Clinical Studies and Practice

Neuroinflammation in obesity: circulating lipopolysaccharide-binding protein associates with brain structure and cognitive performance

Abstract

Background/Objectives:

Growing evidence implicates neuroinflammation in the pathogenesis of diet-induced obesity and cognitive dysfunction in rodent models. Obesity is associated with reduced white matter integrity and cognitive decline. Circulating lipopolysaccharide binding protein (LBP) concentration is known to be increased in patients with obesity. Here, we aimed to evaluate whether circulating LBP is associated longitudinally with white matter structure and cognitive performance according to obesity status.

Subjects/Methods:

This longitudinal study analyzed circulating LBP (ELISA), DTI-metrics (axial diffusivity (L1), fractional anisotropy (FA) and radial diffusivity (RD)) in specific regions of the white matter of 24 consecutive middle-aged obese subjects (13 women) and 20 healthy volunteers (10 women) at baseline and two years later. Digit Span Test (DST) was used as a measure of working memory/short-term verbal memory.

Results:

Circulating LBP concentration was associated with FA and L1 values of several white matter regions both at baseline and follow-up. The associations remained significant after controlling for age, BMI, fat mass and plasma high sensitivity C-reactive protein. Importantly, the increase in LBP over time impacted negatively on FA and L1 values and on DST performance.

Conclusions:

Circulating LBP associates with brain white matter integrity and working memory/short-term verbal memory in both obese and non-obese subjects.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1
Figure 2

References

  1. 1

    Kullmann S, Schweizer F, Veit R, Fritsche A, Preissl H . Compromised white matter integrity in obesity. Obes Rev 2015; 16: 273–281.

    CAS  Article  Google Scholar 

  2. 2

    He Q, Chen C, Dong Q, Xue G, Chen C, Lu ZL et al. Gray and white matter structures in the midcingulate cortex region contribute to body mass index in Chinese young adults. Brain Struct Funct 2015; 220: 319–329.

    Article  Google Scholar 

  3. 3

    Bolzenius JD, Laidlaw DH, Cabeen RP, Conturo TE, McMichael AR, Lane EM et al. Brain structure and cognitive correlates of body mass index in healthy older adults. Behav Brain Res 2015; 278: 342–347.

    Article  Google Scholar 

  4. 4

    Ryan L, Walther K . White matter integrity in older females is altered by increased body fat. Obesity (Silver Spring) 2014; 22: 2039–2046.

    Article  Google Scholar 

  5. 5

    Karlsson HK, Tuulari JJ, Hirvonen J, Lepomäki V, Parkkola R, Hiltunen J et al. Obesity is associated with white matter atrophy: a combined diffusion tensor imaging and voxel-based morphometric study. Obesity (Silver Spring) 2013; 21: 2530–2537.

    Article  Google Scholar 

  6. 6

    Verstynen TD, Weinstein AM, Schneider WW, Jakicic JM, Rofey DL, Erickson KI . Increased body mass index is associated with a global and distributed decrease in white matter microstructural integrity. Psychosom Med 2012; 74: 682–690.

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Xu J, Li Y, Lin H, Sinha R, Potenza MN . Body mass index correlates negatively with white matter integrity in the fornix and corpus callosum: a diffusion tensor imaging study. Hum Brain Mapp 2013; 34: 1044–1052.

    Article  Google Scholar 

  8. 8

    Stanek KM, Grieve SM, Brickman AM, Korgaonkar MS, Paul RH, Cohen RA et al. Obesity is associated with reduced white matter integrity in otherwise healthy adults. Obesity (Silver Spring) 2011; 19: 500–504.

    Article  Google Scholar 

  9. 9

    Zhang Y, Ji G, Xu M, Cai W, Zhu Q, Qian L et al. Recovery of brain structural abnormalities in morbidly obese patients after bariatric surgery. Int J Obes (Lond) 2016; 40: 1558–1565.

    CAS  Article  Google Scholar 

  10. 10

    Tuulari JJ, Karlsson HK, Antikainen O, Hirvonen J, Pham T, Salminen P et al. Bariatric surgery induces white and grey matter density recovery in the morbidly obese: a voxel-based morphometric study. Hum Brain Mapp 2016; 37: 3745–3756.

    Article  Google Scholar 

  11. 11

    De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC et al. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 2005; 146: 4192–41999.

    CAS  Article  Google Scholar 

  12. 12

    Thaler JP, Schwartz MW . Minireview: Inflammation and obesity pathogenesis: the hypothalamus heats up. Endocrinology 2010; 151: 4109–4115.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Posey KA, Clegg DJ, Printz RL, Byun J, Morton GJ, Vivekanandan-Giri A et al. Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am J Physiol Endocrinol Metab 2009; 296: E1003–E1012.

    CAS  Article  Google Scholar 

  14. 14

    Thaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO et al. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 2012; 122: 153–162.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Hailman E, Lichenstein HS, Wurfel MM, Miller DS, Johnson DA, Kelley M et al. Lipopolysaccharide (LPS)-binding protein accelerates the binding of LPS to CD14. J Exp Med 1994; 179: 269–277.

    CAS  Article  Google Scholar 

  16. 16

    Sun L, Yu Z, Ye X, Zou S, Li H, Yu D et al. A marker of endotoxemia is associated with obesity and related metabolic disorders in apparently healthy Chinese. Diabetes Care 2010; 33: 1925–1932.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Moreno-Navarrete JM, Ortega F, Serino M, Luche E, Waget A, Pardo G et al. Circulating lipopolysaccharide-binding protein (LBP) as a marker of obesity-related insulin resistance. Int J Obes (Lond) 2012; 36: 1442–1449.

    CAS  Article  Google Scholar 

  18. 18

    Serrano M, Moreno-Navarrete JM, Puig J, Moreno M, Guerra E, Ortega F et al. Serum lipopolysaccharide-binding protein as a marker of atherosclerosis. Atherosclerosis 2013; 230: 223–227.

    CAS  Article  Google Scholar 

  19. 19

    Tilves CM, Zmuda JM, Kuipers AL, Nestlerode CS, Evans RW, Bunker CH et al. Association of lipopolysaccharide-binding protein with aging-related adiposity change and prediabetes among african ancestry men. Diabetes Care 2016; 39: 385–391.

    CAS  Article  Google Scholar 

  20. 20

    Liu X, Lu L, Yao P, Ma Y, Wang F, Jin Q et al. Lipopolysaccharide binding protein, obesity status and incidence of metabolic syndrome: a prospective study among middle-aged and older Chinese. Diabetologia 2014; 57: 1834–1841.

    CAS  Article  Google Scholar 

  21. 21

    Escribano BM, Medina-Fernández FJ, Aguilar-Luque M, Agüera E, Feijoo M, Garcia-Maceira FI et al. Lipopolysaccharide binding protein and oxidative stress in a multiple sclerosis model. Neurotherapeutics 2017; 14: 199–211.

    CAS  Article  Google Scholar 

  22. 22

    Medina-Fernández FJ, Luque E, Aguilar-Luque M, Agüera E, Feijóo M, García-Maceira FI et al. Transcranial magnetic stimulation modifies astrocytosis, cell density and lipopolysaccharide levels in experimental autoimmune encephalomyelitis. Life Sci 2017; 169: 20–26.

    Article  Google Scholar 

  23. 23

    Lee WY, Park JS, Noh SY, Rhee EJ, Sung KC, Kim BS et al. C-reactive protein concentrations are related to insulin resistance and metabolic syndrome as defined by the ATP III report. Int J Cardiol 2004; 97: 101–106.

    Article  Google Scholar 

  24. 24

    Florez H, Castillo-Florez S, Mendez A, Casanova-Romero P, Larreal-Urdaneta C, Lee D et al. C-reactive protein is elevated in obese patients with the metabolic syndrome. Diabetes Res Clin Pract 2006; 71: 92–100.

    CAS  Article  Google Scholar 

  25. 25

    Pecht T, Gutman-Tirosh A, Bashan N, Rudich A . Peripheral blood leucocyte subclasses as potential biomarkers of adipose tissue inflammation and obesity subphenotypes in humans. Obes Rev 2014; 15: 322–337.

    CAS  Article  Google Scholar 

  26. 26

    Lee D, Thaler JP, Berkseth KE, Melhorn SJ, Schwartz MW, Schur EA . Longer T(2) relaxation time is a marker of hypothalamic gliosis in mice with diet-induced obesity. Am J Physiol Endocrinol Metab 2013; 304: E1245–E1250.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Alkan A, Sahin I, Keskin L, Cikim AS, Karakas HM, Sigirci A et al. Diffusion-weighted imaging features of brain in obesity. Magn Reson Imaging 2008; 26: 446–450.

    Article  Google Scholar 

  28. 28

    Puig J, Blasco G, Daunis-I-Estadella J, Molina X, Xifra G, Ricart W et al. Hypothalamic damage is associated withinflammatory markers and worse cognitive performance in obese subjects. J Clin Endocrinol Metab 2015; 100: E276–E281.

    CAS  Article  Google Scholar 

  29. 29

    Miralbell J, Soriano JJ, Spulber G, López-Cancio E, Arenillas JF, Bargalló N et al. Structural brain changes and cognition in relation to markers of vascular dysfunction. Neurobiol Aging 2012; 33: 1003.e9–17.

    Article  Google Scholar 

  30. 30

    Wersching H, Duning T, Lohmann H, Mohammadi S, Stehling C, Fobker M et al. Serum C-reactive protein is linked to cerebral microstructural integrity and cognitive function. Neurology 2010; 74: 1022–1029.

    CAS  Article  Google Scholar 

  31. 31

    Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE et al. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 2006; 31: 1487–1505.

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 2004; 23: S208–S219.

    Article  PubMed  Google Scholar 

  33. 33

    Eickhoff SB, Stephan KE, Mohlberg H, Grefkes C, Fink GR, Amunts K et al. A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data. Neuroimage 2005; 25: 1325–1335.

    Article  Google Scholar 

  34. 34

    Mori S, Wakana S, Nagae-Poetscher LM, van Zijl PCM . MRI Atlas of Human White Matter. Elsevier: Amsterdam, The Netherlands, 2005.

    Google Scholar 

  35. 35

    Winkler AM, Ridgway GR, Webster MA, Smith SM, Nichols TE . Permutation inference for the general linear model. Neuroimage 2014; 92: 381–397.

    Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Wechsler D . WAIS-III. Escala de inteligencia de Wechsler para adultos-III. Madrid: TEA, 1999.

    Google Scholar 

  37. 37

    Marques EL, Halpern A, Corrêa Mancini M, de Melo ME, Horie NC, Buchpiguel CA et al. Changes in neuropsychological tests and brain metabolism after bariatric surgery. J Clin Endocrinol Metab 2014; 99: E2347–E2352.

    CAS  Article  Google Scholar 

  38. 38

    Fergenbaum JH, Bruce S, Lou W, Hanley AJ, Greenwood C, Young TK . Obesity and lowered cognitive performance in a Canadian First Nations population. Obesity (Silver Spring) 2009; 17: 1957–1963.

    Article  Google Scholar 

  39. 39

    Debette S, Seshadri S, Beiser A, Au R, Himali JJ, Palumbo C et al. Mid life vascular risk factor exposure accelerates structural brain aging and cognitive decline. Neurology 2011; 77: 461–468.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Singh-Manoux A, Czernichow S, Elbaz A, Dugravot A, Sabia S, Hagger-Johnson G et al. Obesity phenotypes in midlife and cognition in earlyoldage: the Whitehall II cohort study. Neurology 2012; 79: 755–762.

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Bressler J, Fornage M, Demerath EW, Knopman DS, Monda KL, North KE et al. Fat mass and obesity gene and cognitive decline: the Atherosclerosis Risk in Communities Study. Neurology 2013; 80: 92–99.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Cazettes F, Cohen JI, Yau PL, Talbot H, Convit A . Obesity-mediated inflammation may damage the brain circuit that regulates food intake. Brain Res 2011; 1373: 101–109.

    CAS  Article  Google Scholar 

  43. 43

    Verstynen TD, Weinstein A, Erickson KI, Sheu LK, Marsland AL, Gianaros PJ . Competing physiological pathways link individual differences in weight and abdominal adiposity to white matter microstructure. Neuroimage 2013; 79: 129–137.

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Gu Y, Vorburger R, Scarmeas N, Luchsinger JA, Manly JJ, Schupf N et al. Circulating inflammatory biomarkers in relation to brain structural measurements in a non-demented elderly population. Brain Behav Immun 2017. epub ahead of print 27 April 2017 doi:10.1016/j.bbi.2017.04.022.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45

    Yang PJ, Lee WJ, Tseng PH, Lee PH, Lin MT, Yang WS . Bariatric surgery decreased the serum level of an endotoxin-associated marker: lipopolysaccharide-binding protein. Surg Obes Relat Dis 2014; 10: 1182–1187.

    Article  Google Scholar 

  46. 46

    Daugherty AM, Raz N . Accumulation of iron in the putamen predicts its shrinkage in healthy older adults: A multi-occasion longitudinal study. Neuroimage 2016; 128: 11–20.

    CAS  Article  Google Scholar 

  47. 47

    Rubin DB . Causal inference using potential outcomes: design, modeling, decisions. J Am Stat Assoc 2005; 100: 322–331.

    CAS  Article  Google Scholar 

  48. 48

    Winship C, Morgan SL . The estimation of causal effects from observational data. Ann Rev Sociol 1999; 25: 659–706.

    Article  Google Scholar 

  49. 49

    Pearl J . Interpretation and identification of causal mediation. Psychol Methods 2014; 19: 459–481.

    Article  Google Scholar 

  50. 50

    Wei L, Simen A, Mane S, Kaffman A . Early life stress inhibits expression of a novel innate immune pathway in the developing hippocampus. Neuropsychopharmacology 2012; 37: 567–580.

    CAS  Article  Google Scholar 

  51. 51

    Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N et al. The classical complement cascade mediates CNS synapse elimination. Cell 2007; 131: 1164–1178.

    CAS  Article  PubMed  Google Scholar 

  52. 52

    Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008; 57: 1470–1481.

    CAS  Article  Google Scholar 

  53. 53

    Wang S, Huang XF, Zhang P, Wang H, Zhang Q, Yu S et al. Chronic rhein treatment improves recognition memory in high-fat diet-induced obese male mice. J Nutr Biochem 2016; 36: 42–50.

    CAS  Article  Google Scholar 

  54. 54

    Sobesky JL, D'Angelo HM, Weber MD, Anderson ND, Frank MG, Watkins LR et al. Glucocorticoids Mediate Short-Term High-Fat Diet Induction of Neuroinflammatory Priming, the NLRP3 Inflammasome, and the Danger Signal HMGB1. eNeuro 2016; 3: 4.

    Article  Google Scholar 

  55. 55

    Guillemot-Legris O, Muccioli GG . Obesity-Induced Neuroinflammation: Beyond the Hypothalamus. Trends Neurosci 2017; 40: 237–253.

    CAS  Article  Google Scholar 

  56. 56

    Balusu S, Van Wonterghem E, De Rycke R, Raemdonck K, Stremersch S, Gevaert K et al. Identification of a novel mechanism of blood-brain communication during peripheral inflammation via choroid plexus-derived extracellular vesicles. EMBO Mol Med 2016; 8: 1162–1183.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Moreno-Navarrete JM, Escoté X, Ortega F, Camps M, Ricart W, Zorzano A et al. Lipopolysaccharide binding protein is an adipokine involved in the resilience of the mouse adipocyte to inflammation. Diabetologia 2015; 58: 2424–2434.

    CAS  Article  Google Scholar 

  58. 58

    Pang J, Xu W, Zhang X, Wong GL, Chan AW, Chan HY et al. Significant positive association of endotoxemia with histological severity in 237 patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2017; 46: 175–182.

    CAS  Article  Google Scholar 

  59. 59

    Laugerette F, Alligier M, Bastard JP, Drai J, Chanséaume E, Lambert-Porcheron S et al. Overfeeding increases postprandial endotoxemia in men: Inflammatory outcome may depend on LPS transporters LBP and sCD14. Mol Nutr Food Res 2014; 58: 1513–1518.

    CAS  Article  Google Scholar 

  60. 60

    Gavaldà-Navarro A, Moreno-Navarrete JM, Quesada-López T, Cairó M, Giralt M, Fernández-Real JM et al. Lipopolysaccharide-binding protein is a negative regulator of adipose tissue browning in mice and humans. Diabetologia 2016; 59: 2208–2218.

    Article  Google Scholar 

  61. 61

    Menon V . Memory and cognitive control circuits in mathematical cognition and learning. Prog Brain Res 2016; 227: 159–186.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was partially supported by research grant PI15/01934 and PI16/02173 from the Instituto de Salud Carlos III from Spain and was also supported by FEDER funds. CIBEROBN Fisiopatología de la Obesidad y Nutrición is an initiative from the Instituto de Salud Carlos III from Spain. We acknowledge the technical assistance of M. Sabater, E. Loshuertos and O. Rovira (both from Endocrinology, IdIBGi, Spain).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to J M Moreno-Navarrete or J M Fernández-Real.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on International Journal of Obesity website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Moreno-Navarrete, J., Blasco, G., Puig, J. et al. Neuroinflammation in obesity: circulating lipopolysaccharide-binding protein associates with brain structure and cognitive performance. Int J Obes 41, 1627–1635 (2017). https://doi.org/10.1038/ijo.2017.162

Download citation

Further reading

Search

Quick links