Skip to main content

Advertisement

SpringerLink
Log in

Effect of Initial Aging and High-Fat/High-Fructose Diet on Mitochondrial Bioenergetics and Oxidative Status in Rat Brain

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Middle age is an early stage of the aging process, during which the consumption of diets rich in saturated fats and/or simple sugars might influence brain function, but only few data are available on this issue. We therefore investigated the impact of a diet rich in saturated fat and fructose (HFF) on mitochondrial physiology in hippocampus and frontal cortex of middle-aged rats (1 year old), by including a group of adult rats (90 days) as a “negative control,” lacking the putative effect of aging. Middle-aged rats were fed HFF or control diet for 4 weeks. Mitochondrial function was analyzed by high-resolution respirometry and by assessing the amount of respiratory complexes. Markers of oxidative balance, as well as the protein content of uncoupling protein 2 (UCP2), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and peroxisome proliferator-activated receptor alpha (PPARα), were also assessed. A decrease in the activity of complex I was detected in both brain areas of middle-aged rats. In hippocampus, mitochondrial respiratory capacity and complex IV content decreased with age and increased with HFF diet. Higher protein oxidative damage, decreased antioxidant defenses, and increased UCP2 and PGC-1α content were found in hippocampus of middle-aged rats. HFF feeding induced a significant reduction in the amount of UCP2, PGC-1α, and PPARα, together with higher protein oxidative damage, in both brain areas. Overall, our results point to middle age as a condition of early brain aging for mitochondrial function, with hippocampus being an area more susceptible to metabolic impairment than frontal cortex.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. National Institute on Aging/World Health Organization (2011) Global health and aging. NIH Publication no:11–7737

  2. Elder AC, Finkelstein J, Johnston C, Gelein R, Oberdorster G (2000) Induction of adaptation to inhaled lipopolysaccharide in young and old rats and mice. Inhal Toxicol 12:225e243

    Google Scholar 

  3. Kodavanti PR, Royland JE, Richards JE, Besas J, Macphail RC (2011) Toluene effects on oxidative stress in brain regions of young-adult, middle-age, and senescent Brown Norway rats. Toxicol Appl Pharmacol 256:386e398

    Google Scholar 

  4. MacPhail RC, Farmer JD, Jarema KA (2012) Toluene effects on the motor activity of adolescent, young-adult, middle-age and senescent male Brown Norway rats. Neurotoxicol 33:111e118

    Google Scholar 

  5. Park SK, O’Neill MS, Vokonas PS, Sparrow D, Schwartz J (2005) Effects of air pollution on heart rate variability: the VA normative aging study. Environ Health Perspect 113:304e309

    Google Scholar 

  6. Royland JE, Kodavanti PR, Schmid JE, MacPhail RC (2012) Toluene effects on gene expression in the hippocampus of young adult, middle-age, and senescent Brown Norway rats. Toxicol Sci 126:193e212

    Google Scholar 

  7. Bruce-Keller AJ, White CL, Gupta S, Knight AG, Pistell PJ, Ingram DK, Morrison CD, Keller JN (2010) NOX activity in brain aging: exacerbation by high fat diet. Free Radic Biol Med 49:22–30

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Morrison CD, Pistell PJ, Ingram DK, Johnson WD, Liu Y, Fernandez-Kim SO, White CL, Purpera MN et al (2010) High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased Nrf2 signaling. J Neurochem 114:1581–1589

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Spencer SJ, D'Angelo H, Soch A, Watkins LR, Maier SF, Barrientos RM (2017) High-fat diet and aging interact to produce neuroinflammation and impair hippocampal- and amygdalar-dependent memory. Neurobiol Aging 58:88–101

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Uranga RM, Bruce-Keller AJ, Morrison CD, Fernandez-Kim SO, Ebenezer PJ, Zhang L, Dasuri K, Keller NJ (2010) Intersection between metabolic dysfunction, high fat diet consumption, and brain aging. J Neurochem 114:344–361

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 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 18:1085–1088

    PubMed  PubMed Central  Google Scholar 

  12. Granholm AC, Bimonte-Nelson H, Moore AB, Nelson ME, Freeman LR, Sambamurti K (2008) Effects of a saturated fat and high cholesterol diet on memory and hippocampal morphology in the middle-aged rat. J Alzheimers Dis 14:133–145

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Freeman LR, Haley-Zitlin V, Rosenberger DS, Granholm AC (2014) Damaging effects of a high-fat diet to the brain and cognition: a review of proposed mechanisms. Nutr Neurosci 7:241–251

    Google Scholar 

  14. Cigliano L, Spagnuolo MS, Crescenzo R, Cancelliere R, Iannotta L, Mazzoli A, Liverini G, Iossa S (2018) Short-term fructose feeding induces inflammation and oxidative stress in the hippocampus of young and adult rats. Mol Neurobiol 55(4):2869–2883

    CAS  PubMed  Google Scholar 

  15. Spagnuolo MS, Bergamo P, Crescenzo R, Iannotta L, Treppiccione L, Iossa S, Cigliano L (2018) Brain Nrf2 pathway, autophagy, and synaptic function proteins are modulated by a short-term fructose feeding in young and adult rats. Nutr Neurosci 24:1–12. https://doi.org/10.1080/1028415X.2018.1501532

    Article  Google Scholar 

  16. Papa L, Rockwell P (2008) Persistent mitochondrial dysfunction and oxidative stress hinder neuronal cell recovery from reversible proteasome inhibition. Apoptosis 13:588–599

    CAS  PubMed  Google Scholar 

  17. Collier TJ, Coleman PD (1991) Divergence of biological and chronological aging: evidence from rodent studies. Neurobiol Aging 12:685–693

    CAS  PubMed  Google Scholar 

  18. Odermatt A (2011) The Western-style diet: a major risk factor for impaired kidney function and chronic kidney disease. Am J Physiol Ren Physiol 301:F919–F931

    CAS  Google Scholar 

  19. Pesta D, Gnaiger E (2012) High-resolution respirometry: OXPHOS protocols for human cells and permeabilized fibers from small biopsies of human muscle. Methods Mol Biol 810:25–58

    CAS  PubMed  Google Scholar 

  20. Picard M, Taivassalo T, Ritchie D, Wright KJ, Thomas MM, Romestaing C, Hepple RT (2011) Mitochondrial structure and function are disrupted by standard isolation methods. PLoS One 6(3):e18317

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Picard M, Taivassalo T, Gouspillou G, Hepple RT (2011) Mitochondria: isolation, structure and function. J Physiol 589:4413–4421

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Papp EA, Leergaarda TB, Calabrese E, Johnson GA, Bjaalie JG (2014) Waxholm Space atlas of the Sprague Dawley rat brain. NeuroImage 97:374–386

    PubMed  Google Scholar 

  23. Burtscher J, Zangrandi L, Schwarzer C, Gnaiger E (2015) Differences in mitochondrial function in homogenated samples from healthy and epileptic specific brain tissues revealed by high-resolution respirometry. Mitochondrion 25:104–112

    CAS  PubMed  Google Scholar 

  24. Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle: new perspectives of mitochondrial physiology. Int J Biochem Cell Biol 41:1837–1845

    CAS  PubMed  Google Scholar 

  25. Gnaiger E (2014) Mitochondrial pathways and respiratory control. An introduction to OXPHOS analysis. OROBOROS MiPNet Publications (4th ed): ISBN 978-973-9502399-9502398-9502390

  26. Srere PA (1969) Citrate synthase. Methods Enzymol 13:3–11

    CAS  Google Scholar 

  27. Fernandes MA, Custódio JB, Santos MS, Moreno AJ, Vicente JA (2006) Tetrandrine concentrations not affecting oxidative phosphorylation protect rat liver mitochondria from oxidative stress. Mitochondrion 6:176–185

    CAS  PubMed  Google Scholar 

  28. Spagnuolo MS, Mollica MP, Maresca B, Cavaliere G, Cefaliello C, Trinchese G, Scudiero R, Crispino M et al (2015) High fat diet and inflammation—modulation of haptoglobin level in rat brain. Front Cell Neurosci 9:479. https://doi.org/10.3389/fncel.2015.00479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Maehly AC, Chance B (1954) The assay of catalases and peroxidases. Methods Biochem Anal 1:357–424

    CAS  PubMed  Google Scholar 

  30. Flohè L, Otting F (1974) Superoxide dismutase assay. Methods Enzymol 105:93–104

    Google Scholar 

  31. Spagnuolo MS, Maresca B, Mollica MP, Cavaliere G, Cefaliello C, Trinchese G, Esposito MG, Scudiero R et al (2014) Haptoglobin increases with age in rat hippocampus and modulates apolipoprotein E mediated cholesterol trafficking in neuroblastoma cell lines. Front Cell Neurosci 8:212

    PubMed  PubMed Central  Google Scholar 

  32. Holloszy JO, Oscai LB, Don IJ, Molé PA (1970) Mitochondrial citric acid cycle and related enzymes: adaptive response to exercise. Biochem Biophys Res Commun 40(6):1368–1373

    CAS  PubMed  Google Scholar 

  33. Halliwell B, Gutteridge JMC (2000) Free radicals, other reactive species and disease. In: Halliwell B, Gutteridge JMC (eds) Free radicals in biology and medicine. Oxford University Press, Oxford, pp. 617–783

    Google Scholar 

  34. Garaschuk O, Semchyshyn HM, Lushchak VI (2018) Healthy brain aging: interplay between reactive species, inflammation and energy supply. Ageing Res Rev 43:26–45

    CAS  PubMed  Google Scholar 

  35. Krauss S, Zhang CY, Lowell BB (2005) The mitochondrial uncoupling-protein homologues. Nat Rev Mol Cell Biol 6:248–261

    CAS  PubMed  Google Scholar 

  36. Mattiasson G, Shamloo M, Gido G, Mathi K, Tomasevic G, Yi S, Warden CH, Castilho RF et al (2003) Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med 9:1062–1068

    CAS  PubMed  Google Scholar 

  37. Barnstable CJ, Reddy R, Li H, Horvath TL (2016) Mitochondrial uncoupling protein 2 (UCP2) regulates retinal ganglion cell number and survival. J Mol Neurosci 58:461–469

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Preston AR, Eichenbaum H (2013) Interplay of hippocampus and prefrontal cortex in memory. Curr Biol 23(17):R764–R773

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Monti JM, Baym CL, Cohen NJ (2014) Identifying and characterizing the effects of nutrition on hippocampal memory. Adv Nutr 5(3):337S–343S

    PubMed  PubMed Central  Google Scholar 

  40. 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

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Rajwade MS, Katyare SS, Fatterpaker P, Sreenivasan A (1975) Regulation of mitochondrial protein turnover by thyroid hormone(s). Biochem J 152:379–387

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Davey GP, Clark JB (1996) Threshold effects and control of oxidative phosphorylation in nonsynaptic rat brain mitochondria. J Neurochem 66(4):1617–1624

    CAS  PubMed  Google Scholar 

  43. Cocco T, Pacelli C, Sgobbo P, Villani G (2009) Control of OXPHOS efficiency by complex I in brain mitochondria. Neurobiol Aging 30:622–629

    CAS  PubMed  Google Scholar 

  44. Navarro A, Boveris A (2009) Brain mitochondrial dysfunction and oxidative damage in Parkinson’s disease. J Bioenerg Biomembr 41:517–521

    CAS  PubMed  Google Scholar 

  45. Grimm A, Eckert A (2017) Brain aging and neurodegeneration: from a mitochondrial point of view. J Neurochem 143(4):418–431

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Braidy N, Poljak A, Grant R, Jayasena T, Mansour H, Chan-Ling T, Guillemin GJ, Smythe G et al (2014) Mapping NAD+ metabolism in the brain of ageing Wistar rats: potential targets for influencing brain senescence. Biogerontol 15:177–198

    CAS  Google Scholar 

  47. Manczak M, Jung Y, Park BS, Partovi D, Reddy PH (2005) Time-course of mitochondrial gene expressions in mice brains: implications for mitochondrial dysfunction, oxidative damage, and cytochrome c in aging. J Neurochem 92:494–504

    CAS  PubMed  Google Scholar 

  48. Navarro A, Bandez MJ, Lopez-Cepero JM, Gomez C, Boveris A (2011) High doses of vitamin E improve mitochondrial dysfunction in rat hippocampus and frontal cortex upon aging. Am J Phys Regul Integr Comp Phys 300:R827–R834

    CAS  Google Scholar 

  49. Thomsen K, Yokota T, Hasan-Olive MM, Sherazi N, Fakouri NB, Desler C, Regnell CE, Larsen S et al (2018) Initial brain aging: heterogeneity of mitochondrial size is associated with decline in complex I-linked respiration in cortex and hippocampus. Neurobiol Aging 61:215–224

    CAS  PubMed  Google Scholar 

  50. Dencher NA, Frenzel M, Reifschneider NH, Sugawa M, Krause F (2007) Proteome alterations in rat mitochondria caused by aging. Ann N Y Acad Sci 1100:291–298

    CAS  PubMed  Google Scholar 

  51. Frenzel M, Rommelspacher H, Sugawa MD, Dencher NA (2010) Ageing alters the supramolecular architecture of OxPhos complexes in rat brain cortex. Exp Gerontol 45:563–572

    CAS  PubMed  Google Scholar 

  52. Dudkina NV, Kouril R, Peters K, Braun HP, Boekema EJ (2010) Structure and function of mitochondrial supercomplexes. Biochim Biophys Acta 1797:664–670

    CAS  PubMed  Google Scholar 

  53. Franko A, von Kleist-Retzow JC, Neschen S, Wu M, Schommers P, Böse M, Kunze A, Hartmann U et al (2014) Liver adapts mitochondrial function to insulin resistant and diabetic states in mice. J Hepatol 60:816–823

    CAS  PubMed  Google Scholar 

  54. Kakimoto PA, Kowaltowski AJ (2016) Effects of high fat diets on rodent liver bioenergetics and oxidative imbalance. Redox Biol 8:216–225

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Wang CH, Wu SB, Wu YT, Wei YH (2013) Oxidative stress response elicited by mitochondrial dysfunction: implication in the pathophysiology of aging. Exp Biol Med (Maywood) 238:450–460

    Google Scholar 

  56. Lu M, Sun XL, Qiao C, Liu Y, Ding JH, Hu G (2014) Uncoupling protein 2 deficiency aggravates astrocytic endoplasmic reticulum stress and nod-like receptor protein 3 inflammasome activation. Neurobiol Aging 35:421–430

    CAS  PubMed  Google Scholar 

  57. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jäger S, Handschin C, Zheng K et al (2006) Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127(2):397–408

    CAS  PubMed  Google Scholar 

  58. Roy A, Jana M, Corbett GT, Ramaswamy S, Kordower JH, Gonzalez FJ, Pahan K (2013) Regulation of cyclic AMP response element binding and hippocampal plasticity-related genes by peroxisome proliferator-activated receptor alpha. Cell Rep 4:724–737

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Roy A, Pahan K (2015) PPARα signaling in the hippocampus: crosstalk between fat and memory. J NeuroImmune Pharmacol 10(1):30–34

    PubMed  PubMed Central  Google Scholar 

  60. Sajan M, Hansen B, Ivey R, Sajan J, Ari C, Song S, Braun U, Leitges M et al (2016) Brain insulin signaling is increased in insulin-resistant states and decreases in FOXOs and PGC-1α and increases in Aβ1-40/42 and phospho-tau may abet Alzheimer development. Diabetes 65(7):1892–1903

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Morselli E, Frank AP, Palmer BF, Rodriguez-Navas C, Criollo A, Clegg DJ (2016) A sexually dimorphic hypothalamic response to chronic high-fat diet consumption. Int J Obes 40:206–209

    CAS  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Dr. Emilia de Santis for skillful management of animal house.

Funding

This work was supported by a grant from University of Naples Federico II - Ricerca Dip 2017 and by a FIRB - Futuro in Ricerca grant (RBFR12QW4I_004) from the Italian Ministry of Education, University and Research (MIUR).

Author information

Authors and Affiliations

  1. Department of Biology, University of Naples Federico II, Complesso Universitario Monte S. Angelo, Edificio 7, Via Cintia, I-80126, Naples, Italy

    Raffaella Crescenzo, Rosa Cancelliere, Lucia Iannotta, Arianna Mazzoli, Cristina Gatto, Susanna Iossa & Luisa Cigliano

  2. Department of Bio-Agrofood Science, Institute for the Animal Production System in Mediterranean Environment, National Research Council (CNR-ISPAAM), Naples, Italy

    Maria Stefania Spagnuolo

Authors
  1. Raffaella Crescenzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Stefania Spagnuolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rosa Cancelliere
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lucia Iannotta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Arianna Mazzoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cristina Gatto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Susanna Iossa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Luisa Cigliano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susanna Iossa.

Ethics declarations

Treatment, housing, and euthanasia of animals met the guidelines set by the Italian Health Ministry. All experimental procedures involving animals were approved by “Comitato Etico-Scientifico per la Sperimentazione Animale” of the University of Naples Federico II.

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

Supplementary Figure 9

Representative traces of oxygen flux in the hippocampus of middle-aged rats. (PNG 1.71 mb)

High resolution image (TIFF 1.71 mb)

Supplementary Figure 10

Representative western blot of respiratory complexes I-V carried out on protein extracts from hippocampus of adult (1) middle-aged (2) and middle-aged HFF (3) rats. (PNG 12.9  mb)

High resolution image (TIFF 12.9 mb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Crescenzo, R., Spagnuolo, M.S., Cancelliere, R. et al. Effect of Initial Aging and High-Fat/High-Fructose Diet on Mitochondrial Bioenergetics and Oxidative Status in Rat Brain. Mol Neurobiol 56, 7651–7663 (2019). https://doi.org/10.1007/s12035-019-1617-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-019-1617-z

Keywords

Search

Navigation