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Buttermilk and Krill Oil Phospholipids Improve Hippocampal Insulin Resistance and Synaptic Signaling in Aged Rats

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Abstract

Impaired glucose metabolism and mitochondrial decay greatly increase with age, when cognitive decline becomes rampant. No pharmacological or dietary intervention has proven effective, but proper diet and lifestyle do postpone the onset of neurodegeneration and some nutrients are being investigated. We studied insulin signaling, mitochondrial activity and biogenesis, and synaptic signaling in the hippocampus and cortex following dietary supplementation with bioactive phospholipid concentrates of krill oil (KOC), buttermilk fat globule membranes (BMFC), and a combination of both in aged rats. After 3 months of supplementation, although all groups of animals showed clear signs of peripheral insulin resistance, the combination of KOC and BMFC was able to improve peripheral insulin sensitivity. We also explored brain energy balance. Interestingly, the hippocampus of supplemented rats—mainly when supplemented with BMFC or the combination of KOC and BMFC—showed an increase in intracellular adenosine triphosphate (ATP) levels, whereas no difference was observed in the cerebral cortex. Moreover, we found a significant increase of brain-derived neurotrophic factor (BDNF) in the hippocampus of BMFC+KO animals. In summary, dietary supplementation with KOC and/or BMFC improves peripheral and central insulin resistance, suggesting that their administration could delay the onset of these phenomena. Moreover, n-3 fatty acids (FAs) ingested as phospholipids increase BDNF levels favoring an improvement in energy state within neurons and facilitating both mitochondrial and protein synthesis, which are necessary for synaptic plasticity. Thus, dietary supplementation with n-3 FAs could protect local protein synthesis and energy balance within dendrites, favoring neuronal health and delaying cognitive decline associated to age-related disrepair.

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Abbreviations

AD:

Alzheimer’s disease

Akt:

Protein kinase B

AMPK:

AMP-activated protein kinase

α-Syn:

Chaperone α-synuclein

ATP:

Adenosine triphosphate

BDNF:

Brain-derived neurotrophic factor

BMFC:

Buttermilk fat globule concentrate

CD:

Cognitive deficiency

DHA:

Docosahexaenoic acid

EPA:

Eicosapentaenoic acid

FAs:

Fatty acids

Glut4:

Glucose transporter type 4

HOMA-IR:

Homeostasis model assessment of insulin resistance index

IRβ:

Insulin receptor-beta subunit

IRS:

Insulin receptor substrate

KOC:

Krill oil concentrate

MFGM:

Milk fat globule membrane

mTOR:

Mammalian target of rapamycin

PUFA:

Polyunsaturated fatty acid

PC:

Phosphatidylcholine

PS:

Phosphatidylserine

PE:

Phosphatidylethanolamine

PI:

Phosphatidylinositol

PLE:

Pressurized liquid extraction

PI3K:

Phosphatidylinositol-3-kinase

PGC-1α:

Proliferator-activated receptor γ coactivator 1-α

SM:

Sphingomyelin

SIRT1:

Sirtuin 1

Stx1A:

Syntaxin 1A

Syn1:

Synapsin I

Syt1:

Synaptotagmin 1

TAG:

Triacylglycerides

Vamp2:

Synaptobrevin 2

References

  1. Bhat AH, Dar KB, Anees S, Zargar MA, Masood A, Sofi MA, Ganie SA (2015) Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomed Pharmacother 74:101–110. https://doi.org/10.1016/j.biopha.2015.07.025S0753-3322(15)00169-9

    Article  PubMed  CAS  Google Scholar 

  2. Bratic I, Trifunovic A (2010) Mitochondrial energy metabolism and ageing. Biochim Biophys Acta 1797(6–7):961–967. https://doi.org/10.1016/j.bbabio.2010.01.004S0005-2728(10)00005-8

    Article  PubMed  CAS  Google Scholar 

  3. 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. https://doi.org/10.1007/s12035-012-8339-9

    Article  PubMed  CAS  Google Scholar 

  4. Kleinridders A, Ferris HA, Cai W, Kahn CR (2014) Insulin action in brain regulates systemic metabolism and brain function. Diabetes 63(7):2232–2243. https://doi.org/10.2337/db14-0568db14-0568

    Article  PubMed  PubMed Central  Google Scholar 

  5. Akintola AA, van Heemst D (2015) Insulin, aging, and the brain: mechanisms and implications. Front Endocrinol (Lausanne) 6:13. https://doi.org/10.3389/fendo.2015.00013

    Article  Google Scholar 

  6. Calder PC, Bosco N, Bourdet-Sicard R, Capuron L, Delzenne N, Dore J, Franceschi C, Lehtinen MJ, Recker T, Salvioli S, Visioli F (2017) Health relevance of the modification of low grade inflammation in ageing (inflammageing) and the role of nutrition. Ageing Res Rev. doi:https://doi.org/10.1016/j.arr.2017.09.001

  7. Gomez LA, Hagen TM (2012) Age-related decline in mitochondrial bioenergetics: does supercomplex destabilization determine lower oxidative capacity and higher superoxide production? Semin Cell Dev Biol 23(7):758–767. https://doi.org/10.1016/j.semcdb.2012.04.002S1084-9521(12)00074-2

    Article  PubMed  CAS  Google Scholar 

  8. Gralle M (2017) The neuronal insulin receptor in its environment. J Neurochem 140(3):359–367. https://doi.org/10.1111/jnc.13909

    Article  PubMed  CAS  Google Scholar 

  9. Unger JW, Livingston JN, Moss AM (1991) Insulin receptors in the central nervous system: localization, signalling mechanisms and functional aspects. Prog Neurobiol 36(5):343–362

    Article  PubMed  CAS  Google Scholar 

  10. Pearson-Leary J, McNay EC (2016) Novel roles for the insulin-regulated glucose transporter-4 in hippocampally dependent memory. J Neurosci 36(47):11851–11864. https://doi.org/10.1523/JNEUROSCI.1700-16.2016

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Biessels GJ, Reagan LP (2015) Hippocampal insulin resistance and cognitive dysfunction. Nat Rev Neurosci 16(11):660–671. https://doi.org/10.1038/nrn4019

    Article  PubMed  CAS  Google Scholar 

  12. Bartke A (2008) Insulin and aging. Cell Cycle 7(21):3338–3343. https://doi.org/10.4161/cc.7.21.7012

    Article  PubMed  CAS  Google Scholar 

  13. Solfrizzi V, Panza F (2014) Mediterranean diet and cognitive decline. A lesson from the whole-diet approach: what challenges lie ahead? J Alzheimers Dis 39(2):283–286. https://doi.org/10.3233/JAD-130831F076J887L8877J0V

    Article  PubMed  Google Scholar 

  14. Crespo MC, Tome-Carneiro J, Pintado C, Davalos A, Visioli F, Burgos-Ramos E (2017) Hydroxytyrosol restores proper insulin signaling in an astrocytic model of Alzheimer's disease. Biofactors 43(4):540–548. https://doi.org/10.1002/biof.1356

    Article  PubMed  CAS  Google Scholar 

  15. Jicha GA, Markesbery WR (2010) Omega-3 fatty acids: potential role in the management of early Alzheimer’s disease. Clin Interv Aging 5:45–61

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Vauzour D, Camprubi-Robles M, Miquel-Kergoat S, Andres-Lacueva C, Banati D, Barberger-Gateau P, Bowman GL, Caberlotto L et al (2017) Nutrition for the ageing brain: Towards evidence for an optimal diet. Ageing Res Rev 35:222–240. https://doi.org/10.1016/j.arr.2016.09.010

    Article  PubMed  Google Scholar 

  17. FAO, WFP, IFAD (2012) The state of food insecurity in the world 2012. Economic growth is necessary but not sufficient to accelerate reduction of hunger and malnutrition. http://www.faoorg/docrep/016/i3027e/i3027epdf

  18. Riediger ND, Othman RA, Suh M, Moghadasian MH (2009) A systemic review of the roles of n-3 fatty acids in health and disease. J Am Diet Assoc 109(4):668–679. https://doi.org/10.1016/j.jada.2008.12.022S0002-8223(08)02335-3

    Article  PubMed  CAS  Google Scholar 

  19. Wijendran V, Huang MC, Diau GY, Boehm G, Nathanielsz PW, Brenna JT (2002) Efficacy of dietary arachidonic acid provided as triglyceride or phospholipid as substrates for brain arachidonic acid accretion in baboon neonates. Pediatr Res 51(3):265–272. https://doi.org/10.1203/00006450-200203000-00002

    Article  PubMed  CAS  Google Scholar 

  20. Berge K, Musa-Veloso K, Harwood M, Hoem N, Burri L (2014) Krill oil supplementation lowers serum triglycerides without increasing low-density lipoprotein cholesterol in adults with borderline high or high triglyceride levels. Nutr Res 34(2):126–133. https://doi.org/10.1016/j.nutres.2013.12.003

    Article  PubMed  CAS  Google Scholar 

  21. Deutsch L (2007) Evaluation of the effect of Neptune Krill Oil on chronic inflammation and arthritic symptoms. J Am Coll Nutr 26(1):39–48

    Article  PubMed  CAS  Google Scholar 

  22. Konagai C, Yanagimoto K, Hayamizu K, Han L, Tsuji T, Koga Y (2013) Effects of krill oil containing n-3 polyunsaturated fatty acids in phospholipid form on human brain function: a randomized controlled trial in healthy elderly volunteers. Clin Interv Aging 8:1247–1257. https://doi.org/10.2147/CIA.S50349cia-8-1247

    Article  PubMed  PubMed Central  Google Scholar 

  23. Castro-Gomez P, Garcia-Serrano A, Visioli F, Fontecha J (2015) Relevance of dietary glycerophospholipids and sphingolipids to human health. Prostaglandins Leukot Essent Fatty Acids 101:41–51. doi:https://doi.org/10.1016/j.plefa.2015.07.004S0952-3278(15)00138-6

  24. Castro-Gomez P, Rodriguez-Alcala LM, Monteiro KM, Ruiz AL, Carvalho JE, Fontecha J (2016) Antiproliferative activity of buttermilk lipid fractions isolated using food grade and non-food grade solvents on human cancer cell lines. Food Chem 212:695–702. https://doi.org/10.1016/j.foodchem.2016.06.030S0308-8146(16)30922-0

    Article  PubMed  CAS  Google Scholar 

  25. Osella MC, Re G, Badino P, Bergamasco L, Miolo A (2008) Phosphatidylserine (PS) as a potential nutraceutical for canine brain aging: a review. J Vet Behav: Clin Appl 3(2):41–51. https://doi.org/10.1016/j.jveb.2007.08.003

    Article  Google Scholar 

  26. Lu PH, Lee GJ, Raven EP, Tingus K, Khoo T, Thompson PM, Bartzokis G (2011) Age-related slowing in cognitive processing speed is associated with myelin integrity in a very healthy elderly sample. J Clin Exp Neuropsychol 33(10):1059–1068. https://doi.org/10.1080/13803395.2011.595397

    Article  PubMed  PubMed Central  Google Scholar 

  27. Castro-Gomez MP, Rodriguez-Alcala LM, Calvo MV, Romero J, Mendiola JA, Ibanez E, Fontecha J (2014) Total milk fat extraction and quantification of polar and neutral lipids of cow, goat, and ewe milk by using a pressurized liquid system and chromatographic techniques. J Dairy Sci 97(11):6719–6728. https://doi.org/10.3168/jds.2014-8128S0022-0302(14)00600-6

    Article  PubMed  CAS  Google Scholar 

  28. Umegaki H, Makino T, Uemura K, Shimada H, Hayashi T, Cheng XW, Kuzuya M (2017) The associations among insulin resistance, hyperglycemia, physical performance, diabetes mellitus, and cognitive function in relatively healthy older adults with subtle cognitive dysfunction. Front Aging Neurosci 9:72. https://doi.org/10.3389/fnagi.2017.00072

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Burgos-Ramos E, Chowen JA, Arilla-Ferreiro E, Canelles S, Argente J, Barrios V (2011) Chronic central leptin infusion modifies the response to acute central insulin injection by reducing the interaction of the insulin receptor with IRS2 and increasing its association with SOCS3. J Neurochem 117(1):175–185. https://doi.org/10.1111/j.1471-4159.2011.07191.x

    Article  PubMed  CAS  Google Scholar 

  30. Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P et al (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458(7241):1056–1060. https://doi.org/10.1038/nature07813

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Marosi K, Mattson MP (2014) BDNF mediates adaptive brain and body responses to energetic challenges. Trends Endocrinol Metab 25(2):89–98. https://doi.org/10.1016/j.tem.2013.10.006S1043-2760(13)00178-1

    Article  PubMed  CAS  Google Scholar 

  32. Takei N, Inamura N, Kawamura M, Namba H, Hara K, Yonezawa K, Nawa H (2004) Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J Neurosci 24(44):9760–9769. https://doi.org/10.1523/JNEUROSCI.1427-04.2004

    Article  PubMed  CAS  Google Scholar 

  33. Fontana L, Kennedy BK, Longo VD, Seals D, Melov S (2014) Medical research: treat ageing. Nature 511(7510):405–407. https://doi.org/10.1038/511405a

    Article  PubMed  CAS  Google Scholar 

  34. Daviglus ML, Plassman BL, Pirzada A, Bell CC, Bowen PE, Burke JR, Connolly ES Jr, Dunbar-Jacob JM et al (2011) Risk factors and preventive interventions for Alzheimer disease: state of the science. Arch Neurol 68(9):1185–1190. https://doi.org/10.1001/archneurol.2011.100

    Article  PubMed  Google Scholar 

  35. Jackson PA, Pialoux V, Corbett D, Drogos L, Erickson KI, Eskes GA, Poulin MJ (2016) Promoting brain health through exercise and diet in older adults: a physiological perspective. J Physiol 594(16):4485–4498. https://doi.org/10.1113/JP271270

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, Aros F, Gomez-Gracia E, Ruiz-Gutierrez V et al (2013) Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 368(14):1279–1290. https://doi.org/10.1056/NEJMoa1200303

    Article  PubMed  CAS  Google Scholar 

  37. Schubert M, Contreras C, Franz N, Hellhammer J (2011) Milk-based phospholipids increase morning cortisol availability and improve memory in chronically stressed men. Nutr Res 31(6):413–420. https://doi.org/10.1016/j.nutres.2011.05.012S0271-5317(11)00115-1

    Article  PubMed  CAS  Google Scholar 

  38. Hernell O, Timby N, Domellof M, Lonnerdal B (2016) Clinical benefits of milk fat globule membranes for infants and children. J Pediatr 173(Suppl):S60–S65. https://doi.org/10.1016/j.jpeds.2016.02.077S0022-3476(16)00300-0

    Article  PubMed  CAS  Google Scholar 

  39. Kim H, Suzuki T, Kim M, Kojima N, Ota N, Shimotoyodome A, Hase T, Hosoi E et al (2015) Effects of exercise and milk fat globule membrane (MFGM) supplementation on body composition, physical function, and hematological parameters in community-dwelling frail Japanese women: a randomized double blind, placebo-controlled, follow-up trial. PLoS One 10(2):e0116256. https://doi.org/10.1371/journal.pone.0116256PONE-D-14-31959

    Article  PubMed  PubMed Central  Google Scholar 

  40. Minegishi Y, Ota N, Soga S, Shimotoyodome A (2016) Effects of nutritional supplementation with milk fat globule membrane on physical and muscle function in healthy adults aged 60 and over with semiweekly light exercise: a randomized double-blind, placebo-controlled pilot trial. J Nutr Sci Vitaminol (Tokyo) 62(6):409–415. https://doi.org/10.3177/jnsv.62.409

    Article  CAS  Google Scholar 

  41. Lobraico JM, DiLello LC, Butler AD, Cordisco ME, Petrini JR, Ahmadi R (2015) Effects of krill oil on endothelial function and other cardiovascular risk factors in participants with type 2 diabetes, a randomized controlled trial. BMJ Open Diabetes Res Care 3(1):e000107. https://doi.org/10.1136/bmjdrc-2015-000107bmjdrc-2015-000107

    Article  PubMed  PubMed Central  Google Scholar 

  42. Demmer E, Van Loan MD, Rivera N, Rogers TS, Gertz ER, German JB, Smilowitz JT, Zivkovic AM (2016) Addition of a dairy fraction rich in milk fat globule membrane to a high-saturated fat meal reduces the postprandial insulinaemic and inflammatory response in overweight and obese adults. J Nutr Sci 5:e14. https://doi.org/10.1017/jns.2015.4200042

    Article  PubMed  PubMed Central  Google Scholar 

  43. Lamaziere A, Richard D, Barbe U, Kefi K, Bausero P, Wolf C, Visioli F (2011) Differential distribution of DHA-phospholipids in rat brain after feeding: a lipidomic approach. Prostaglandins Leukot Essent Fatty Acids 84 (1–2):7–11. doi:https://doi.org/10.1016/j.plefa.2010.11.001

  44. Orlando M, Lignani G, Maragliano L, Fassio A, Onofri F, Baldelli P, Giovedi S, Benfenati F (2014) Functional role of ATP binding to synapsin I in synaptic vesicle trafficking and release dynamics. J Neurosci 34(44):14752–14768. https://doi.org/10.1523/JNEUROSCI.1093-14.201434/44/14752

    Article  PubMed  Google Scholar 

  45. Wu A, Ying Z, Gomez-Pinilla F (2004) Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats. J Neurotrauma 21(10):1457–1467. https://doi.org/10.1089/neu.2004.21.1457

    Article  PubMed  Google Scholar 

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Acknowledgements

Buttermilk powder was a kind gift of Reny Picot (Oviedo, Spain), and Antarctic krill oil from Euphausia superba was kindly donated by AKO3™ (Aker Biomarine Antarctic AS, Oslo, Norway).

Funding

This study was supported in part by grants from the Spanish Ministerio de Economía y Competitividad (AGL2014-56464-R1 and AGL2014-54565-R2); by the Comunidad de Madrid through the “Programa de actividades en tecnologias” (ALIBIRD-CM S2013/ABI-2728); and by the Castilla-La Mancha University through the “Programa de ayuda I+D a grupos emergentes” (GI20173998) to EBR. AD lab is supported in part by the Spanish Agencia Estatal de Investigación and European Feder Funds (AGL2016-78922-R) and Fundación Ramón Areces (Madrid, Spain).

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Authors and Affiliations

  1. Laboratory of Functional Foods, Madrid Institute for Advanced Studies (IMDEA)-Food, CEI UAM + CSIC, 28049, Madrid, Spain

    Joao Tomé-Carneiro, M. Carmen Crespo & Francesco Visioli

  2. Área de Bioquímica, Universidad de Castilla-La-Mancha, 45071, Toledo, Spain

    Emma Burgos-Ramos

  3. Department of Functional Biology (Physiology), University of Oviedo, 33006, Oviedo, Spain

    Cristina Tomas-Zapico

  4. Universidad Autónoma de Chile, 7500912, Santiago, Chile

    Cristina Tomas-Zapico

  5. Institute of Food Science Research, Spanish National Research Council (CIAL, CSIC-UAM), Bioactivity and Food Analysis Department, Food Lipid Biomarkers and Health, Campus of Autónoma University of Madrid, 28049, Madrid, Spain

    Alba García-Serrano, Pilar Castro-Gómez & Javier Fontecha

  6. Department of Psychobiology, Faculty of Psychology, UNED, 28040, Madrid, Spain

    Cesar Venero, Inmaculada Pereda-Pérez, Shishir Baliyan & Azucena Valencia

  7. Faculty of Biosanitary Sciences, Francisco de Vitoria University, Pozuelo de Alarcón, 28223, Madrid, Spain

    Inmaculada Pereda-Pérez

  8. Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies (IMDEA)-Food, CEI UAM + CSIC, 28049, Madrid, Spain

    Alberto Dávalos

  9. Department of Molecular Medicine, University of Padova, 35121, Padova, Italy

    Francesco Visioli

Authors
  1. Joao Tomé-Carneiro
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  2. M. Carmen Crespo
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  3. Emma Burgos-Ramos
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  4. Cristina Tomas-Zapico
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  5. Alba García-Serrano
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  6. Pilar Castro-Gómez
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  7. Cesar Venero
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  8. Inmaculada Pereda-Pérez
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  10. Azucena Valencia
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  11. Javier Fontecha
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  12. Alberto Dávalos
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  13. Francesco Visioli
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Contributions

JF, CV, and FV designed the study. JTC, MCC, EBR, IPP, SB AGS, PCG, and AV performed experiments. MCC, JTC, EBR, CTZ, AD, and FV wrote the manuscript. All authors approved the submission of the final version of the manuscript.

Corresponding author

Correspondence to Alberto Dávalos.

Ethics declarations

Animal experiments were approved by the Animal Experimentation Committee of the National Distance Education University (UNED, Spain).

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Joao Tomé-Carneiro and M. Carmen Crespo contribute equally to this work.

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Tomé-Carneiro, J., Carmen Crespo, M., Burgos-Ramos, E. et al. Buttermilk and Krill Oil Phospholipids Improve Hippocampal Insulin Resistance and Synaptic Signaling in Aged Rats. Mol Neurobiol 55, 7285–7296 (2018). https://doi.org/10.1007/s12035-018-0934-y

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