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Pediatrics

Visceral fat-related systemic inflammation and the adolescent brain: a mediating role of circulating glycerophosphocholines

International Journal of Obesity volume 43, pages 1223–1230 (2019)Cite this article

Subjects

Abstract

Objective

Life-long maintenance of brain health is important for the prevention of cognitive impairment in older age. Low-grade peripheral inflammation associated with excess visceral fat (VF) may influence brain structure and function. Here we examined (i) if this type of inflammation is associated with altered white-matter (WM) microstructure and lower cognitive functioning in adolescents, and (ii) if recently identified circulating glycerophosphocholines (GPCs) can index this type of inflammation and associated variations in WM microstructure and cognitive functioning.

Subjects

We studied a community-based sample of 872 adolescents (12–18 years, 48% males) in whom we assessed VF and WM microstructure with magnetic resonance imaging, processing speed with cognitive testing, serum C-reactive protein (CRP, a common marker of peripheral inflammation) with a high-sensitivity assay, and serum levels of a panel of 64 GPCs with advanced mass spectrometry.

Results

VF was associated with CRP, and CRP in turn was associated with “altered” WM microstructure and lower processing speed (all p < 0.003). Further, “altered” WM microstructure was associated with lower processing speed (p < 0.0001). Of all 64 tested GPCs, 4 were associated with both VF and CRP (at Bonferroni corrected p < 0.0004). One of them, PC16:0/2:0, was also associated with WM microstructure (p < 0.0001) and processing speed (p = 0.0003), and mediated the directed associations between VF and both WM microstructure (p < 0.0001) and processing speed (p = 0.02). As a mediator, PC16:0/2:0 explained 21% of shared variance between VF and WM microstructure, and 22% of shared variance between VF and processing speed. Similar associations were observed in an auxiliary study of 80 middle-aged adults.

Conclusions

Our results show that VF-related peripheral inflammation is associated with "altered" WM microstructure and lower cognitive functioning already in adolescents, and a specific circulating GPC may be a new molecule indexing this VF-related peripheral inflammation and its influences on brain structure and function.

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References

  1. Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential for primary prevention of Alzheimer’s disease: an analysis of population-based data. Lancet Neurol. 2014;13:788–94.

    PubMed  Google Scholar 

  2. Buckman LB, Hasty AH, Flaherty DK, Buckman CT, Thompson MM, Matlock BK, et al. Obesity induced by a high-fat diet is associated with increased immune cell entry into the central nervous system. Brain Behav Immun. 2014;35:33–42.

    CAS  PubMed  Google Scholar 

  3. Hoogland IC, Houbolt C, van Westerloo DJ, van Gool WA, van de Beek D. Systemic inflammation and microglial activation: systematic review of animal experiments. J Neuroinflamm. 2015;12:114.

    Google Scholar 

  4. Guillemot-Legris O, Muccioli GG. Obesity-induced neuroinflammation: beyond the hypothalamus. Trends Neurosci. 2017;40:237–53.

    CAS  PubMed  Google Scholar 

  5. Bocarsly ME, Fasolino M, Kane GA, LaMarca EA, Kirschen GW, Karatsoreos IN, et al. Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function. Proc Natl Acad Sci USA. 2015;112:15731–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Hao S, Dey A, Yu X, Stranahan AM. Dietary obesity reversibly induces synaptic stripping by microglia and impairs hippocampal plasticity. Brain Behav Immun. 2016;51:230-9.

  7. Shin JA, Jeong SI, Kim M, Yoon JC, Kim HS, Park EM. Visceral adipose tissue inflammation is associated with age-related brain changes and ischemic brain damage in aged mice. Brain Behav Immun. 2015;50:221–31.

    PubMed  Google Scholar 

  8. Schmidt R, Schmidt H, Curb JD, Masaki K, White LR, Launer LJ. Early inflammation and dementia: a 25-year follow-up of the Honolulu-Asia Aging Study. Ann Neurol. 2002;52:168–74.

    PubMed  Google Scholar 

  9. Engelhart MJ, Geerlings MI, Meijer J, Kiliaan A, Ruitenberg A, van Swieten JC, et al. Inflammatory proteins in plasma and the risk of dementia: the Rotterdam Study. Arch Neurol. 2004;61:668–72.

    PubMed  Google Scholar 

  10. Desikan RS, Schork AJ, Wang Y, Thompson WK, Dehghan A, Ridker PM, et al. Polygenic overlap between C-reactive protein, plasma lipids, and Alzheimer disease. Circulation. 2015;131:2061–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Koyama A, O’Brien J, Weuve J, Blacker D, Metti AL, Yaffe K. The role of peripheral inflammatory markers in dementia and Alzheimer’s disease: a meta-analysis. J Gerontol A Biol Sci Med Sci. 2013;68:433–40.

    CAS  PubMed  Google Scholar 

  12. van Himbergen TM, Beiser AS, Ai M, Seshadri S, Otokozawa S, Au R, et al. Biomarkers for insulin resistance and inflammation and the risk for all-cause dementia and alzheimer disease: results from the Framingham Heart Study. Arch Neurol. 2012;69:594–600.

    PubMed  Google Scholar 

  13. Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci. 2015;16:358–72.

    CAS  PubMed  Google Scholar 

  14. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388–405.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med. 2012;18:363–74.

    CAS  PubMed  Google Scholar 

  16. Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr. 2004;92:347–55.

    CAS  PubMed  Google Scholar 

  17. Canada S Canadian Health Measures Survey, 2012 to 2013. Health Fact Sheets 2015: (82-625-X).

  18. O’Rourke RW, Metcalf MD, White AE, Madala A, Winters BR, Maizlin II. et al. Depot-specific differences in inflammatory mediators and a role for NK cells and IFN-gamma in inflammation in human adipose tissue. Int J Obes. 2009;33:978–90.

    Google Scholar 

  19. Gabriely I, Ma XH, Yang XM, Atzmon G, Rajala MW, Berg AH, et al. Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process? Diabetes. 2002;51:2951–8.

    CAS  PubMed  Google Scholar 

  20. Thorne A, Lonnqvist F, Apelman J, Hellers G, Arner P. A pilot study of long-term effects of a novel obesity treatment: omentectomy in connection with adjustable gastric banding. Int J Obes Relat Metab Disord. 2002;26:193–9.

    CAS  PubMed  Google Scholar 

  21. Klein S, Fontana L, Young VL, Coggan AR, Kilo C, Patterson BW, et al. Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease. N Engl J Med. 2004;350:2549–57.

    CAS  PubMed  Google Scholar 

  22. Tchernof A, Despres JP. Pathophysiology of human visceral obesity: an update. Physiol Rev. 2013;93:359–404.

    CAS  PubMed  Google Scholar 

  23. Pou KM, Massaro JM, Hoffmann U, Vasan RS, Maurovich-Horvat P, Larson MG, et al. Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the Framingham Heart Study. Circulation. 2007;116:1234–41.

    CAS  PubMed  Google Scholar 

  24. Hocking SL, Stewart RL, Brandon AE, Suryana E, Stuart E, Baldwin EM, et al. Subcutaneous fat transplantation alleviates diet-induced glucose intolerance and inflammation in mice. Diabetologia. 2015;58:1587–600.

    CAS  PubMed  Google Scholar 

  25. Debette S, Beiser A, Hoffmann U, Decarli C, O’Donnell CJ, Massaro JM, et al. Visceral fat is associated with lower brain volume in healthy middle-aged adults. Ann Neurol. 2010;68:136–44.

    PubMed  PubMed Central  Google Scholar 

  26. Kim KW, Seo H, Kwak MS, Kim D. Visceral obesity is associated with white matter hyperintensity and lacunar infarct. Int J Obes. 2017;41:683–8.

    CAS  Google Scholar 

  27. Yamashiro K, Tanaka R, Tanaka Y, Miyamoto N, Shimada Y, Ueno Y, et al. Visceral fat accumulation is associated with cerebral small vessel disease. Eur J Neurol. 2014;21:667–73.

    CAS  PubMed  Google Scholar 

  28. Higuchi S, Kabeya Y, Kato K. Visceral-to-subcutaneous fat ratio is independently related to small and large cerebrovascular lesions even in healthy subjects. Atherosclerosis. 2017;259:41–5.

    CAS  PubMed  Google Scholar 

  29. Schwartz DH, Dickie E, Pangelinan MM, Leonard G, Perron M, Pike GB, et al. Adiposity is associated with structural properties of the adolescent brain. Neuroimage. 2014;103:192–201.

    PubMed  Google Scholar 

  30. Schwartz DH, Leonard G, Perron M, Richer L, Syme C, Veillette S, et al. Visceral fat is associated with lower executive functioning in adolescents. Int J Obes. 2013;37:1336–43.

    CAS  Google Scholar 

  31. Syme C, Czajkowski S, Shin J, Abrahamowicz M, Leonard G, Perron M, et al. Glycerophosphocholine metabolites and cardiovascular disease risk factors in adolescents: a cohort study. Circulation. 2016;134:1629–36.

    CAS  PubMed  Google Scholar 

  32. Pickens CA, Vazquez AI, Jones AD, Fenton JI. Obesity, adipokines, and C-peptide are associated with distinct plasma phospholipid profiles in adult males, an untargeted lipidomic approach. Sci Rep. 2017;7:6335.

    PubMed  PubMed Central  Google Scholar 

  33. Heimerl S, Fischer M, Baessler A, Liebisch G, Sigruener A, Wallner S, et al. Alterations of plasma lysophosphatidylcholine species in obesity and weight loss. PLoS ONE. 2014;9:e111348.

    PubMed  PubMed Central  Google Scholar 

  34. Ganna A, Salihovic S, Sundstrom J, Broeckling CD, Hedman AK, Magnusson PK, et al. Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease. PLoS Genet. 2014;10:e1004801.

    PubMed  PubMed Central  Google Scholar 

  35. Sevastou I, Kaffe E, Mouratis MA, Aidinis V. Lysoglycerophospholipids in chronic inflammatory disorders: the PLA(2)/LPC and ATX/LPA axes. Biochim Biophys Acta. 2013;1831:42–60.

    CAS  PubMed  Google Scholar 

  36. Marathe GK, Pandit C, Lakshmikanth CL, Chaithra VH, Jacob SP, D’Souza CJ. To hydrolyze or not to hydrolyze: the dilemma of platelet-activating factor acetylhydrolase. J Lipid Res. 2014;55:1847–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Yan JJ, Jung JS, Lee JE, Lee J, Huh SO, Kim HS, et al. Therapeutic effects of lysophosphatidylcholine in experimental sepsis. Nat Med. 2004;10:161–7.

    CAS  PubMed  Google Scholar 

  38. Ojala PJ, Hirvonen TE, Hermansson M, Somerharju P, Parkkinen J. Acyl chain-dependent effect of lysophosphatidylcholine on human neutrophils. J Leukoc Biol. 2007;82:1501–9.

    CAS  PubMed  Google Scholar 

  39. Mapstone M, Cheema AK, Fiandaca MS, Zhong X, Mhyre TR, MacArthur LH, et al. Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med. 2014;20:415–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Klavins K, Koal T, Dallmann G, Marksteiner J, Kemmler G, Humpel C. The ratio of phosphatidylcholines to lysophosphatidylcholines in plasma differentiates healthy controls from patients with Alzheimer’s disease and mild cognitive impairment. Alzheimer’s Dement. 2015;1:295–302.

    Google Scholar 

  41. Jove M, Mauri-Capdevila G, Suarez I, Cambray S, Sanahuja J, Quilez A, et al. Metabolomics predicts stroke recurrence after transient ischemic attack. Neurology. 2015;84:36–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Sigruener A, Kleber ME, Heimerl S, Liebisch G, Schmitz G, Maerz W. Glycerophospholipid and sphingolipid species and mortality: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. PLoS ONE. 2014;9:e85724.

    PubMed  PubMed Central  Google Scholar 

  43. Pausova Z, Paus T, Abrahamowicz M, Bernard M, Gaudet D, Leonard G, et al. Cohort profile: the Saguenay Youth Study (SYS). Int J Epidemiol. 2017; 46(2)e19.

  44. Ridker PM. Cardiology patient page. C-reactive protein: a simple test to help predict risk of heart attack and stroke. Circulation. 2003;108:e81–5.

    CAS  PubMed  Google Scholar 

  45. Ruff R, Allen C. Ruff 2 and 7 selective attention test: Professional manual. Odessa, Florida: Psychological Assessment Resources. 1996.

  46. Xu H, Valenzuela N, Fai S, Figeys D, Bennett SA. Targeted lipidomics - advances in profiling lysophosphocholine and platelet-activating factor second messengers. FEBS J. 2013;280:5652–67.

    CAS  PubMed  Google Scholar 

  47. Peterson A, Crockett L, Richards M, Boxer A. A self-report measure of pubertal status: reliability, validity, and initial norms. J Youth Adolesc. 1988;17:117–33.

    Google Scholar 

  48. Shirtcliff EA, Dahl RE, Pollak SD. Pubertal development: correspondence between hormonal and physical development. Child Dev. 2009;80:327–37.

    PubMed  PubMed Central  Google Scholar 

  49. Bates DMM, Bolker B and Walker S. _lme4: linear mixed-effects models using Eigen and S4_. R package version 1.1–7; 2014.

  50. Sobel ME. Asymptotic confidence intervals for indirect effects in structural equation models. Sociol Methodol. 1982;13:290–312.

    Google Scholar 

  51. Baron RM, Kenny DA. The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol. 1986;51:1173–82.

    CAS  PubMed  Google Scholar 

  52. Walker KA, Hoogeveen RC, Folsom AR, Ballantyne CM, Knopman DS, Windham BG, et al. Midlife systemic inflammatory markers are associated with late-life brain volume: the ARIC study. Neurology. 2017;89:2262–70.

    PubMed  PubMed Central  Google Scholar 

  53. Walker KA, Power MC, Hoogeveen RC, Folsom AR, Ballantyne CM, Knopman DS, et al. Midlife systemic inflammation, late-life white matter integrity, and cerebral small vessel disease: the atherosclerosis risk in communities study. Stroke. 2017;48:3196–202.

    PubMed  PubMed Central  Google Scholar 

  54. Bettcher BM, Yaffe K, Boudreau RM, Neuhaus J, Aizenstein H, Ding J, et al. Declines in inflammation predict greater white matter microstructure in older adults. Neurobiol Aging. 2015;36:948–54.

    PubMed  Google Scholar 

  55. Swardfager W, Yu D, Ramirez J, Cogo-Moreira H, Szilagyi G, Holmes MF, et al. Peripheral inflammatory markers indicate microstructural damage within periventricular white matter hyperintensities in Alzheimer’s disease: a preliminary report. Alzheimer’s Dement. 2017;7:56–60.

    Google Scholar 

  56. Lerch JP, van der Kouwe AJ, Raznahan A, Paus T, Johansen-Berg H, Miller KL, et al. Studying neuroanatomy using MRI. Nat Neurosci. 2017;20:314–26.

    CAS  PubMed  Google Scholar 

  57. Vavasour IM, Laule C, Li DK, Traboulsee AL, MacKay AL. Is the magnetization transfer ratio a marker for myelin in multiple sclerosis? J Magn Reson Imaging. 2011;33:713–8.

    PubMed  Google Scholar 

  58. Pike GB. Pulsed magnetization transfer contrast in gradient echo imaging: a two-pool analytic description of signal response. Magn Reson Med. 1996;36:95–103.

    CAS  PubMed  Google Scholar 

  59. Wishart DS. Emerging applications of metabolomics in drug discovery and precision medicine. Nat Rev Drug Discov. 2016;15:473–84.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the following individuals for their contributions in acquiring data in the SYS: Manon Bernard (database architect, The Hospital for Sick Children), Hélène Simard and her team of research assistants (Cégep de Jonquière), and Jacynthe Tremblay and her team of research nurses (Chicoutimi Hospital). We thank all participants who took part in the Saguenay Youth Study.

Funding

The Saguenay Youth Study has been funded by the Canadian Institutes of Health Research (TP and ZP), Heart and Stroke Foundation of Canada (ZP), and the Canadian Foundation for Innovation (ZP). Dr. Syme is a post-doctoral research fellow funded by the SickKids Research Institute. Dr. Abrahamowicz is a James McGill Professor at McGill University.

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Authors and Affiliations

  1. The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

    Catriona Syme, Stephanie Pelletier, Jean Shin, Lisa J. Strug & Zdenka Pausova

  2. Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, ON, Canada

    Catriona Syme, Stephanie Pelletier, Jean Shin & Zdenka Pausova

  3. Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada

    Michal Abrahamowicz

  4. Montreal Neurological Institute, McGill University, Montreal, QC, Canada

    Gabriel Leonard

  5. Department of Human Sciences, Université du Québec à Chicoutimi, Chicoutimi, QC, Canada

    Michel Perron & Suzanne Veillette

  6. Department of Health Sciences, Université du Québec à Chicoutimi, Chicoutimi, QC, Canada

    Louis Richer

  7. Community Genomic Centre, Université de Montréal, Chicoutimi, QC, Canada

    Daniel Gaudet

  8. Department of Radiology and Clinical Neurosciences, University of Calgary, Calgary, AB, Canada

    Bruce Pike

  9. Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada

    Lisa J. Strug

  10. Neural Regeneration Laboratory, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada

    Yun Wang, Hongbin Xu, Graeme Taylor & Steffany Bennett

  11. Bloorview Research Institute, Toronto, ON, Canada

    Tomas Paus

  12. Departments of Psychology and Psychiatry, University of Toronto, Toronto, ON, Canada

    Tomas Paus

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  1. Catriona Syme
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Correspondence to Zdenka Pausova.

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Syme, C., Pelletier, S., Shin, J. et al. Visceral fat-related systemic inflammation and the adolescent brain: a mediating role of circulating glycerophosphocholines. Int J Obes 43, 1223–1230 (2019). https://doi.org/10.1038/s41366-018-0202-2

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