Molecular Neurobiology

, Volume 55, Issue 8, pp 6984–6999 | Cite as

Impairment of Novel Object Recognition Memory and Brain Insulin Signaling in Fructose- but Not Glucose-Drinking Female Rats

  • Gemma Sangüesa
  • Mar Cascales
  • Christian Griñán
  • Rosa María Sánchez
  • Núria Roglans
  • Mercè Pallàs
  • Juan Carlos LagunaEmail author
  • Marta AlegretEmail author


Excessive sugar intake has been related to cognitive alterations, but it remains unclear whether these effects are related exclusively to increased energy intake, and the molecular mechanisms involved are not fully understood. We supplemented Sprague-Dawley female rats with 10% w/v fructose in drinking water or with isocaloric glucose solution for 7 months. Cognitive function was assessed through the Morris water maze (MWM) and the novel object recognition (NOR) tests. Plasma parameters and protein/mRNA expression in the frontal cortex and hippocampus were determined. Results showed that only fructose-supplemented rats displayed postprandial and fasting hypertriglyceridemia (1.4 and 1.9-fold, p < 0.05) and a significant reduction in the discrimination index in the NOR test, whereas the results of the MWM test showed no differences between groups. Fructose-drinking rats displayed an abnormal glucose tolerance test and impaired insulin signaling in the frontal cortex, as revealed by significant reductions in insulin receptor substrate-2 protein levels (0.77-fold, p < 0.05) and Akt phosphorylation (0.72-fold, p < 0.05), and increased insulin-degrading enzyme levels (1.86-fold, p < 0.001). Fructose supplementation reduced the expression of antioxidant enzymes and altered the amount of proteins involved in mitochondrial fusion/fission in the frontal cortex. In conclusion, cognitive deficits induced by chronic liquid fructose consumption are not exclusively related to increased caloric intake and are correlated with hypertriglyceridemia, impaired insulin signaling, increased oxidative stress and altered mitochondrial dynamics, especially in the frontal cortex.


Simple sugars Cognitive deficit Frontal cortex Hippocampus Metabolic dysfunctions 



We are a Consolidated Research Group of the Autonomous Government of Catalonia (SGR13-00066). We would like to thank the University of Barcelona’s Language Advisory Service for revising the manuscript.

Funding Information

This study was supported by the Fundació Privada Catalana de Nutrició i Lípids, Ministry of Economy and Competitiveness (grant number SAF2013-42982-R) and European Commission FEDER funds. Miguel Baena and Gemma Sangüesa were supported by FPI and FPU grants from the Spanish Ministry of Science and Innovation.

Supplementary material

12035_2017_863_MOESM1_ESM.docx (21 kb)
Supplemental Table 1 (DOCX 21 kb)
12035_2017_863_MOESM2_ESM.docx (20 kb)
Supplemental Table 2 (DOCX 20 kb)


  1. 1.
    de la Monte SM, Longato L, Tong M, Wands JR (2009) Insulin resistance and neurodegeneration: roles of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis. Curr Opin Investig Drugs 10(10):1049–1060. PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Biessels GJ, Reagan LP (2015) Hippocampal insulin resistance and cognitive dysfunction. Nat Rev Neurosci 16(11):660–671. CrossRefPubMedGoogle Scholar
  3. 3.
    Dekker MJ, Su Q, Baker C, Rutledge AC, Adeli K (2010) Fructose: a highly lipogenic nutrient implicated in insulin resistance, hepatic steatosis, and the metabolic syndrome. Am J Physiol Endocrinol Metab 299(5):E685–E694. CrossRefPubMedGoogle Scholar
  4. 4.
    Tappy L, Lê KA, Tran C, Paquot N (2010) Fructose and metabolic diseases: new findings, new questions. Nutrition 26(11-12):1044–1049. CrossRefPubMedGoogle Scholar
  5. 5.
    Stanhope KL, Havel PJ (2008) Endocrine and metabolic effects of consuming beverages sweetened with fructose, glucose, sucrose, or high fructose corn syrup. Am J Clin Nutr 88(6):1733S–1737S. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Campos VC, Tappy L (2016) Physiological handling of dietary fructose-containing sugars: implications for health. Int J Obes 40(S1):S6–S11. CrossRefGoogle Scholar
  7. 7.
    Lakhan S, Kirchgessner A (2013) The emerging role of dietary fructose in obesity and cognitive decline. Nutr J 12(1):1–12. CrossRefGoogle Scholar
  8. 8.
    Beilharz JE, Maniam J, Morris MJ (2015) Diet-induced cognitive deficits: the role of fat and sugar, potential mechanisms and nutritional interventions. Nutrients 7(8):6719–6738. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Lowette K, Roosen L, Tack J, Van den Berghe P (2015) Effects of high-fructose diets on central appetite signaling and cognitive function. Front Nutr 2:5. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Popkin BM, Hawkes C (2016) Sweetening of the global diet, particularly beverages: patterns, trends, and policy responses. Lancet Diabetes Endocrinol 4(2):174–186. CrossRefPubMedGoogle Scholar
  11. 11.
    Stanhope KL, Schwarz JM, Keim NL et al (2009) Consuming fructose-sweetened, not glucose-sweetened, beverages increase visceral adiposity and lipids and decrease insulin sensitivity in overweight/obese men. J Clin Invest 1334:1322–1334. CrossRefGoogle Scholar
  12. 12.
    Schaefer EJ, Gleason JA, Dansinger ML (2009) Dietary fructose and glucose differentially affect lipid and glucose homeostasis1–3. J Nutr 139(6):1257S–1262S. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Baena M, Sangüesa G, Dávalos A, Latasa MJ, Sala-Vila A, Sánchez RM, Roglans N, Laguna JC et al (2016) Fructose, but not glucose, impairs insulin signaling in the three major insulin-sensitive tissues. Sci Rep 6(1):26149. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Sangüesa G, Shaligram S, Akhter F et al (2017) Type of supplemented simple sugar, not merely calorie intake, determines adverse effects on metabolism and aortic function in female rats. Am J Physiol Heart Circ Physiol 312(2):H289–H304. CrossRefPubMedGoogle Scholar
  15. 15.
    Geda YE, Ragossnig M, Roberts LA, Roberts RO, Pankratz VS, Christianson TJ, Mielke MM, Levine JA et al (2013) Caloric intake, aging, and mild cognitive impairment: a population-based study. J Alzheimers Dis 34(2):501–507. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Roberts RO, Roberts LA, Geda YE, Cha RH, Pankratz VS, O'Connor HM, Knopman DS, Petersen RC (2012) Relative intake of macronutrients impacts risk of mild cognitive impairment or dementia. J Alzheimers Dis 32(2):329–339. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Vilà L, Roglans N, Perna V, Sánchez RM, Vázquez-Carrera M, Alegret M, Laguna JC (2011) Liver AMP/ATP ratio and fructokinase expression are related to gender differences in AMPK activity and glucose intolerance in rats ingesting liquid fructose. J Nutr Biochem 22(8):741–751. CrossRefPubMedGoogle Scholar
  18. 18.
    Sengupta P (2013) The laboratory rat: relating age with human’s. Int J Prev Med 4(6):624–630PubMedPubMedCentralGoogle Scholar
  19. 19.
    Helenius M, Hänninen M, Lehtinen SK, Salminen A (1996) Aging-induced up-regulation of nuclear binding activities of oxidative stress responsive NF-kB transcription factor in mouse cardiac muscle. J Mol Cell Cardiol 28(3):487–498. CrossRefPubMedGoogle Scholar
  20. 20.
    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72(1-2):248–254. CrossRefPubMedGoogle Scholar
  21. 21.
    Roglans N, Vilà L, Farré M, Alegret M, Sánchez RM, Vázquez-Carrera M, Laguna JC (2007) Impairment of hepatic Stat-3 activation and reduction of PPARalpha activity in fructose-fed rats. Hepatology 45(3):778–788. CrossRefPubMedGoogle Scholar
  22. 22.
    Bedse G, Di Domenico F, Serviddio G, Cassano T (2015) Aberrant insulin signaling in Alzheimer’s disease: current knowledge. Front Neurosci 9:1–13. CrossRefGoogle Scholar
  23. 23.
    Benton D, Maconie A, Williams C (2007) The influence of the glycaemic load of breakfast on the behaviour of children in school. Physiol Behav 92(4):717–724. CrossRefPubMedGoogle Scholar
  24. 24.
    Nabb S, Benton D (2006) The influence on cognition of the interaction between the macro-nutrient content of breakfast and glucose tolerance. Physiol Behav 87(1):16–23. CrossRefPubMedGoogle Scholar
  25. 25.
    Smith MA, Foster JK (2008) The impact of a high versus a low glycaemic index breakfast cereal meal on verbal episodic memory in healthy adolescents. Nutr Neurosci 11(5):219–227. CrossRefPubMedGoogle Scholar
  26. 26.
    Messier C (2004) Glucose improvement of memory: a review. Eur J Pharmacol 490(1-3):33–57. CrossRefPubMedGoogle Scholar
  27. 27.
    Stollery B, Christian L (2016) Glucose improves object-location binding in visual-spatial working memory. Psychopharmacology 233(3):529–547. CrossRefPubMedGoogle Scholar
  28. 28.
    Kanoski SE, Davidson TL (2011) Western diet consumption and cognitive impairment: Links to hippocampal dysfunction and obesity. Physiol Behav 103(1):59–68. CrossRefPubMedGoogle Scholar
  29. 29.
    Antunes M, Biala G (2012) The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process 13(2):93–110. CrossRefPubMedGoogle Scholar
  30. 30.
    Sharma S, Rakoczy S, Brown-Borg H (2010) Assessment of spatial memory in mice. Life Sci 87(17-18):521–536. CrossRefPubMedGoogle Scholar
  31. 31.
    Francis BM, Kim J, Barakat ME, Fraenkl S, Yücel YH, Peng S, Michalski B, Fahnestock M et al (2012) Object recognition memory and BDNF expression are reduced in young TgCRND8 mice. Neurobiol Aging 33(3):555–563. CrossRefPubMedGoogle Scholar
  32. 32.
    Brown MW, Barker GRI, Aggleton JP, Warburton EC (2012) What pharmacological interventions indicate concerning the role of the perirhinal cortex in recognition memory. Neuropsychologia 50(13):3122–3140. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ross AP, Bartness TJ, Mielke JG, Parent MB (2009) A high fructose diet impairs spatial memory in male rats. Neurobiol Learn Mem 92(3):410–416. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Yin QQ, Pei JJ, Xu S, Luo DZ, Dong SQ, Sun MH, You L, Sun ZJ et al (2013) Pioglitazone improves cognitive function via increasing insulin sensitivity and strengthening antioxidant defense system in fructose-drinking insulin resistance rats. PLoS One 8(3):e59313. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Bruggeman EC, Li C, Ross AP, Doherty JM, Williams BF, Frantz KJ, Parent MB (2011) A high fructose diet does not affect amphetamine self-administration or spatial water maze learning and memory in female rats. Pharmacol Biochem Behav 99(3):356–364. CrossRefPubMedGoogle Scholar
  36. 36.
    Abbott KN, Morris MJ, Westbrook RF, Reichelt AC (2016) Sex-specific effects of daily exposure to sucrose on spatial memory performance in male and female rats, and implications for estrous cycle stage. Physiol Behav 162:52–60. CrossRefPubMedGoogle Scholar
  37. 37.
    Stranahan AM, Norman ED, Lee K, Cutler RG, Telljohann RS, Egan JM, Mattson MP (2008) Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle-aged rats. Hippocampus 18(11):1085–1088. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Molteni R, Barnard RJ, Ying Z, Roberts CK, Gómez-Pinilla F (2002) A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning. Neuroscience 112(4):803–814. CrossRefPubMedGoogle Scholar
  39. 39.
    Drew P, Smith E, Thomas P (1998) Fat distribution and changes in the blood brain barrier in a rat model of cerebral arterial fat embolism. J Neurol Sci 156(2):138–143. CrossRefPubMedGoogle Scholar
  40. 40.
    Farr SA, Yamada KA, Butterfield DA, Abdul HM, Xu L, Miller NE, Banks WA, Morley JE (2008) Obesity and hypertriglyceridemia produce cognitive impairment. Endocrinology 149(5):2628–2636. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Agrawal R, Gomez-Pinilla F (2012) “Metabolic syndrome” in the brain: deficiency in omega-3 fatty acid exacerbates dysfunctions in insulin receptor signalling and cognition. J Physiol 590(10):2485–2499. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Lewis GF, Carpentier A, Adeli K, Giacca A (2002) Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 23(2):201–229. CrossRefPubMedGoogle Scholar
  43. 43.
    Yarchoan M, Arnold SE (2014) Repurposing diabetes drugs for brain insulin resistance in Alzheimer disease. Diabetes 63(7):2253–2261. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Mielke JG, Taghibiglou C, Liu L, Zhang Y, Jia Z, Adeli K, Wang YT (2005) A biochemical and functional characterization of diet-induced brain insulin resistance. J Neurochem 93(6):1568–1578. CrossRefPubMedGoogle Scholar
  45. 45.
    Cigliano L, Spagnuolo MS, Crescenzo R, Cancelliere R, Iannotta L, Mazzoli A, Liverini G, Iossa S (2017) Short-term fructose feeding induces inflammation and oxidative stress in the hippocampus of young and adult rats. Mol Neurobiol.
  46. 46.
    McNay EC, Recknagel AK (2011) Brain insulin signaling: a key component of cognitive processes and a potential basis for cognitive impairment in type 2 diabetes. Neurobiol Learn Mem 96(4):517–528. CrossRefPubMedGoogle Scholar
  47. 47.
    Monti JM, Moulton CJ, Cohen NJ (2015) The role of nutrition on cognition and brain health in ageing: a targeted approach. Nutr Res Rev 28(02):167–180. CrossRefPubMedGoogle Scholar
  48. 48.
    Kleinridders A, Ferris HA, Cai W, Kahn CR (2014) Insulin action in brain regulates systemic metabolism and brain function. Diabetes 63(7):2232–2243. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Ho L, Qin W, Pompl PN et al (2004) Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer’s disease. FASEB J 18:902–904. CrossRefPubMedGoogle Scholar
  50. 50.
    Zhao L (2004) Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: implications for Alzheimer’s disease intervention. J Neurosci 24(49):11120–11126. CrossRefPubMedGoogle Scholar
  51. 51.
    Di Luccia B, Crescenzo R, Mazzoli A, Cigliano L, Venditti P, Walser JC, Widmer A, Baccigalupi L et al (2015) Rescue of fructose-induced metabolic syndrome by antibiotics or faecal transplantation in a rat model of obesity. PLoS One 10(8):1–19. CrossRefGoogle Scholar
  52. 52.
    Sangüesa G, Baena M, Hutter N, Montañés J, Sánchez R, Roglans N, Laguna J, Alegret M (2017) The addition of liquid fructose to a western-type diet in LDL-R-/- mice induces liver inflammation and fibrogenesis markers without disrupting insulin receptor signalling after an insulin challenge. Nutrients 9(3):1–15. CrossRefGoogle Scholar
  53. 53.
    Abbasi A, de Paula Vieira R, Bischof F, Walter M, Movassaghi M, Berchtold NC, Niess AM, Cotman CW et al (2016) Sex-specific variation in signaling pathways and gene expression patterns in human leukocytes in response to endotoxin and exercise. J Neuroinflammation 13(1):289. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Nowotny K, Jung T, Höhn A, Weber D, Grune T (2015) Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomol Ther 5(1):194–222. CrossRefGoogle Scholar
  55. 55.
    Guimarães ELM, Empsen C, Geerts A, van Grunsven LA (2010) Advanced glycation end products induce production of reactive oxygen species via the activation of NADPH oxidase in murine hepatic stellate cells. J Hepatol 52(3):389–397. CrossRefPubMedGoogle Scholar
  56. 56.
    Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, Stern DM, Nawroth PP (2005) Understanding RAGE, the receptor for advanced glycation end products. J Mol Med 83(11):876–886. CrossRefPubMedGoogle Scholar
  57. 57.
    Chang Y, Chang W, Tsai N et al (2014) The roles of biomarkers of oxidative stress and antioxidant in Alzheimer’s disease: a systematic review. Biomed Res Int 2014:182303PubMedPubMedCentralGoogle Scholar
  58. 58.
    Gugliucci A (2017) Formation of fructose-mediated advanced glycation end products and their roles in metabolic and in flammatory diseases. 54–62.
  59. 59.
    Trevisan M, Browne R, Ram M, Muti P, Freudenheim J, Carosella AM, Armstrong D (2001) Correlates of markers of oxidative status in the general population. Am J Epidemiol 154(4):348–356. CrossRefPubMedGoogle Scholar
  60. 60.
    Seo AY, Joseph A-MM, Dutta D et al (2010) New insights into the role of mitochondria in aging: mitochondrial dynamics and more. J Cell Sci 123(15):2533–2542. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Itoh K, Nakamura K, Iijima M, Sesaki H (2013) Mitochondrial dynamics in neurodegeneration. Trends Cell Biol 23(2):64–71. CrossRefPubMedGoogle Scholar
  62. 62.
    Reddy PH (2014) Inhibitors of mitochondrial fission as a therapeutic strategy for diseases with oxidative stress and mitochondrial dysfunction. J Alzheimers Dis 40(2):245–256. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Edwards JL, Quattrini A, Lentz SI, Figueroa-Romero C, Cerri F, Backus C, Hong Y, Feldman EL (2010) Diabetes regulates mitochondrial biogenesis and fission in mouse neurons. Diabetologia 53(1):160–169. CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food SciencesUniversity of BarcelonaBarcelonaSpain
  2. 2.CIBER Enfermedades Neurodegenerativas (CIBERNED)Instituto de Salud Carlos III (ISCIII)MadridSpain
  3. 3.Institute of BiomedicineUniversity of BarcelonaBarcelonaSpain
  4. 4.CIBER Fisiología de la Obesidad y Nutrición (CIBEROBN)Instituto de Salud Carlos III (ISCIII)MadridSpain

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