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Milk fat globule membrane attenuates high fat diet-induced neuropathological changes in obese Ldlr−/−.Leiden mice

International Journal of Obesity volume 46, pages 342–349 (2022)Cite this article

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Abstract

Background

Milk-fat globule membrane (MFGM) is a complex structure secreted by the mammary gland and present in mammalian milk. MFGM contains lipids and glycoproteins as well as gangliosides, which may be involved in myelination processes. Notably, myelination and thereby white matter integrity are often altered in obesity. Furthermore, MFGM interventions showed beneficial effects in obesity by affecting inflammatory processes and the microbiome. In this study, we investigated the impact of a dietary MFGM intervention on fat storage, neuroinflammatory processes and myelination in a rodent model of high fat diet (HFD)-induced obesity.

Methods

12-week-old male low density lipoprotein receptor-deficient Leiden mice were exposed to a HFD, a HFD enriched with 3% whey protein lipid concentrate (WPC) high in MFGM components, or a low fat diet. The impact of MFGM supplementation during 24-weeks of HFD-feeding was examined over time by analyzing body weight and fat storage, assessing cognitive tasks and MRI scanning, analyzing myelinization with polarized light imaging and examining neuroinflammation using immunohistochemistry.

Results

We found in this study that 24 weeks of HFD-feeding induced excessive fat storage, increased systolic blood pressure, altered white matter integrity, decreased functional connectivity, induced neuroinflammation and impaired spatial memory. Notably, supplementation with 3% WPC high in MFGM components restored HFD-induced neuroinflammation and attenuated the reduction in hippocampal-dependent spatial memory and hippocampal functional connectivity.

Conclusions

We showed that supplementation with WPC high in MFGM components beneficially contributed to hippocampal-dependent spatial memory, functional connectivity in the hippocampus and anti-inflammatory processes in HFD-induced obesity in rodents. Current knowledge regarding exact biological mechanisms underlying these effects should be addressed in future studies.

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Fig. 1: Hippocampal-dependent spatial memory.
Fig. 2: Functional connectivity based on partial correlations.
Fig. 3: Brain volumetry.
Fig. 4: White matter integrity in the hippocampus and fimbria hippocampi.
Fig. 5: Neuroinflammation.

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References

  1. Manno FAM, Isla AG, Manno SHC, Ahmed I, Cheng SH, Barrios FA, et al. Early stage alterations in white matter and decreased functional interhemispheric hippocampal connectivity in the 3xTg mouse model of alzheimer’s disease. Front Aging Neurosci. 2019;11:39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Moukarzel S, Dyer RA, Garcia C, Wiedeman AM, Boyce G, Weinberg J, et al. Milk fat globule membrane supplementation in formula-fed rat pups improves reflex development and may alter brain lipid composition. Scientific Rep. 2018;8:15277.

    Article  Google Scholar 

  3. Timby N, Domellof E, Hernell O, Lonnerdal B, Domellof M. Neurodevelopment, nutrition, and growth until 12 mo of age in infants fed a low-energy, low-protein formula supplemented with bovine milk fat globule membranes: a randomized controlled trial. Am J Clin Nutr. 2014;99:860–8.

    Article  CAS  PubMed  Google Scholar 

  4. Zhang D, Wen J, Zhou J, Cai W, Qian L. Milk fat globule membrane ameliorates necrotizing enterocolitis in neonatal rats and suppresses lipopolysaccharide-induced inflammatory response in IEC-6 enterocytes. JPEN J Parenter Enteral Nutr. 2019;43:863–73.

  5. Oshida K, Shimizu T, Takase M, Tamura Y, Shimizu T, Yamashiro Y. Effects of dietary sphingomyelin on central nervous system myelination in developing rats. Pediatr Res. 2003;53:589–93.

    Article  CAS  PubMed  Google Scholar 

  6. Vickers MH, Guan J, Gustavsson M, Krageloh CU, Breier BH, Davison M, et al. Supplementation with a mixture of complex lipids derived from milk to growing rats results in improvements in parameters related to growth and cognition. Nutr Res. 2009;29:426–35.

    Article  CAS  PubMed  Google Scholar 

  7. Milard M, Laugerette F, Durand A, Buisson C, Meugnier E, Loizon E, et al. Milk polar lipids in a high-fat diet can prevent body weight gain: modulated abundance of gut bacteria in relation with fecal loss of specific fatty acids. Mol Nutr Food Res. 2019;63:e1801078.

    Article  PubMed  Google Scholar 

  8. Demmer E, Van Loan MD, Rivera N, Rogers TS, Gertz ER, German JB, et al. 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. 2016;5:e14.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Brink LR, Gueniot JP, Lönnerdal B. Effects of milk fat globule membrane and its various components on neurologic development in a postnatal growth restriction rat model. J Nutr Biochem. 2019;69:163–71.

    Article  CAS  PubMed  Google Scholar 

  10. Lee H, Padhi E, Hasegawa Y, Larke J, Parenti M, Wang A, et al. Compositional dynamics of the milk fat globule and its role in infant development. Front Pediatrics. 2018;6:313.

    Article  Google Scholar 

  11. McJarrow P, Schnell N, Jumpsen J, Clandinin T. Influence of dietary gangliosides on neonatal brain development. Nutr Rev. 2009;67:451–63.

    Article  PubMed  Google Scholar 

  12. Palmano K, Rowan A, Guillermo R, Guan J, McJarrow P. The role of gangliosides in neurodevelopment. Nutrients. 2015;7:3891–913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Arnoldussen IA, Kiliaan AJ, Gustafson DR. Obesity and dementia: adipokines interact with the brain. Eur Neuropsychopharmacol. 2014;24:1982–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Arnoldussen IAC, Wiesmann M, Pelgrim CE, Wielemaker EM, van Duyvenvoorde W, Amaral-Santos PL, et al. Butyrate restores HFD-induced adaptations in brain function and metabolism in mid-adult obese mice. Int J Obes (Lond). 2017;41:935–44.

    Article  CAS  Google Scholar 

  15. Pelgrim CE, Franx BAA, Snabel J, Kleemann R, Arnoldussen IAC, Kiliaan AJ. Butyrate reduces HFD-induced adipocyte hypertrophy and metabolic risk factors in obese LDLr−/−. Leiden Mice. Nutrients. 2017;9:1–15.

  16. Gazdzinski S, Kornak J, Weiner MW, Meyerhoff DJ. Body mass index and magnetic resonance markers of brain integrity in adults. Ann Neurol. 2008;63:652–7.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Pannacciulli N, Del Parigi A, Chen K, Le DSN, Reiman EM, Tataranni PA. Brain abnormalities in human obesity: a voxel-based morphometric study. Neuroimage. 2006;31:1419–25.

    Article  PubMed  Google Scholar 

  18. Raji CA, Ho AJ, Parikshak NN, Becker JT, Lopez OL, Kuller LH, et al. Brain structure and obesity. Hum Brain Mapp. 2010;31:353–64.

    PubMed  Google Scholar 

  19. Sui SX, Pasco JA. Obesity and brain function: the brain-body crosstalk. Medicina (Kaunas). 2020;56:499.

    Article  Google Scholar 

  20. Van Opstal A, Wijngaarden M, van der Grond J, Pijl H. Changes in brain activity after weight loss. Obes Sci Pract. 2019;5:459–67.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Yau PL, Kang EH, Javier DC, Convit A. Preliminary evidence of cognitive and brain abnormalities in uncomplicated adolescent obesity. Obesity. 2014;22:1865–71.

    Article  PubMed  Google Scholar 

  22. Morrison MC, Mulder P, Salic K, Verheij J, Liang W, van Duyvenvoorde W, et al. Intervention with a caspase-1 inhibitor reduces obesity-associated hyperinsulinemia, non-alcoholic steatohepatitis and hepatic fibrosis in LDLR−/−. Leiden mice. Int J Obes (Lond). 2016;40:1416–23.

    Article  CAS  Google Scholar 

  23. Mueller AM, Kleemann R, Gart E, van Duyvenvoorde W, Verschuren L, Caspers M, et al. Cholesterol accumulation as a driver of hepatic inflammation under translational dietary conditions can be attenuated by a multicomponent medicine. Front Endocrinol. 2021;12:601160.

    Article  Google Scholar 

  24. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research. Plos Biol. 2010;8:1–5.

  25. Brink LR, Herren AW, McMillen S, Fraser K, Agnew M, Roy N, et al. Omics analysis reveals variations among commercial sources of bovine milk fat globule membrane. J Dairy Sci. 2020;103:3002–16.

    Article  CAS  PubMed  Google Scholar 

  26. Luque-Sierra A, Alvarez-Amor L, Kleemann R, Martín F, Varela LM. Extra-virgin olive oil with natural phenolic content exerts an anti-inflammatory effect in adipose tissue and attenuates the severity of atherosclerotic lesions in Ldlr−/−. Leiden Mice. Mol Nutr Food Res. 2018;62:e1800295.

    Article  PubMed  Google Scholar 

  27. Schoemaker MH, Kleemann R, Morrison MC, Verheij J, Salic K, van Tol EAF, et al. A casein hydrolysate based formulation attenuates obesity and associated non-alcoholic fatty liver disease and atherosclerosis in LDLr−/−. Leiden mice. PLoS ONE. 2017;12:e0180648.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Tengeler AC, Gart E, Wiesmann M, Arnoldussen IAC, van Duyvenvoorde W, Hoogstad M, et al. Propionic acid and not caproic acid, attenuates nonalcoholic steatohepatitis and improves (cerebro) vascular functions in obese Ldlr(−/−). Leiden mice. FASEB J. 2020;34:9575–93.

  29. Jakobsdottir G, Xu J, Molin G, Ahrne S, Nyman M. High-fat diet reduces the formation of butyrate, but increases succinate, inflammation, liver fat and cholesterol in rats, while dietary fibre counteracts these effects. PLoS ONE. 2013;8:e80476.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Liu C, Li P, Li H, Wang S, Ding L, Wang H, et al. TREM2 regulates obesity-induced insulin resistance via adipose tissue remodeling in mice of high-fat feeding. J Transl Med. 2019;17:300.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Pei Y, Li H, Cai Y, Zhou J, Luo X, Ma L, et al. Regulation of adipose tissue inflammation by adenosine 2A receptor in obese mice. J Endocrinol. 2018;239:365–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gainey SJ, Kwakwa KA, Bray JK, Pillote MM, Tir VL, Towers AE, et al. Short-term high-fat diet (HFD) induced anxiety-like behaviors and cognitive impairment are improved with treatment by glyburide. Front Behav Neurosci. 2016;10:156.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Wang Q, Yuan J, Yu Z, Lin L, Jiang Y, Cao Z, et al. FGF21 attenuates high-fat diet-induced cognitive impairment via metabolic regulation and anti-inflammation of obese mice. Mol Neurobiol. 2018;55:4702–17.

    Article  CAS  PubMed  Google Scholar 

  34. Alghamdi BS. The effect of short-term feeding of a high-coconut oil or high-fat diet on neuroinflammation and the performance of an object–place task in rats. Neurochem Res. 2021;46:287–98.

    Article  CAS  PubMed  Google Scholar 

  35. Cai D. Neuroinflammation and neurodegeneration in overnutrition-induced diseases. Trend Endocrinol Metab. 2013;24:40–7.

    Article  CAS  Google Scholar 

  36. Cavaliere G, Trinchese G, Penna E, Cimmino F, Pirozzi C, Lama A, et al. High-fat diet induces neuroinflammation and mitochondrial impairment in mice cerebral cortex and synaptic fraction. Front Cell Neurosci. 2019;13:509–21.

  37. Kullmann S, Callaghan MF, Heni M, Weiskopf N, Scheffler K, Häring HU, et al. Specific white matter tissue microstructure changes associated with obesity. Neuroimage. 2016;125:36–44.

    Article  PubMed  Google Scholar 

  38. Kullmann S, Schweizer F, Veit R, Fritsche A, Preissl H. Compromised white matter integrity in obesity. Obes Rev. 2015;16:273–81.

    Article  CAS  PubMed  Google Scholar 

  39. Samara A, Murphy T, Strain J, Rutlin J, Sun P, Neyman O, et al. Neuroinflammation and white matter alterations in obesity assessed by diffusion basis spectrum imaging. Front Hum Neurosci. 2019;13:464.

    Article  PubMed  Google Scholar 

  40. Huang HT, Tsai SF, Wu HT, Huang HY, Hsieh HH, Kuo YM, et al. Chronic exposure to high fat diet triggers myelin disruption and interleukin-33 upregulation in hypothalamus. BMC Neurosci. 2019;20:33.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Graham LC, Harder JM, Soto I, de Vries WN, John SWM, Howell GR. Chronic consumption of a western diet induces robust glial activation in aging mice and in a mouse model of Alzheimer’s disease. Scientific Rep. 2016;6:21568.

    Article  CAS  Google Scholar 

  42. Graham LC, Grabowska WA, Chun Y, Risacher SL, Philip VM, Saykin AJ, et al. Exercise prevents obesity-induced cognitive decline and white matter damage in mice. Neurobiol Aging.2019;80:154–72.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Graham LC, Kocalis HE, Soto I, Howell GR. Deficiency of complement component C1Q prevents cerebrovascular damage and white matter loss in a mouse model of chronic obesity. eNeuro.2020;86:154–72.

    Google Scholar 

  44. Zhou AL, Ward RE. Milk polar lipids modulate lipid metabolism, gut permeability, and systemic inflammation in high-fat-fed C57BL/6J ob/ob mice, a model of severe obesity. J Dairy Sci. 2019;102:4816–31.

    Article  CAS  PubMed  Google Scholar 

  45. Li T, Du M, Wang H, Mao X. Milk fat globule membrane and its component phosphatidylcholine induce adipose browning both in vivo and in vitro. J Nutr Biochem. 2020;81:108372.

    Article  CAS  PubMed  Google Scholar 

  46. Li T, Gao J, Du M, Song J, Mao X. Milk fat globule membrane attenuates high-fat diet-induced obesity by inhibiting adipogenesis and increasing uncoupling protein 1 expression in white adipose tissue of mice. Nutrients. 2018;10:331.

    Article  PubMed Central  Google Scholar 

  47. O’Mahony SM, McVey Neufeld KA, Waworuntu RV, Pusceddu MM, Manurung S, Murphy K, et al. The enduring effects of early-life stress on the microbiota-gut-brain axis are buffered by dietary supplementation with milk fat globule membrane and a prebiotic blend. Eur J Neurosci. 2020;51:1042–58.

    Article  PubMed  Google Scholar 

  48. Mudd AT, Alexander LS, Berding K, Waworuntu RV, Berg BM, Donovan SM, et al. Dietary prebiotics, milk fat globule membrane, and lactoferrin affects structural neurodevelopment in the young piglet. Front Pediatr.2016;4:1–10.

    Article  Google Scholar 

  49. Fil JE, Fleming SA, Chichlowski M, Gross G, Berg BM, Dilger RN. Evaluation of dietary bovine milk fat globule membrane supplementation on growth, serum cholesterol and lipoproteins, and neurodevelopment in the young pig. Front Pediatr. 2019;7:417.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Gurnida DA, Rowan AM, Idjradinata P, Muchtadi D, Sekarwana N. Association of complex lipids containing gangliosides with cognitive development of 6-month-old infants. Early Hum Dev. 2012;88:595–601.

    Article  CAS  PubMed  Google Scholar 

  51. Tanaka K, Hosozawa M, Kudo N, Yoshikawa N, Hisata K, Shoji H, et al. The pilot study: Sphingomyelin-fortified milk has a positive association with the neurobehavioural development of very low birth weight infants during infancy, randomized control trial. Brain Dev. 2013;35:45–52.

    Article  CAS  PubMed  Google Scholar 

  52. Lopez PHH, Báez BB. Gangliosides in axon stability and regeneration. Prog Mol Biol Transl Sci. 2018;156:383–412.

    Article  CAS  PubMed  Google Scholar 

  53. McGonigal R, Barrie JA, Yao D, McLaughlin M, Cunningham ME, Rowan EG, et al. Glial sulfatides and neuronal complex gangliosides are functionally interdependent in maintaining myelinating axon integrity. J Neurosci. 2019;39:63–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Correa SG, Bianco ID, Riera CM, Fidelio GD. Anti-inflammatory effect of gangliosides in the rat hindpaw edema test. Eur J Pharmacol. 1991;199:93–8.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Anouk Tengeler, Jos Dederen, Andor Veltien, Manuela van Rooij, Ferdinand Geus, Christian Smets, Bas de Cocq (all Radboudumc), Wim van Duyvenvoorde, and Jessica Snabel (all TNO Leiden) for their excellent scientific input. We thank the technicians of PRIME for their support in the execution of the experiment.

Funding

This research was funded by the Europees Fonds voor Regionale Ontwikkeling (EFRO), project BriteN 2016.

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Authors and Affiliations

  1. Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Preclinical Imaging Center PRIME, Nijmegen, the Netherlands

    Ilse A. C. Arnoldussen, Maximilian Wiesmann, Vivienne Verweij, Bram Geenen, Natàlia Pujol Gualdo, Lonneke van der Logt & Amanda J. Kiliaan

  2. Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), Leiden, the Netherlands

    Martine C. Morrison, Nicole Worms, Marijke Voskuilen & Robert Kleemann

  3. Human and Animal Physiology, Wageningen University, Wageningen, the Netherlands

    Martine C. Morrison

  4. Medical and Scientific Affairs, Reckitt Mead Johnson Nutrition Institute, Nijmegen, the Netherlands

    Janna A. van Diepen & Gabriele Gross

  5. Department of Vascular Surgery, Leiden University Medical Center, Leiden, the Netherlands

    Robert Kleemann

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  1. Ilse A. C. Arnoldussen
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Contributions

Study design: RK, AK, GG, MM, JvD, and IA. Experimental work: IA, NPG, NW, MV, LvL, VV, and BG. Data analyses: IA, MW, and MM. Prepared full paper: IA, MM, MW, RK, and AJ. All authors reviewed the paper.

Corresponding author

Correspondence to Amanda J. Kiliaan.

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Authors of Radboudumc and TNO have nothing to disclose. JAvD and GG are employees of Reckitt Mead Johnson Nutrition Institute.

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Arnoldussen, I.A.C., Morrison, M.C., Wiesmann, M. et al. Milk fat globule membrane attenuates high fat diet-induced neuropathological changes in obese Ldlr−/−.Leiden mice. Int J Obes 46, 342–349 (2022). https://doi.org/10.1038/s41366-021-00998-w

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