-cell line INS-1**This work was supported by grants from the NIH (GK-55267), the Juvenile Diabetes Foundation International, the German Research Society, and BetaGene, Inc. Endocrinology 142(1):229–240. https://doi.org/10.1210/endo.142.1.7863

    Article  CAS  PubMed  Google Scholar 

  43. Zindler E, Zipp F (2010) Neuronal injury in chronic CNS inflammation. Best Pract Res Clin Anaesthesiol 24(4):551–562. https://doi.org/10.1016/j.bpa.2010.11.001

    Article  CAS  PubMed  Google Scholar 

  44. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid–induced insulin resistance. J Clin Investig 116(11):3015–3025. https://doi.org/10.1172/JCI28898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. You M, Miao Z, Sienkiewicz O, Jiang X, Zhao X, Hu F (2020) 10-Hydroxydecanoic acid inhibits LPS-induced inflammation by targeting p53 in microglial cells. Int Immunopharmacol 84:106501. https://doi.org/10.1016/j.intimp.2020.106501

    Article  CAS  PubMed  Google Scholar 

  46. Tang LL, Wu YB, Fang CQ, Qu P, Gao ZL (2016) NDRG2 promoted secreted miR-375 in microvesicles shed from M1 microglia, which induced neuron damage. Biochem Biophys Res Commun 469(3):392–398. https://doi.org/10.1016/j.bbrc.2015.11.098

    Article  CAS  PubMed  Google Scholar 

  47. Renaud J, Martinoli M-G (2016) Development of an insert co-culture system of two cellular types in the absence of cell-cell contact. JoVE 113:e54356. https://doi.org/10.3791/54356

    Article  Google Scholar 

  48. Bureau G, Longpré F, Martinoli MG (2008) Resveratrol and quercetin, two natural polyphenols, reduce apoptotic neuronal cell death induced by neuroinflammation. J Neurosci Res 86(2):403–410. https://doi.org/10.1002/jnr.21503

    Article  CAS  PubMed  Google Scholar 

  49. Bournival J, Quessy P, Martinoli MG (2009) Protective effects of resveratrol and quercetin against MPP+ -induced oxidative stress act by modulating markers of apoptotic death in dopaminergic neurons. Cell Mol Neurobiol 29(8):1169–1180. https://doi.org/10.1007/s10571-009-9411-5

    Article  CAS  PubMed  Google Scholar 

  50. Bournival J, Plouffe M, Renaud J, Provencher C, Martinoli M-G (2012) Quercetin and sesamin protect dopaminergic cells from MPP(+)-induced neuroinflammation in a microglial (N9)-neuronal (PC12) coculture system. Oxidative Med Cell Longev 2012:921941–921911. https://doi.org/10.1155/2012/921941

    Article  CAS  Google Scholar 

  51. Gelinas S, Martinoli MG (2002) Neuroprotective effect of estradiol and phytoestrogens on MPP+-induced cytotoxicity in neuronal PC12 cells. J Neurosci Res 70(1):90–96. https://doi.org/10.1002/jnr.10315

    Article  CAS  PubMed  Google Scholar 

  52. Arel-Dubeau AM, Longpre F, Bournival J, Tremblay C, Demers-Lamarche J, Haskova P, Attard E, Germain M et al (2014) Cucurbitacin E has neuroprotective properties and autophagic modulating activities on dopaminergic neurons. Oxidative Med Cell Longev 2014:425496–425415. https://doi.org/10.1155/2014/425496

    Article  Google Scholar 

  53. Duffy CM, Xu H, Nixon JP, Bernlohr DA, Butterick TA (2017) Identification of a fatty acid binding protein4-UCP2 axis regulating microglial mediated neuroinflammation. Mol Cell Neurosci 80:52–57. https://doi.org/10.1016/j.mcn.2017.02.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Karpe F, Dickmann JR, Frayn KN (2011) Fatty acids, obesity, and insulin resistance: time for a reevaluation. Diabetes 60(10):2441–2449. https://doi.org/10.2337/db11-0425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Martin A, Clynes M (1991) Acid phosphatase: endpoint for in vitro toxicity tests. In Vitro Cell Dev Biol 27A(3 Pt 1):183–184. https://doi.org/10.1007/bf02630912

    Article  CAS  PubMed  Google Scholar 

  56. Renaud J, Bournival J, Zottig X, Martinoli MG (2014) Resveratrol protects DAergic PC12 cells from high glucose-induced oxidative stress and apoptosis: effect on p53 and GRP75 localization. Neurotox Res 25(1):110–123. https://doi.org/10.1007/s12640-013-9439-7

    Article  CAS  PubMed  Google Scholar 

  57. Tanaka T, Kai S, Matsuyama T, Adachi T, Fukuda K, Hirota K (2013) General anesthetics inhibit LPS-induced IL-1beta expression in glial cells. PLoS One 8(12):e82930. https://doi.org/10.1371/journal.pone.0082930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Liu PW, Chen MF, Tsai AP, Lee TJ (2012) STAT1 mediates oroxylin a inhibition of iNOS and pro-inflammatory cytokines expression in microglial BV-2 cells. PLoS One 7(12):e50363. https://doi.org/10.1371/journal.pone.0050363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Oh YT, Lee JY, Lee J, Kim H, Yoon KS, Choe W, Kang I (2009) Oleic acid reduces lipopolysaccharide-induced expression of iNOS and COX-2 in BV2 murine microglial cells: possible involvement of reactive oxygen species, p38 MAPK, and IKK/NF-kappaB signaling pathways. Neurosci Lett 464(2):93–97. https://doi.org/10.1016/j.neulet.2009.08.040

    Article  CAS  PubMed  Google Scholar 

  60. Hickman S, Izzy S, Sen P, Morsett L, El Khoury J (2018) Microglia in neurodegeneration. Nat Neurosci 21(10):1359–1369. https://doi.org/10.1038/s41593-018-0242-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tansey MG, Goldberg MS (2010) Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis 37(3):510–518. https://doi.org/10.1016/j.nbd.2009.11.004

    Article  CAS  PubMed  Google Scholar 

  62. Barnum CJ, Tansey MG (2012) Neuroinflammation and non-motor symptoms: the dark passenger of Parkinson’s disease? Curr Neurol Neurosci Rep 12(4):350–358. https://doi.org/10.1007/s11910-012-0283-6

    Article  CAS  PubMed  Google Scholar 

  63. Hidalgo-Lanussa O, Baez-Jurado E, Echeverria V, Ashraf GM, Sahebkar A, Garcia-Segura LM, Melcangi RC, Barreto GE (2020) Lipotoxicity, neuroinflammation, glial cells and oestrogenic compounds. J Neuroendocrinol 32(1):e12776. https://doi.org/10.1111/jne.12776

    Article  CAS  PubMed  Google Scholar 

  64. Sharma N, Nehru B (2015) Characterization of the lipopolysaccharide induced model of Parkinson’s disease: role of oxidative stress and neuroinflammation. Neurochem Int 87:92–105. https://doi.org/10.1016/j.neuint.2015.06.004

    Article  CAS  PubMed  Google Scholar 

  65. Jellinger KA (2000) Cell death mechanisms in Parkinson’s disease. J Neural Transm (Vienna) 107(1):1–29. https://doi.org/10.1007/s007020050001

    Article  CAS  Google Scholar 

  66. Riera-Borrull M, Cuevas VD, Alonso B, Vega MA, Joven J, Izquierdo E, Corbí ÁL (2017) Palmitate conditions macrophages for enhanced responses toward inflammatory stimuli via JNK activation. J Immunol 199:3858–3869

    Article  CAS  PubMed  Google Scholar 

  67. Morselli E, Fuente-Martin E, Finan B, Kim M, Frank A, Garcia-Caceres C, Navas CR, Gordillo R et al (2014) Hypothalamic PGC-1alpha protects against high-fat diet exposure by regulating ERalpha. Cell Rep 9(2):633–645. https://doi.org/10.1016/j.celrep.2014.09.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Sergi D, Campbell FM, Grant C, Morris AC, Bachmair EM, Koch C, McLean FH, Muller A et al (2018) SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice. Genes Nutr 13:28. https://doi.org/10.1186/s12263-018-0619-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Gao Y, Bielohuby M, Fleming T, Grabner GF, Foppen E, Bernhard W, Guzman-Ruiz M, Layritz C et al (2017) Dietary sugars, not lipids, drive hypothalamic inflammation. Mol Metab 6(8):897–908. https://doi.org/10.1016/j.molmet.2017.06.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sergi D, Boulestin H, Campbell FM, Williams LM (2020) The role of dietary advanced glycation end products in metabolic dysfunction. Mol Nutr Food Res 65:e1900934. https://doi.org/10.1002/mnfr.201900934

    Article  CAS  PubMed  Google Scholar 

  71. Vukic V, Callaghan D, Walker D, Lue LF, Liu QY, Couraud PO, Romero IA, Weksler B et al (2009) Expression of inflammatory genes induced by beta-amyloid peptides in human brain endothelial cells and in Alzheimer’s brain is mediated by the JNK-AP1 signaling pathway. Neurobiol Dis 34(1):95–106. https://doi.org/10.1016/j.nbd.2008.12.007

    Article  CAS  PubMed  Google Scholar 

  72. Wang Y, Mao L, Zhang L, Zhang L, Yang M, Zhang Z, Li D, Fan C et al (2016) Adoptive regulatory T-cell therapy attenuates subarachnoid Hemor-rhage-induced cerebral inflammation by suppressing TLR4/NF-B signaling pathway. Curr Neurovasc Res 13(2):121–126. https://doi.org/10.2174/1567202613666160314151536

    Article  CAS  PubMed  Google Scholar 

  73. Vitkovic L, Konsman JP, Bockaert J, Dantzer R, Homburger V, Jacque C (2000) Cytokine signals propagate through the brain. Mol Psychiatry 5(6):604–615. https://doi.org/10.1038/sj.mp.4000813

    Article  CAS  PubMed  Google Scholar 

  74. Tang D, Kang R, Coyne CB, Zeh HJ, Lotze MT (2012) PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol Rev 249(1):158–175. https://doi.org/10.1111/j.1600-065X.2012.01146.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454(7203):428–435. https://doi.org/10.1038/nature07201

    Article  CAS  PubMed  Google Scholar 

  76. Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444(7121):860–867. https://doi.org/10.1038/nature05485

    Article  CAS  PubMed  Google Scholar 

  77. Revelo NH, Ter Beest M, van den Bogaart G (2019) Membrane trafficking as an active regulator of constitutively secreted cytokines. J Cell Sci 133(5):jcs234781. https://doi.org/10.1242/jcs.234781

    Article  CAS  PubMed  Google Scholar 

  78. Kim H, Youn K, Yun E-Y, Hwang J-S, Jeong W-S, Ho C-T, Jun M (2015) Oleic acid ameliorates Aβ-induced inflammation by downregulation of COX-2 and iNOS via NFκB signaling pathway. J Funct Foods 14:1–11

    Article  Google Scholar 

  79. DeLany JP, Windhauser MM, Champagne CM, Bray GA (2000) Differential oxidation of individual dietary fatty acids in humans. Am J Clin Nutr 72(4):905–911. https://doi.org/10.1093/ajcn/72.4.905

    Article  CAS  PubMed  Google Scholar 

  80. Almaguel FG, Liu JW, Pacheco FJ, Casiano CA, De Leon M (2009) Activation and reversal of lipotoxicity in PC12 and rat cortical cells following exposure to palmitic acid. J Neurosci Res 87(5):1207–1218. https://doi.org/10.1002/jnr.21918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Mayer CM, Belsham DD (2010) Palmitate attenuates insulin signaling and induces endoplasmic reticulum stress and apoptosis in hypothalamic neurons: rescue of resistance and apoptosis through adenosine 5' monophosphate-activated protein kinase activation. Endocrinology 151(2):576–585. https://doi.org/10.1210/en.2009-1122

    Article  CAS  PubMed  Google Scholar 

  82. Chaudhari N, Talwar P, Parimisetty A, Lefebvre d'Hellencourt C, Ravanan P (2014) A molecular web: endoplasmic reticulum stress, inflammation, and oxidative stress. Front Cell Neurosci 8:213. https://doi.org/10.3389/fncel.2014.00213

    Article  PubMed  PubMed Central  Google Scholar 

  83. Coll T, Eyre E, Rodriguez-Calvo R, Palomer X, Sanchez RM, Merlos M, Laguna JC, Vazquez-Carrera M (2008) Oleate reverses palmitate-induced insulin resistance and inflammation in skeletal muscle cells. J Biol Chem 283(17):11107–11116. https://doi.org/10.1074/jbc.M708700200

    Article  CAS  PubMed  Google Scholar 

  84. Kwon B, Lee HK, Querfurth HW (2014) Oleate prevents palmitate-induced mitochondrial dysfunction, insulin resistance and inflammatory signaling in neuronal cells. Biochim Biophys Acta 1843(7):1402–1413. https://doi.org/10.1016/j.bbamcr.2014.04.004

    Article  CAS  PubMed  Google Scholar 

  85. Jana A, Hogan EL, Pahan K (2009) Ceramide and neurodegeneration: susceptibility of neurons and oligodendrocytes to cell damage and death. J Neurol Sci 278(1-2):5–15. https://doi.org/10.1016/j.jns.2008.12.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lim JH, Gerhart-Hines Z, Dominy JE, Lee Y, Kim S, Tabata M, Xiang YK, Puigserver P (2013) Oleic acid stimulates complete oxidation of fatty acids through protein kinase A-dependent activation of SIRT1-PGC1alpha complex. J Biol Chem 288(10):7117–7126. https://doi.org/10.1074/jbc.M112.415729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Nicholas DA, Zhang K, Hung C, Glasgow S, Aruni AW, Unternaehrer J, Payne KJ, Langridge WHR et al (2017) Palmitic acid is a toll-like receptor 4 ligand that induces human dendritic cell secretion of IL-1beta. PLoS One 12(5):e0176793. https://doi.org/10.1371/journal.pone.0176793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lancaster GI, Langley KG, Berglund NA, Kammoun HL, Reibe S, Estevez E, Weir J, Mellett NA et al (2018) Evidence that TLR4 is not a receptor for saturated fatty acids but mediates lipid-induced inflammation by reprogramming macrophage metabolism. Cell Metab 27(5):1096–1110 e1095. https://doi.org/10.1016/j.cmet.2018.03.014

    Article  CAS  PubMed  Google Scholar 

  89. Erridge C, Samani NJ (2009) Saturated fatty acids do not directly stimulate Toll-like receptor signaling. Arterioscler Thromb Vasc Biol 29(11):1944–1949. https://doi.org/10.1161/ATVBAHA.109.194050

    Article  CAS  PubMed  Google Scholar 

  90. Hsiao YH, Lin CI, Liao H, Chen YH, Lin SH (2014) Palmitic acid-induced neuron cell cycle G2/M arrest and endoplasmic reticular stress through protein palmitoylation in SH-SY5Y human neuroblastoma cells. Int J Mol Sci 15(11):20876–20899. https://doi.org/10.3390/ijms151120876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Patil S, Chan C (2005) Palmitic and stearic fatty acids induce Alzheimer-like hyperphosphorylation of tau in primary rat cortical neurons. Neurosci Lett 384(3):288–293. https://doi.org/10.1016/j.neulet.2005.05.003

    Article  CAS  PubMed  Google Scholar 

  92. Patil S, Sheng L, Masserang A, Chan C (2006) Palmitic acid-treated astrocytes induce BACE1 upregulation and accumulation of C-terminal fragment of APP in primary cortical neurons. Neurosci Lett 406(1):55–59. https://doi.org/10.1016/j.neulet.2006.07.015

    Article  CAS  PubMed  Google Scholar 

  93. McLean FH, Campbell FM, Sergi D, Grant C, Morris AC, Hay EA, MacKenzie A, Mayer CD et al (2019) Early and reversible changes to the hippocampal proteome in mice on a high-fat diet. Nutr Metab (Lond) 16:57. https://doi.org/10.1186/s12986-019-0387-y

    Article  CAS  Google Scholar 

  94. Ulloth JE, Casiano CA, De Leon M (2003) Palmitic and stearic fatty acids induce caspase-dependent and -independent cell death in nerve growth factor differentiated PC12 cells. J Neurochem 84(4):655–668. https://doi.org/10.1046/j.1471-4159.2003.01571.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kim JY, Lee HJ, Lee S-J, Jung YH, Yoo DY, Hwang IK, Seong JK, Ryu JM et al (2017) Palmitic Acid-BSA enhances Amyloid-β production through GPR40-mediated dual pathways in neuronal cells: Involvement of the Akt/mTOR/HIF-1α and Akt/NF-κB pathways. Sci Rep 7:4335. https://doi.org/10.1038/s41598-017-04175-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Montero ML, Liu JW, Orozco J, Casiano CA, De Leon M (2020) Docosahexaenoic acid protection against palmitic acid-induced lipotoxicity in NGF-differentiated PC12 cells involves enhancement of autophagy and inhibition of apoptosis and necroptosis. J Neurochem 155:559–576. https://doi.org/10.1111/jnc.15038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ni Y, Zhao L, Yu H, Ma X, Bao Y, Rajani C, Loo LW, Shvetsov YB et al (2015) Circulating unsaturated fatty acids delineate the metabolic status of obese individuals. EBioMedicine 2(10):1513–1522. https://doi.org/10.1016/j.ebiom.2015.09.004

    Article  PubMed  PubMed Central  Google Scholar 

  98. Silva Figueiredo P, Carla Inada A, Marcelino G, Maiara Lopes Cardozo C, de Cassia Freitas K, de Cassia Avellaneda Guimaraes R, Pereira de Castro A, Aragao do Nascimento V et al (2017) Fatty acids consumption: the role metabolic aspects involved in obesity and its associated disorders. Nutrients 9(10). https://doi.org/10.3390/nu9101158

  99. Hryhorczuk C, Sheng Z, Decarie-Spain L, Giguere N, Ducrot C, Trudeau LE, Routh VH, Alquier T et al (2018) Oleic acid in the ventral tegmental area inhibits feeding, food reward, and dopamine tone. Neuropsychopharmacology 43(3):607–616. https://doi.org/10.1038/npp.2017.203

    Article  CAS  PubMed  Google Scholar 

  100. Melo HM, Seixas da Silva GDS, Sant’Ana MR, Teixeira CVL, Clarke JR, Miya Coreixas VS, de Melo BC, Fortuna JTS et al (2020) Palmitate is increased in the cerebrospinal fluid of humans with obesity and induces memory impairment in mice via pro-inflammatory TNF-alpha. Cell Rep 30(7):2180–2194 e2188. https://doi.org/10.1016/j.celrep.2020.01.072

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to Dr. L. M. Williams (Rowett Institute, University of Aberdeen, Scotland) for helpful discussions and to Mrs. Mélodie B. Plourde (UQTR) for technical assistance.

Data Availability (data transparency)

All data are available upon reasonable request to Dr. M-G Martinoli.

Code availability (software application or custom code)

Not applicable.

Funding

This work was supported by grants from the NSERC (National Science and Engineering Research Council) of Canada to MGM (no. 04321) and to HG (no. 227859). GC was supported by PON AIM (PON ricerca e innovazione 2014-2020, - azione I.2. D.D. N.407 del 27 febbraio2018 - “attraction and international mobility”), and DS by The Commonwealth Scientific and Industrial Research Organisation (CSIRO)’s Precision Health Future Science Platform (FSP) and is the recipient of a CSIRO (Australia) Postdoctoral Research Fellowship.

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  1. Department of Medical Biology, Université du Québec à Trois-Rivières, 3351 boul. des Forges, G9A 5H7, Trois-Rivières, QC, Canada

    Jimmy Beaulieu, Justine Renaud, Amélie Moitié & Maria-Grazia Martinoli

  2. Department of Biomedical Sciences, Section of Neurosciences, University of Cagliari, Cagliari, Italy

    Giulia Costa

  3. Department of Biological and Ecological Sciences, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada

    Hélène Glémet

  4. Nutrition & Health Substantiation Group, Nutrition and Health Program, Health and Biosecurity, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Adelaide, South Australia, Australia

    Domenico Sergi

  5. Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia

    Domenico Sergi

  6. Department of Psychiatry & Neurosciences, Université Laval and CHU Research Center, Québec, Canada

    Maria-Grazia Martinoli

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Beaulieu, J., Costa, G., Renaud, J. et al. The Neuroinflammatory and Neurotoxic Potential of Palmitic Acid Is Mitigated by Oleic Acid in Microglial Cells and Microglial-Neuronal Co-cultures. Mol Neurobiol 58, 3000–3014 (2021). https://doi.org/10.1007/s12035-021-02328-7

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