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Crosstalk Between Insulin and Toll-like Receptor Signaling Pathways in the Central Nervous system

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Abstract

Neuroinflammation is known as a key player in a variety of neurodegenerative and/or neurological diseases. Brain Toll-like receptors (TLRs) are leading elements in the initiation and progression of neuroinflammation and the development of different neuronal diseases. Furthermore, TLR activation is one of the most important elements in the induction of insulin resistance in different organs such as the central nervous system. Involvement of insulin signaling dysregulation and insulin resistance are also shown to contribute to the pathology of neurological diseases. Considering the important roles of TLRs in neuroinflammation and central insulin resistance and the effects of these processes in the initiation and progression of neurodegenerative and neurological diseases, here we are going to review current knowledge about the potential crosstalk between TLRs and insulin signaling pathways in neuroinflammatory disorders of the central nervous system.

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References

  1. Lucas SM, Rothwell NJ, Gibson RM (2006) The role of inflammation in CNS injury and disease. Br J Pharmacol 147(Suppl 1):S232–S240. doi:10.1038/sj.bjp.0706400

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Hanamsagar R, Hanke ML, Kielian T (2012) Toll-like receptor (TLR) and inflammasome actions in the central nervous system. Trends Immunol 33(7):333–342. doi:10.1016/j.it.2012.03.001

    CAS  PubMed Central  PubMed  Google Scholar 

  3. More SV, Kumar H, Kim IS, Song SY, Choi DK (2013) Cellular and molecular mediators of neuroinflammation in the pathogenesis of Parkinson’s disease. Mediat Inflamm 2013:952375. doi:10.1155/2013/952375

    Google Scholar 

  4. Najjar S, Pearlman DM, Alper K, Najjar A, Devinsky O (2013) Neuroinflammation and psychiatric illness. J Neuroinflammation 10:43. doi:10.1186/1742-2094-10-43

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Nataf S (2009) Neuroinflammation responses and neurodegeneration in multiple sclerosis. Rev Neurol 165(12):1023–1028. doi:10.1016/j.neurol.2009.09.012

    CAS  PubMed  Google Scholar 

  6. Obulesu M, Jhansilakshmi M (2013) Neuroinflammation in Alzheimer’s disease: an understanding of physiology and pathology. Int J Neurosci. doi:10.3109/00207454.2013.831852

    PubMed  Google Scholar 

  7. Hanke ML, Kielian T (2011) Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin Sci (London, England: 1979) 121(9):367–387. doi:10.1042/cs20110164

    CAS  Google Scholar 

  8. Shatz M, Menendez D, Resnick MA (2012) The human TLR innate immune gene family is differentially influenced by DNA stress and p53 status in cancer cells. Cancer Res 72(16):3948–3957. doi:10.1158/0008-5472.can-11-4134

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Konner AC, Bruning JC (2011) Toll-like receptors: linking inflammation to metabolism. TEM 22(1):16–23. doi:10.1016/j.tem.2010.08.007

    PubMed  Google Scholar 

  10. Benomar Y, Gertler A, De Lacy P, Crepin D, Ould Hamouda H, Riffault L, Taouis M (2013) Central resistin overexposure induces insulin resistance through Toll-like receptor 4. Diabetes 62(1):102–114. doi:10.2337/db12-0237

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A (2013) Insulin in the brain: sources, localization and functions. Mol Neurobiol 47(1):145–171. doi:10.1007/s12035-012-8339-9

    CAS  PubMed  Google Scholar 

  12. Ghasemi R, Dargahi L, Haeri A, Moosavi M, Mohamed Z, Ahmadiani A (2013) Brain insulin dysregulation: implication for neurological and neuropsychiatric disorders. Mol Neurobiol 47(3):1045–1065. doi:10.1007/s12035-013-8404-z

    CAS  PubMed  Google Scholar 

  13. Libby P (2007) Inflammatory mechanisms: the molecular basis of inflammation and disease. Nutr Rev 65(12 Pt 2):S140–S146

    PubMed  Google Scholar 

  14. Cain D, Kondo M, Chen H, Kelsoe G (2009) Effects of acute and chronic inflammation on B-cell development and differentiation. J Investig Dermatol 129(2):266–277. doi:10.1038/jid.2008.286

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Xiao BG, Link H (1998) Immune regulation within the central nervous system. J Neurol Sci 157(1):1–12

    CAS  PubMed  Google Scholar 

  16. Konnecke H, Bechmann I (2013) The Role of Microglia and Matrix Metalloproteinases Involvement in Neuroinflammation and Gliomas. Clin Dev Immunol 2013:914104. doi:10.1155/2013/914104

    PubMed Central  PubMed  Google Scholar 

  17. Balistreri CR, Colonna-Romano G, Lio D, Candore G, Caruso C (2009) TLR4 polymorphisms and ageing: implications for the pathophysiology of age-related diseases. J Clin Immunol 29(4):406–415. doi:10.1007/s10875-009-9297-5

    CAS  PubMed  Google Scholar 

  18. Di Virgilio F, Ceruti S, Bramanti P, Abbracchio MP (2009) Purinergic signalling in inflammation of the central nervous system. Trends Neurosci 32(2):79–87. doi:10.1016/j.tins.2008.11.003

    PubMed  Google Scholar 

  19. Husemann J, Loike JD, Anankov R, Febbraio M, Silverstein SC (2002) Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system. Glia 40(2):195–205. doi:10.1002/glia.10148

    PubMed  Google Scholar 

  20. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140(6):918–934. doi:10.1016/j.cell.2010.02.016

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Streit WJ (2002) Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40(2):133–139. doi:10.1002/glia.10154

    PubMed  Google Scholar 

  22. Medzhitov R (2001) Toll-like receptors and innate immunity. Nat Rev Immunol 1(2):135–145. doi:10.1038/35100529

    CAS  PubMed  Google Scholar 

  23. McGettrick AF, O'Neill LA (2010) Localisation and trafficking of Toll-like receptors: an important mode of regulation. Curr Opin Immunol 22(1):20–27. doi:10.1016/j.coi.2009.12.002

    CAS  PubMed  Google Scholar 

  24. Wang YC, Lin S, Yang QW (2011) Toll-like receptors in cerebral ischemic inflammatory injury. J Neuroinflammation 8:134. doi:10.1186/1742-2094-8-134

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Liu T, Gao YJ, Ji RR (2012) Emerging role of Toll-like receptors in the control of pain and itch. Neurosci Bull 28(2):131–144. doi:10.1007/s12264-012-1219-5

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Akira S (2006) TLR signaling. Curr Top Microbiol Immunol 311:1–16

    CAS  PubMed  Google Scholar 

  27. Crack PJ, Bray PJ (2007) Toll-like receptors in the brain and their potential roles in neuropathology. Immunol Cell Biol 85(6):476–480. doi:10.1038/sj.icb.7100103

    CAS  PubMed  Google Scholar 

  28. Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124(4):783–801. doi:10.1016/j.cell.2006.02.015

    CAS  PubMed  Google Scholar 

  29. Kawai T, Akira S (2006) TLR signaling. Cell Death Differ 13(5):816–825. doi:10.1038/sj.cdd.4401850

    CAS  PubMed  Google Scholar 

  30. Kenny EF, O'Neill LA (2008) Signalling adaptors used by Toll-like receptors: an update. Cytokine 43(3):342–349. doi:10.1016/j.cyto.2008.07.010

    CAS  PubMed  Google Scholar 

  31. Lucas K, Maes M (2013) Role of the toll like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway. Mol Neurobiol 48(1):190–204. doi:10.1007/s12035-013-8425-7

    CAS  PubMed  Google Scholar 

  32. Downes CE, Crack PJ (2010) Neural injury following stroke: are Toll-like receptors the link between the immune system and the CNS? Br J Pharmacol 160(8):1872–1888. doi:10.1111/j.1476-5381.2010.00864.x

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Williamson RT (1901) On the treatment of glycosuria and diabetes mellitus with sodium salicylate. Br Med J 1(2100):760–762

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Feingold KR, Soued M, Staprans I, Gavin LA, Donahue ME, Huang BJ, Moser AH, Gulli R, Grunfeld C (1989) Effect of tumor necrosis factor (TNF) on lipid metabolism in the diabetic rat. Evidence that inhibition of adipose tissue lipoprotein lipase activity is not required for TNF-induced hyperlipidemia. J Clin Invest 83(4):1116–1121. doi:10.1172/jci113991

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Sci (New York, NY) 259(5091):87–91

    CAS  Google Scholar 

  36. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389(6651):610–614. doi:10.1038/39335

    CAS  PubMed  Google Scholar 

  37. Holland WL, Bikman BT, Wang LP, Yuguang G, Sargent KM, Bulchand S, Knotts TA, Shui G, Clegg DJ, Wenk MR, Pagliassotti MJ, Scherer PE, Summers SA (2011) Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J Clin Invest 121(5):1858–1870. doi:10.1172/jci43378

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Lumeng CN, Saltiel AR (2011) Inflammatory links between obesity and metabolic disease. J Clin Invest 121(6):2111–2117. doi:10.1172/jci57132

    CAS  PubMed Central  PubMed  Google Scholar 

  39. 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 Invest 116(11):3015–3025. doi:10.1172/jci28898

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Jang HJ, Kim HS, Hwang DH, Quon MJ, Kim JA (2013) Toll-like receptor 2 mediates high-fat diet-induced impairment of vasodilator actions of insulin. Am J Physiol Endocrinol Metab 304(10):E1077–E1088. doi:10.1152/ajpendo.00578.2012

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Hennige AM, Sartorius T, Lutz SZ, Tschritter O, Preissl H, Hopp S, Fritsche A, Rammensee HG, Ruth P, Haring HU (2009) Insulin-mediated cortical activity in the slow frequency range is diminished in obese mice and promotes physical inactivity. Diabetologia 52(11):2416–2424. doi:10.1007/s00125-009-1522-5

    CAS  PubMed  Google Scholar 

  42. Sartorius T, Lutz SZ, Hoene M, Waak J, Peter A, Weigert C, Rammensee HG, Kahle PJ, Haring HU, Hennige AM (2012) Toll-like receptors 2 and 4 impair insulin-mediated brain activity by interleukin-6 and osteopontin and alter sleep architecture. FASEB J Off Publ Fed Am Soc Exp Biol 26(5):1799–1809. doi:10.1096/fj.11-191023

    CAS  Google Scholar 

  43. Arruda AP, Milanski M, Coope A, Torsoni AS, Ropelle E, Carvalho DP, Carvalheira JB, Velloso LA (2011) Low-grade hypothalamic inflammation leads to defective thermogenesis, insulin resistance, and impaired insulin secretion. Endocrinology 152(4):1314–1326. doi:10.1210/en.2010-0659

    CAS  PubMed  Google Scholar 

  44. Milanski M, Degasperi G, Coope A, Morari J, Denis R, Cintra DE, Tsukumo DM, Anhe G, Amaral ME, Takahashi HK, Curi R, Oliveira HC, Carvalheira JB, Bordin S, Saad MJ, Velloso LA (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 Off J Soc Neurosci 29(2):359–370. doi:10.1523/jneurosci.2760-08.2009

    CAS  Google Scholar 

  45. Arumugam TV, Okun E, Tang SC, Thundyil J, Taylor SM, Woodruff TM (2009) Toll-like receptors in ischemia-reperfusion injury. Shock (Augusta, Ga) 32(1):4–16. doi:10.1097/SHK.0b013e318193e333

    CAS  Google Scholar 

  46. Lee H, Lee S, Cho IH, Lee SJ (2013) Toll-like receptors: sensor molecules for detecting damage to the nervous system. Curr Protein Pept Sci 14(1):33–42

    CAS  PubMed  Google Scholar 

  47. Okun E, Griffioen KJ, Mattson MP (2011) Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci 34(5):269–281. doi:10.1016/j.tins.2011.02.005

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Chen K, Iribarren P, Hu J, Chen J, Gong W, Cho EH, Lockett S, Dunlop NM, Wang JM (2006) Activation of Toll-like receptor 2 on microglia promotes cell uptake of Alzheimer disease-associated amyloid beta peptide. J Biol Chem 281(6):3651–3659. doi:10.1074/jbc.M508125200

    CAS  PubMed  Google Scholar 

  49. Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE (2009) CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J Neurosci Off J Soc Neurosci 29(38):11982–11992. doi:10.1523/jneurosci.3158-09.2009

    CAS  Google Scholar 

  50. Jin JJ, Kim HD, Maxwell JA, Li L, Fukuchi K (2008) Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer’s disease. J Neuroinflammation 5:23. doi:10.1186/1742-2094-5-23

    PubMed Central  PubMed  Google Scholar 

  51. Tahara K, Kim HD, Jin JJ, Maxwell JA, Li L, Fukuchi K (2006) Role of toll-like receptor signalling in Abeta uptake and clearance. Brain J Neurol 129(Pt 11):3006–3019. doi:10.1093/brain/awl249

    Google Scholar 

  52. Richard KL, Filali M, Prefontaine P, Rivest S (2008) Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1-42 and delay the cognitive decline in a mouse model of Alzheimer’s disease. J Neurosci Off J Soc Neurosci 28(22):5784–5793. doi:10.1523/jneurosci.1146-08.2008

    CAS  Google Scholar 

  53. Landreth GE, Reed-Geaghan EG (2009) Toll-like receptors in Alzheimer’s disease. Curr Top Microbiol Immunol 336:137–153. doi:10.1007/978-3-642-00549-7_8

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Cameron B, Landreth GE (2010) Inflammation, microglia, and Alzheimer’s disease. Neurobiol Dis 37(3):503–509. doi:10.1016/j.nbd.2009.10.006

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Koenigsknecht-Talboo J, Landreth GE (2005) Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J Neurosci Off J Soc Neurosci 25(36):8240–8249. doi:10.1523/jneurosci.1808-05.2005

    CAS  Google Scholar 

  56. Dehay B, Bezard E (2011) New animal models of Parkinson’s disease. Mov Disord Off J Mov Disord Soc 26(7):1198–1205

    Google Scholar 

  57. Hirsch EC, Hunot S (2009) Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol 8(4):382–397. doi:10.1016/s1474-4422(09)70062-6

    CAS  PubMed  Google Scholar 

  58. Noelker C, Morel L, Lescot T, Osterloh A, Alvarez-Fischer D, Breloer M, Henze C, Depboylu C, Skrzydelski D, Michel PP, Dodel RC, Lu L, Hirsch EC, Hunot S, Hartmann A (2013) Toll like receptor 4 mediates cell death in a mouse MPTP model of Parkinson disease. Sci Rep 3:1393. doi:10.1038/srep01393

    PubMed Central  PubMed  Google Scholar 

  59. Panaro MA, Lofrumento DD, Saponaro C, De Nuccio F, Cianciulli A, Mitolo V, Nicolardi G (2008) Expression of TLR4 and CD14 in the central nervous system (CNS) in a MPTP mouse model of Parkinson's-like disease. Immunopharmacol Immunotoxicol 30(4):729–740. doi:10.1080/08923970802278557

    CAS  PubMed  Google Scholar 

  60. Ros-Bernal F, Hunot S, Herrero MT, Parnadeau S, Corvol JC, Lu L, Alvarez-Fischer D, Carrillo-de Sauvage MA, Saurini F, Coussieu C, Kinugawa K, Prigent A, Hoglinger G, Hamon M, Tronche F, Hirsch EC, Vyas S (2011) Microglial glucocorticoid receptors play a pivotal role in regulating dopaminergic neurodegeneration in parkinsonism. Proc Natl Acad Sci U S A 108(16):6632–6637. doi:10.1073/pnas.1017820108

    CAS  PubMed Central  PubMed  Google Scholar 

  61. De Miranda J, Yaddanapudi K, Hornig M, Villar G, Serge R, Lipkin WI (2010) Induction of Toll-like receptor 3-mediated immunity during gestation inhibits cortical neurogenesis and causes behavioral disturbances. mBio 1 (4). doi:10.1128/mBio.00176-10

  62. Forrest CM, Khalil OS, Pisar M, Smith RA, Darlington LG, Stone TW (2012) Prenatal activation of Toll-like receptors-3 by administration of the viral mimetic poly(I:C) changes synaptic proteins, N-methyl-D-aspartate receptors and neurogenesis markers in offspring. Mol Brain 5:22. doi:10.1186/1756-6606-5-22

    CAS  PubMed Central  PubMed  Google Scholar 

  63. McKernan DP, Dennison U, Gaszner G, Cryan JF, Dinan TG (2011) Enhanced peripheral toll-like receptor responses in psychosis: further evidence of a pro-inflammatory phenotype. Transl Psychiatry 1:e36. doi:10.1038/tp.2011.37

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Troutman TD, Bazan JF, Pasare C (2012) Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by PI3K. Cell Cycle (Georgetown, Tex) 11(19):3559–3567. doi:10.4161/cc.21572

    CAS  Google Scholar 

  65. Hazeki K, Nigorikawa K, Hazeki O (2007) Role of phosphoinositide 3-kinase in innate immunity. Biol Pharm Bull 30(9):1617–1623

    CAS  PubMed  Google Scholar 

  66. van der Heide LP, Ramakers GM, Smidt MP (2006) Insulin signaling in the central nervous system: learning to survive. Prog Neurobiol 79(4):205–221. doi:10.1016/j.pneurobio.2006.06.003

    PubMed  Google Scholar 

  67. Gunjima K, Tomiyama R, Takakura K, Yamada T, Hashida K, Nakamura Y, Konishi T, Matsugo S, Hori O (2013) 3,4-Dihydroxybenzalacetone protects against Parkinson’s disease-related neurotoxin 6-OHDA through Akt/Nrf2/glutathione pathway. J Cell Biochem. doi:10.1002/jcb.24643

    Google Scholar 

  68. Zhang L, Huang L, Chen L, Hao D, Chen J (2013) Neuroprotection by tetrahydroxystilbene glucoside in the MPTP mouse model of Parkinson’s disease. Toxicol Lett 222(2):155–163. doi:10.1016/j.toxlet.2013.07.020

    CAS  PubMed  Google Scholar 

  69. Solano DC, Sironi M, Bonfini C, Solerte SB, Govoni S, Racchi M (2000) Insulin regulates soluble amyloid precursor protein release via phosphatidyl inositol 3 kinase-dependent pathway. FASEB J Off Publ Fed Am Soc Exp Biol 14(7):1015–1022

    CAS  Google Scholar 

  70. Leibrock C, Ackermann TF, Hierlmeier M, Lang F, Borgwardt S, Lang UE (2013) Akt2 deficiency is associated with anxiety and depressive behavior in mice. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol 32(3):766–777. doi:10.1159/000354478

    CAS  Google Scholar 

  71. Zheng W, Wang H, Zeng Z, Lin J, Little PJ, Srivastava LK, Quirion R (2012) The possible role of the Akt signaling pathway in schizophrenia. Brain Res 1470:145–158. doi:10.1016/j.brainres.2012.06.032

    CAS  PubMed  Google Scholar 

  72. Fukao T, Koyasu S (2003) PI3K and negative regulation of TLR signaling. Trends Immunol 24(7):358–363

    CAS  PubMed  Google Scholar 

  73. Gelman AE, LaRosa DF, Zhang J, Walsh PT, Choi Y, Sunyer JO, Turka LA (2006) The adaptor molecule MyD88 activates PI-3 kinase signaling in CD4+ T cells and enables CpG oligodeoxynucleotide-mediated costimulation. Immunity 25(5):783–793. doi:10.1016/j.immuni.2006.08.023

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Guha M, Mackman N (2002) The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. J Biol Chem 277(35):32124–32132. doi:10.1074/jbc.M203298200

    CAS  PubMed  Google Scholar 

  75. Pahan K, Raymond JR, Singh I (1999) Inhibition of phosphatidylinositol 3-kinase induces nitric-oxide synthase in lipopolysaccharide- or cytokine-stimulated C6 glial cells. J Biol Chem 274(11):7528–7536

    CAS  PubMed  Google Scholar 

  76. Park YC, Lee CH, Kang HS, Chung HT, Kim HD (1997) Wortmannin, a specific inhibitor of phosphatidylinositol-3-kinase, enhances LPS-induced NO production from murine peritoneal macrophages. Biochem Biophys Res Commun 240(3):692–696. doi:10.1006/bbrc.1997.7722

    CAS  PubMed  Google Scholar 

  77. Bauerfeld CP, Rastogi R, Pirockinaite G, Lee I, Huttemann M, Monks B, Birnbaum MJ, Franchi L, Nunez G, Samavati L (2012) TLR4-mediated AKT activation is MyD88/TRIF dependent and critical for induction of oxidative phosphorylation and mitochondrial transcription factor A in murine macrophages. J Immunol (Baltimore, Md: 1950) 188(6):2847–2857. doi:10.4049/jimmunol.1102157

    CAS  Google Scholar 

  78. Androulidaki A, Iliopoulos D, Arranz A, Doxaki C, Schworer S, Zacharioudaki V, Margioris AN, Tsichlis PN, Tsatsanis C (2009) The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity 31(2):220–231. doi:10.1016/j.immuni.2009.06.024

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Chaurasia B, Mauer J, Koch L, Goldau J, Kock AS, Bruning JC (2010) Phosphoinositide-dependent kinase 1 provides negative feedback inhibition to Toll-like receptor-mediated NF-kappaB activation in macrophages. Mol Cell Biol 30(17):4354–4366. doi:10.1128/mcb.00069-10

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Rayasam GV, Tulasi VK, Sodhi R, Davis JA, Ray A (2009) Glycogen synthase kinase 3: more than a namesake. Br J Pharmacol 156(6):885–898. doi:10.1111/j.1476-5381.2008.00085.x

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Wang Y, Feng W, Xue W, Tan Y, Hein DW, Li XK, Cai L (2009) Inactivation of GSK-3beta by metallothionein prevents diabetes-related changes in cardiac energy metabolism, inflammation, nitrosative damage, and remodeling. Diabetes 58(6):1391–1402. doi:10.2337/db08-1697

    PubMed Central  PubMed  Google Scholar 

  82. Liu Y, Tanabe K, Baronnier D, Patel S, Woodgett J, Cras-Meneur C, Permutt MA (2010) Conditional ablation of Gsk-3beta in islet beta cells results in expanded mass and resistance to fat feeding-induced diabetes in mice. Diabetologia 53(12):2600–2610. doi:10.1007/s00125-010-1882-x

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Gong CX, Iqbal K (2008) Hyperphosphorylation of microtubule-associated protein tau: a promising therapeutic target for Alzheimer disease. Curr Med Chem 15(23):2321–2328

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Hooper C, Killick R, Lovestone S (2008) The GSK3 hypothesis of Alzheimer’s disease. J Neurochem 104(6):1433–1439. doi:10.1111/j.1471-4159.2007.05194.x

    CAS  PubMed Central  PubMed  Google Scholar 

  85. King MR, Anderson NJ, Guernsey LS, Jolivalt CG (2013) Glycogen synthase kinase-3 inhibition prevents learning deficits in diabetic mice. J Neurosci Res 91(4):506–514. doi:10.1002/jnr.23192

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA (2004) Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet 36(2):131–137. doi:10.1038/ng1296

    CAS  PubMed  Google Scholar 

  87. Wilkinson MB, Dias C, Magida J, Mazei-Robison M, Lobo M, Kennedy P, Dietz D, Covington H 3rd, Russo S, Neve R, Ghose S, Tamminga C, Nestler EJ (2011) A novel role of the WNT-dishevelled-GSK3beta signaling cascade in the mouse nucleus accumbens in a social defeat model of depression. J Neurosci Off J Soc Neurosci 31(25):9084–9092. doi:10.1523/jneurosci.0039-11.2011

    CAS  Google Scholar 

  88. Beurel E, Michalek SM, Jope RS (2010) Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3). Trends Immunol 31(1):24–31. doi:10.1016/j.it.2009.09.007

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Hofmann C, Dunger N, Scholmerich J, Falk W, Obermeier F (2010) Glycogen synthase kinase 3-beta: a master regulator of toll-like receptor-mediated chronic intestinal inflammation. Inflamm Bowel Dis 16(11):1850–1858. doi:10.1002/ibd.21294

    PubMed  Google Scholar 

  90. Beurel E, Jope RS (2009) Lipopolysaccharide-induced interleukin-6 production is controlled by glycogen synthase kinase-3 and STAT3 in the brain. J Neuroinflammation 6:9. doi:10.1186/1742-2094-6-9

    PubMed Central  PubMed  Google Scholar 

  91. Yuskaitis CJ, Jope RS (2009) Glycogen synthase kinase-3 regulates microglial migration, inflammation, and inflammation-induced neurotoxicity. Cell Signal 21(2):264–273. doi:10.1016/j.cellsig.2008.10.014

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Beurel E, Jope RS (2010) Glycogen synthase kinase-3 regulates inflammatory tolerance in astrocytes. Neuroscience 169(3):1063–1070. doi:10.1016/j.neuroscience.2010.05.044

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Li H, Sun X, LeSage G, Zhang Y, Liang Z, Chen J, Hanley G, He L, Sun S, Yin D (2010) beta-arrestin 2 regulates Toll-like receptor 4-mediated apoptotic signalling through glycogen synthase kinase-3beta. Immunology 130(4):556–563. doi:10.1111/j.1365-2567.2010.03256.x

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, Ye J (2002) Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem 277(50):48115–48121. doi:10.1074/jbc.M209459200

    CAS  PubMed  Google Scholar 

  95. Kawai T, Akira S (2007) Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med 13(11):460–469. doi:10.1016/j.molmed.2007.09.002

    CAS  PubMed  Google Scholar 

  96. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE (2001) Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Sci (New York, NY) 293(5535):1673–1677. doi:10.1126/science.1061620

    CAS  Google Scholar 

  97. Zhang J, Gao Z, Yin J, Quon MJ, Ye J (2008) S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-(alpha) signaling through IKK2. J Biol Chem 283(51):35375–35382. doi:10.1074/jbc.M806480200

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Tonks NK, Neel BG (2001) Combinatorial control of the specificity of protein tyrosine phosphatases. Curr Opin Cell Biol 13(2):182–195

    CAS  PubMed  Google Scholar 

  99. Gonzalez-Rodriguez A, Mas Gutierrez JA, Sanz-Gonzalez S, Ros M, Burks DJ, Valverde AM (2010) Inhibition of PTP1B restores IRS1-mediated hepatic insulin signaling in IRS2-deficient mice. Diabetes 59(3):588–599. doi:10.2337/db09-0796

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Murillo-Cuesta S, Camarero G, Gonzalez-Rodriguez A, De La Rosa LR, Burks DJ, Avendano C, Valverde AM, Varela-Nieto I (2012) Insulin receptor substrate 2 (IRS2)-deficient mice show sensorineural hearing loss that is delayed by concomitant protein tyrosine phosphatase 1B (PTP1B) loss of function. Mol Med (Cambridge, Mass) 18:260–269. doi:10.2119/molmed.2011.00328

    CAS  Google Scholar 

  101. Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy AL, Normandin D, Cheng A, Himms-Hagen J, Chan CC, Ramachandran C, Gresser MJ, Tremblay ML, Kennedy BP (1999) Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Sci (New York, NY) 283(5407):1544–1548

    CAS  Google Scholar 

  102. Picardi PK, Calegari VC, Prada PO, Moraes JC, Araujo E, Marcondes MC, Ueno M, Carvalheira JB, Velloso LA, Saad MJ (2008) Reduction of hypothalamic protein tyrosine phosphatase improves insulin and leptin resistance in diet-induced obese rats. Endocrinology 149(8):3870–3880. doi:10.1210/en.2007-1506

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Yu IC, Lin HY, Liu NC, Sparks JD, Yeh S, Fang LY, Chen L, Chang C (2013) Neuronal androgen receptor regulates insulin sensitivity via suppression of hypothalamic NF-kappaB-mediated PTP1B expression. Diabetes 62(2):411–423. doi:10.2337/db12-0135

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Ito Y, Banno R, Hagimoto S, Ozawa Y, Arima H, Oiso Y (2012) TNFalpha increases hypothalamic PTP1B activity via the NFkappaB pathway in rat hypothalamic organotypic cultures. Regul Pept 174(1–3):58–64. doi:10.1016/j.regpep.2011.11.010

    CAS  PubMed  Google Scholar 

  105. Zabolotny JM, Kim YB, Welsh LA, Kershaw EE, Neel BG, Kahn BB (2008) Protein-tyrosine phosphatase 1B expression is induced by inflammation in vivo. J Biol Chem 283(21):14230–14241. doi:10.1074/jbc.M800061200

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Mody N, Agouni A, McIlroy GD, Platt B, Delibegovic M (2011) Susceptibility to diet-induced obesity and glucose intolerance in the APP (SWE)/PSEN1 (A246E) mouse model of Alzheimer’s disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein. Diabetologia 54(8):2143–2151. doi:10.1007/s00125-011-2160-2

    CAS  PubMed  Google Scholar 

  107. Choi HS, Liew H, Jang A, Kim YM, Lashuel H, Suh YH (2012) Phosphorylation of alpha-synuclein is crucial in compensating for proteasomal dysfunction. Biochem Biophys Res Commun 424(3):597–603. doi:10.1016/j.bbrc.2012.06.159

    CAS  PubMed  Google Scholar 

  108. Ginion A, Auquier J, Benton CR, Mouton C, Vanoverschelde JL, Hue L, Horman S, Beauloye C, Bertrand L (2011) Inhibition of the mTOR/p70S6K pathway is not involved in the insulin-sensitizing effect of AMPK on cardiac glucose uptake. Am J Physiol Heart Circ Physiol 301(2):H469–H477. doi:10.1152/ajpheart.00986.2010

    CAS  PubMed  Google Scholar 

  109. Crowe DL, Shemirani B (2000) The transcription factor ATF-2 inhibits extracellular signal regulated kinase expression and proliferation of human cancer cells. Anticancer Res 20(5A):2945–2949

    CAS  PubMed  Google Scholar 

  110. Peroval MY, Boyd AC, Young JR, Smith AL (2013) A critical role for MAPK signalling pathways in the transcriptional regulation of toll like receptors. PloS one 8(2):e51243. doi:10.1371/journal.pone.0051243

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Johnsen IB, Nguyen TT, Bergstrom B, Lien E, Anthonsen MW (2012) Toll-like receptor 3-elicited MAPK activation induces stabilization of interferon-beta mRNA. Cytokine 57(3):337–346. doi:10.1016/j.cyto.2011.11.024

    CAS  PubMed  Google Scholar 

  112. Li H, Yu X (2013) Emerging role of JNK in insulin resistance. Curr Diabetes Rev 9(5):422–428

    CAS  PubMed  Google Scholar 

  113. Benzler J, Ganjam GK, Legler K, Stohr S, Kruger M, Steger J, Tups A (2013) Acute inhibition of central c-Jun N-terminal kinase restores hypothalamic insulin signalling and alleviates glucose intolerance in diabetic mice. J Neuroendocrinol 25(5):446–454. doi:10.1111/jne.12018

    CAS  PubMed  Google Scholar 

  114. Aguirre V, Uchida T, Yenush L, Davis R, White MF (2000) The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J Biol Chem 275(12):9047–9054

    CAS  PubMed  Google Scholar 

  115. Solinas G, Naugler W, Galimi F, Lee MS, Karin M (2006) Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. Proc Natl Acad Sci U S A 103(44):16454–16459. doi:10.1073/pnas.0607626103

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Engelman JA, Berg AH, Lewis RY, Lisanti MP, Scherer PE (2000) Tumor necrosis factor alpha-mediated insulin resistance, but not dedifferentiation, is abrogated by MEK1/2 inhibitors in 3T3-L1 adipocytes. Mol Endocrinol (Baltimore, Md) 14(10):1557–1569

    CAS  Google Scholar 

  117. Tanti JF, Jager J (2009) Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. Curr Opin Pharmacol 9(6):753–762. doi:10.1016/j.coph.2009.07.004

    CAS  PubMed  Google Scholar 

  118. Subramaniam S, Unsicker K (2010) ERK and cell death: ERK1/2 in neuronal death. FEBS J 277(1):22–29

    CAS  PubMed  Google Scholar 

  119. Zhuang S, Schnellmann RG (2006) A death-promoting role for extracellular signal-regulated kinase. J Pharmacol Exp Ther 319(3):991–997. doi:10.1124/jpet.106.107367

    CAS  PubMed  Google Scholar 

  120. Cheung EC, Slack RS (2004) Emerging role for ERK as a key regulator of neuronal apoptosis. Sci Signal 2004(251):pe45

    Google Scholar 

  121. Li G, Barrett EJ, Barrett MO, Cao W, Liu Z (2007) Tumor necrosis factor-alpha induces insulin resistance in endothelial cells via a p38 mitogen-activated protein kinase-dependent pathway. Endocrinology 148(7):3356–3363. doi:10.1210/en.2006-1441

    CAS  PubMed  Google Scholar 

  122. Zhu X, Castellani RJ, Takeda A, Nunomura A, Atwood CS, Perry G, Smith MA (2001) Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: the ‘two hit’ hypothesis. Mech Ageing Dev 123(1):39–46

    CAS  PubMed  Google Scholar 

  123. Dehvari N, Isacsson O, Winblad B, Cedazo-Minguez A, Cowburn RF (2008) Presenilin regulates extracellular regulated kinase (Erk) activity by a protein kinase C alpha dependent mechanism. Neurosci Lett 436(1):77–80. doi:10.1016/j.neulet.2008.02.063

    CAS  PubMed  Google Scholar 

  124. Savage MJ, Lin YG, Ciallella JR, Flood DG, Scott RW (2002) Activation of c-Jun N-terminal kinase and p38 in an Alzheimer’s disease model is associated with amyloid deposition. J Neurosci Off J Soc Neurosci 22(9):3376–3385

    CAS  Google Scholar 

  125. Cho HJ, Kim SK, Jin SM, Hwang EM, Kim YS, Huh K, Mook-Jung I (2007) IFN-gamma-induced BACE1 expression is mediated by activation of JAK2 and ERK1/2 signaling pathways and direct binding of STAT1 to BACE1 promoter in astrocytes. Glia 55(3):253–262. doi:10.1002/glia.20451

    PubMed  Google Scholar 

  126. Colombo A, Bastone A, Ploia C, Sclip A, Salmona M, Forloni G, Borsello T (2009) JNK regulates APP cleavage and degradation in a model of Alzheimer’s disease. Neurobiol Dis 33(3):518–525. doi:10.1016/j.nbd.2008.12.014

    CAS  PubMed  Google Scholar 

  127. Xuan A, Long D, Li J, Ji W, Zhang M, Hong L, Liu J (2012) Hydrogen sulfide attenuates spatial memory impairment and hippocampal neuroinflammation in beta-amyloid rat model of Alzheimer’s disease. J Neuroinflammation 9:202. doi:10.1186/1742-2094-9-202

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Pan J, Zhao YX, Wang ZQ, Jin L, Sun ZK, Chen SD (2007) Expression of FasL and its interaction with Fas are mediated by c-Jun N-terminal kinase (JNK) pathway in 6-OHDA-induced rat model of Parkinson disease. Neurosci Lett 428(2–3):82–87. doi:10.1016/j.neulet.2007.09.032

    CAS  PubMed  Google Scholar 

  129. Wefers B, Hitz C, Holter SM, Trumbach D, Hansen J, Weber P, Putz B, Deussing JM, de Angelis MH, Roenneberg T, Zheng F, Alzheimer C, Silva A, Wurst W, Kuhn R (2012) MAPK signaling determines anxiety in the juvenile mouse brain but depression-like behavior in adults. PloS one 7(4):e35035. doi:10.1371/journal.pone.0035035

    CAS  PubMed Central  PubMed  Google Scholar 

  130. Funk AJ, McCullumsmith RE, Haroutunian V, Meador-Woodruff JH (2012) Abnormal activity of the MAPK- and cAMP-associated signaling pathways in frontal cortical areas in postmortem brain in schizophrenia. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 37(4):896–905. doi:10.1038/npp.2011.267

    CAS  Google Scholar 

  131. Kariko K, Weissman D, Welsh FA (2004) Inhibition of toll-like receptor and cytokine signaling—a unifying theme in ischemic tolerance. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 24(11):1288–1304. doi:10.1097/01.wcb.0000145666.68576.71

    CAS  Google Scholar 

  132. Howard JK, Flier JS (2006) Attenuation of leptin and insulin signaling by SOCS proteins. TEM 17(9):365–371. doi:10.1016/j.tem.2006.09.007

    CAS  PubMed  Google Scholar 

  133. Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D (2008) Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 135(1):61–73. doi:10.1016/j.cell.2008.07.043

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Mori H, Hanada R, Hanada T, Aki D, Mashima R, Nishinakamura H, Torisu T, Chien KR, Yasukawa H, Yoshimura A (2004) Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat Med 10(7):739–743. doi:10.1038/nm1071

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia

    Fatemeh Hemmati, Norlinah Mohamed Ibrahim & Azman Ali Raymond

  2. Neuroscience Research Center and Department of Physiology, Shiraz University of Medical Sciences, Shiraz, Iran

    Rasoul Ghasemi

  3. NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Leila Dargahi & Abolhassan Ahmadiani

  4. Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Leila Dargahi & Abolhassan Ahmadiani

  5. Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia

    Zahurin Mohamed & Abolhassan Ahmadiani

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  1. Fatemeh Hemmati
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Correspondence to Abolhassan Ahmadiani.

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Fatemeh Hemmati and Rasoul Ghasemi contributed equally to this work and should be considered as co-first authors.

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Hemmati, F., Ghasemi, R., Mohamed Ibrahim, N. et al. Crosstalk Between Insulin and Toll-like Receptor Signaling Pathways in the Central Nervous system. Mol Neurobiol 50, 797–810 (2014). https://doi.org/10.1007/s12035-013-8631-3

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