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Metabolic Brain Disease

, Volume 32, Issue 5, pp 1735–1745 | Cite as

Beneficial effects of liraglutide (GLP1 analog) in the hippocampal inflammation

  • Andre R. C. Barreto-Vianna
  • Marcia B. Aguila
  • Carlos A. Mandarim-de-Lacerda
Original Article

Abstract

The brain is very sensitive to metabolic dysfunctions induced by diets high in saturated fatty acids, leading to neuroinflammation. The liraglutide has been found to have neuroprotective effects. However, its neuroprotective action in a model of palmitate-induced neuroinflammation had not yet been evaluated. Mice were intracerebroventricular (ICV) infused with palmitate and received subcutaneous liraglutide. The hippocampal dentate gyrus and CA1 regions were analyzed (morphology and inflammation-related proteins in microglia and astrocyte by confocal microscopy). Also, a real-time PCR was performed to measure the levels of tumor necrosis factor (TNF) alpha and interleukin (IL) 6. Palmitate ICV infusion resulted in pronounced inflammation response in the hippocampus, reactive microgliosis, and astrogliosis, with hypertrophied IBA1 immunoreactive microglia, increased microglial density with ameboid shape, decreased in the number of branches and junctions and increased the major histocompatibility complex (MHC) II expression. Also, we observed in the hippocampus of ICV palmitate infused mice an elevation in the pro-inflammatory cytokine levels TNFalpha and IL6. Liraglutide induced the neuroprotective microglial phenotype, characterized by an increased microglia complexity (enlarged Feret’s diameter), an improved number of both cell junctions and processes, and lower circularity, accompanied by a significant reduction in TNFalpha and IL6 expressions. The study provides evidence that liraglutide may be a suitable treatment against the palmitate-induced neuroinflammation, which it is characterized by the reactive microgliosis and astrogliosis, as well as increased pro-inflammatory cytokines, which has been described as one of the primary causes of several pathologies of the central nervous system.

Keywords

Intracerebroventricular infusion Saturated fatty acids Neuroinflammation Hippocampus Microglia 

Notes

Acknowledgements

The study was financially supported by the FAPERJ (Rio de Janeiro State Foundation for Scientific Research, www.faperj.br, grant number E26/201.186/2014 to CAML) and CNPq (Brazilian Council of Science and Technology, grant numbers 302154/20116 and 442673/20140 to CAML).

Compliance with ethical standards

Competing interests

The authors declare that they have no competing of interests.

References

  1. Allan SM, Rothwell NJ (2003) Inflammation in central nervous system injury. Philos Trans R Soc Lond Ser B Biol Sci 358:1669–1677. doi: 10.1098/rstb.2003.1358 CrossRefGoogle Scholar
  2. Athauda D, Foltynie T (2016) The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson's disease: mechanisms of action. Drug Discov Today 21:802–818. doi: 10.1016/j.drudis.2016.01.013 CrossRefPubMedGoogle Scholar
  3. Baron R, Babcock AA, Nemirovsky A, Finsen B, Monsonego A (2014) Accelerated microglial pathology is associated with Abeta plaques in mouse models of Alzheimer's disease. Aging Cell 13:584–595. doi: 10.1111/acel.12210 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Barreto-Vianna AR, Aguila MB, Mandarim-de-Lacerda CA (2016) Effects of liraglutide in hypothalamic arcuate nucleus of obese mice. Obesity (Silver Spring) 24:626–633. doi: 10.1002/oby.21387 CrossRefGoogle Scholar
  5. Bays H, Pi-Sunyer X, Hemmingsson JU, Claudius B, Jensen CB, Van Gaal L (2016) Liraglutide 3.0 mg for weight management: weight-loss dependent and independent effects. Curr Med Res Opin:1–5. doi: 10.1080/03007995.2016.1251892
  6. Bruck D, Wenning GK, Stefanova N, Fellner L (2016) Glia and alpha-synuclein in neurodegeneration: a complex interaction. Neurobiol Dis 85:262–274. doi: 10.1016/j.nbd.2015.03.003 CrossRefPubMedGoogle Scholar
  7. Cano V, Valladolid-Acebes I, Hernandez-Nuno F, Merino B, Del Olmo N, Chowen JA, Ruiz-Gayo M (2014) Morphological changes in glial fibrillary acidic protein immunopositive astrocytes in the hippocampus of dietary-induced obese mice. Neuroreport 25:819–822. doi: 10.1097/WNR.0000000000000180 CrossRefGoogle Scholar
  8. Christou GA, Katsiki N, Kiortsis DN (2016) The current role of Liraglutide in the pharmacotherapy of obesity. Curr Vasc Pharmacol 14:201–207CrossRefPubMedGoogle Scholar
  9. Contreras A, Del Rio D, Martinez A, Gil C, Morales L, Ruiz-Gayo M, Del Olmo N (2017) Inhibition of hippocampal long-term potentiation by HF diets: is it related to an effect of palmitic acid involving glycogen synthase kinase-3? Neuroreport 28:354–359. doi: 10.1097/WNR.0000000000000774 CrossRefPubMedGoogle Scholar
  10. Erion JR, Wosiski-Kuhn M, Dey A, Hao S, Davis CL, Pollock NK, Stranahan AM (2014) Obesity elicits interleukin 1-mediated deficits in hippocampal synaptic plasticity. J Neurosci 34:2618–2631. doi: 10.1523/JNEUROSCI.4200-13.2014 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Femminella GD, Edison P (2014) Evaluation of neuroprotective effect of glucagon-like peptide 1 analogs using neuroimaging. Alzheimers Dement 10:S55–S61. doi: 10.1016/j.jalz.2013.12.012 CrossRefPubMedGoogle Scholar
  12. Gupta S, Knight AG, Gupta S, Keller JN, Bruce-Keller AJ (2012) Saturated long-chain fatty acids activate inflammatory signaling in astrocytes. J Neurochem 120:1060–1071. doi: 10.1111/j.1471-4159.2012.07660.x PubMedPubMedCentralGoogle Scholar
  13. Hao S, Dey A, Yu X, Stranahan AM (2016) Dietary obesity reversibly induces synaptic stripping by microglia and impairs hippocampal plasticity. Brain Behav Immun 51:230–239. doi: 10.1016/j.bbi.2015.08.023 CrossRefPubMedGoogle Scholar
  14. Holland WL et al (2011) Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J Clin Invest 121:1858–1870. doi: 10.1172/JCI43378 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Holm TH, Draeby D, Owens T (2012) Microglia are required for astroglial toll-like receptor 4 response and for optimal TLR2 and TLR3 response. Glia 60:630–638. doi: 10.1002/glia.22296 CrossRefPubMedGoogle Scholar
  16. Hou J, Manaenko A, Hakon J, Hansen-Schwartz J, Tang J, Zhang JH (2012) Liraglutide, a long-acting GLP1 mimetic, and its metabolite attenuate inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab 32:2201–2210. doi: 10.1038/jcbfm.2012.133 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Hunter K, Holscher C (2012) Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci 13:33. doi: 10.1186/1471-2202-13-33 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Iwai T, Ito S, Tanimitsu K, Udagawa S, Oka J (2006) Glucagon-like peptide-1 inhibits LPS-induced IL-1beta production in cultured rat astrocytes. Neurosci Res 55:352–360. doi: 10.1016/j.neures.2006.04.008 CrossRefPubMedGoogle Scholar
  19. Kanoski SE, Davidson TL (2011) Western diet consumption and cognitive impairment: links to hippocampal dysfunction and obesity. Physiol Behav 103:59–68. doi: 10.1016/j.physbeh.2010.12.003 CrossRefPubMedGoogle Scholar
  20. Karmi A et al (2010) Increased brain fatty acid uptake in metabolic syndrome. Diabetes 59:2171–2177. doi: 10.2337/db09-0138 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Kleinridders A et al (2009) MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab 10:249–259. doi: 10.1016/j.cmet.2009.08.013 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Leal MC, Casabona JC, Puntel M, Pitossi FJ (2013) Interleukin-1beta and tumor necrosis factor-alpha: reliable targets for protective therapies in Parkinson's disease? Front Cell Neurosci 7:53. doi: 10.3389/fncel.2013.00053 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 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 276:16683–16689. doi: 10.1074/jbc.M011695200 CrossRefPubMedGoogle Scholar
  24. Lehnardt S et al (2003) Activation of innate immunity in the CNS triggers neurodegeneration through a toll-like receptor 4-dependent pathway. Proc Natl Acad Sci U S A 100:8514–8519. doi: 10.1073/pnas.1432609100 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Letra L, Santana I, Seiça R (2014) Obesity as a risk factor for Alzheimer’s disease: the role of adipocytokines. Metab Brain Dis 29:563–568. doi: 10.1007/s11011-014-9501-z CrossRefPubMedGoogle Scholar
  26. Liu L, Chan C (2014) The role of inflammasome in Alzheimer's disease. Ageing Res Rev 15:6–15. doi: 10.1016/j.arr.2013.12.007 CrossRefPubMedGoogle Scholar
  27. Liu L, Martin R, Chan C (2013) Palmitate-activated astrocytes via serine palmitoyltransferase increase BACE1 in primary neurons by sphingomyelinases. Neurobiol Aging 34:540–550. doi: 10.1016/j.neurobiolaging.2012.05.017 CrossRefPubMedGoogle Scholar
  28. Liu JT, Chen BY, Zhang JQ, Kuang F, Chen LW (2015) Lead exposure induced microgliosis and astrogliosis in hippocampus of young mice potentially by triggering TLR4-MyD88-NFkappaB signaling cascades. Toxicol Lett 239:97–107. doi: 10.1016/j.toxlet.2015.09.015 CrossRefPubMedGoogle Scholar
  29. Lull ME, Block ML (2010) Microglial activation and chronic neurodegeneration. Neurotherapeutics 7:354–365. doi: 10.1016/j.nurt.2010.05.014 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Mandarim-de-Lacerda CA, Santos CF, Aguila MB (2010) Image analysis and quantitative morphology. Methods Mol Biol 611:211–225. doi: 10.1007/978-1-60327-345-9_17 CrossRefPubMedGoogle Scholar
  31. McClean PL, Holscher C (2014) Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer's disease. Neuropharmacology 76 Pt A:57–67. doi: 10.1016/j.neuropharm.2013.08.005
  32. McClean PL, Jalewa J, Holscher C (2015) Prophylactic liraglutide treatment prevents amyloid plaque deposition, chronic inflammation and memory impairment in APP/PS1 mice. Behav Brain Res 293:96–106. doi: 10.1016/j.bbr.2015.07.024 CrossRefPubMedGoogle Scholar
  33. Michael-Titus AT, Priestley JV (2014) Omega-3 fatty acids and traumatic neurological injury: from neuroprotection to neuroplasticity? Trends Neurosci 37:30–38. doi: 10.1016/j.tins.2013.10.005 CrossRefPubMedGoogle Scholar
  34. Milanski M 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 29:359–370. doi: 10.1523/JNEUROSCI.2760-08.2009 CrossRefPubMedGoogle Scholar
  35. Morrison HW, Filosa JA (2013) A quantitative spatiotemporal analysis of microglia morphology during ischemic stroke and reperfusion. J Neuroinflammation 10:4. doi: 10.1186/1742-2094-10-4 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Nair AB, Jacob S (2016) A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 7:27–31. doi: 10.4103/0976-0105.177703 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Oh H, Boghossian S, York DA, Park-York M (2013) The effect of high fat diet and saturated fatty acids on insulin signaling in the amygdala and hypothalamus of rats. Brain Res 1537:191–200. doi: 10.1016/j.brainres.2013.09.025 CrossRefPubMedGoogle Scholar
  38. Park S, Kang S, Kim DS, Moon BR (2017) Agrimonia pilosa Ledeb., Cinnamomum cassia Blume, and Lonicera japonica Thunb. protect against cognitive dysfunction and energy and glucose dysregulation by reducing neuroinflammation and hippocampal insulin resistance in beta-amyloid-infused rats. Nutr Neurosci 20:77–88. doi: 10.1080/1028415X.2015.1135572 CrossRefPubMedGoogle Scholar
  39. Parthsarathy V, Holscher C (2013) The type 2 diabetes drug liraglutide reduces chronic inflammation induced by irradiation in the mouse brain. Eur J Pharmacol 700:42–50. doi: 10.1016/j.ejphar.2012.12.012 CrossRefPubMedGoogle Scholar
  40. Paxinos GF, Franklin K (2001) KBJ: the mouse brain in stereotaxic coordinates. Academic Press, New YorkGoogle Scholar
  41. Pistell PJ, Morrison CD, Gupta S, Knight AG, Keller JN, Ingram DK, Bruce-Keller AJ (2010) Cognitive impairment following high fat diet consumption is associated with brain inflammation. J Neuroimmunol 219:25–32. doi: 10.1016/j.jneuroim.2009.11.010 CrossRefPubMedGoogle Scholar
  42. Posey KA et al (2009) Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a HF diet. Am J Physiol Endocrinol Metab 296:E1003–E1012. doi: 10.1152/ajpendo.90377.2008 CrossRefPubMedGoogle Scholar
  43. Proctor C, Thiennimitr P, Chattipakorn N, Chattipakorn SC (2017) Diet, gut microbiota and cognition. Metab Brain Dis 32:1–17. doi: 10.1007/s11011-016-9917-8 CrossRefPubMedGoogle Scholar
  44. Reeves PG, Nielsen FH, Fahey GC Jr (1993) AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr 123:1939–1951PubMedGoogle Scholar
  45. Rodriguez-Navas C, Morselli E, Clegg DJ (2016) Sexually dimorphic brain fatty acid composition in low and high fat diet-fed mice. Mol Metab 5:680–689. doi: 10.1016/j.molmet.2016.06.014 CrossRefPubMedPubMedCentralGoogle Scholar
  46. Sabin MA et al (2007) Fasting nonesterified fatty acid profiles in childhood and their relationship with adiposity, insulin sensitivity, and lipid levels. Pediatrics 120:e1426–e1433. doi: 10.1542/peds.2007-0189 CrossRefPubMedGoogle Scholar
  47. Sahin TD, Karson A, Balci F, Yazir Y, Bayramgurler D, Utkan T (2015) TNFalpha inhibition prevents cognitive decline and maintains hippocampal BDNF levels in the unpredictable chronic mild stress rat model of depression. Behav Brain Res 292:233–240. doi: 10.1016/j.bbr.2015.05.062 CrossRefPubMedGoogle Scholar
  48. Santiago JA, Potashkin JA (2013) Shared dysregulated pathways lead to Parkinson's disease and diabetes. Trends Mol Med 19:176–186. doi: 10.1016/j.molmed.2013.01.002 CrossRefPubMedGoogle Scholar
  49. Secher A et al (2014) The arcuate nucleus mediates GLP1 receptor agonist liraglutide-dependent weight loss. J Clin Invest 124:4473–4488. doi: 10.1172/JCI75276 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 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 116:3015–3025. doi: 10.1172/JCI28898 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Srodulski S et al (2014) Neuroinflammation and neurologic deficits in diabetes linked to brain accumulation of amylin. Mol Neurodegener 9:30. doi: 10.1186/1750-1326-9-30 CrossRefPubMedPubMedCentralGoogle Scholar
  52. Stranahan AM (2015) Models and mechanisms for hippocampal dysfunction in obesity and diabetes. Neuroscience 309:125–139. doi: 10.1016/j.neuroscience.2015.04.045 CrossRefPubMedPubMedCentralGoogle Scholar
  53. Valladolid-Acebes I et al (2012) HF diets induce changes in hippocampal glutamate metabolism and neurotransmission. Am J Physiol Endocrinol Metab 302:E396–E402. doi: 10.1152/ajpendo.00343.2011 CrossRefPubMedGoogle Scholar
  54. Vinet J et al (2012) Neuroprotective function for ramified microglia in hippocampal excitotoxicity. J Neuroinflammation 9:27. doi: 10.1186/1742-2094-9-27 CrossRefPubMedPubMedCentralGoogle Scholar
  55. Zanier ER, Fumagalli S, Perego C, Pischiutta F, De Simoni MG (2015) Shape descriptors of the "never resting" microglia in three different acute brain injury models in mice. Intensive Care Med Exp 3:39. doi: 10.1186/s40635-015-0039-0 CrossRefPubMedGoogle Scholar
  56. Zhang W, Li P, Hu X, Zhang F, Chen J, Gao Y (2011) Omega-3 polyunsaturated fatty acids in the brain: metabolism and neuroprotection. Front Biosci (Landmark Ed) 16:2653–2670CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Andre R. C. Barreto-Vianna
    • 1
  • Marcia B. Aguila
    • 1
  • Carlos A. Mandarim-de-Lacerda
    • 1
    • 2
  1. 1.Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of BiologyState University of Rio de JaneiroRio de JaneiroBrazil
  2. 2.Centro Biomedico, Instituto de Biologia, Laboratorio de Morfometria, Metabolismo e doenca Cardiovascular (www.lmmc.uerj.br)Universidade do Estado do Rio de JaneiroRio de JaneiroBrazil

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