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Blood-Brain Barriers in Obesity

  • Review Article
  • Theme: CNS Barriers in Health and Disease
  • Published:
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Abstract

After decades of rapid increase, the rate of obesity in adults in the USA is beginning to slow and the rate of childhood obesity is stabilizing. Despite these improvements, the obesity epidemic continues to be a major health and financial burden. Obesity is associated with serious negative health outcomes such as cardiovascular disease, type II diabetes, and, more recently, cognitive decline and various neurodegenerative dementias such as Alzheimer’s disease. In the past decade, major advancements have contributed to the understanding of the role of the central nervous system (CNS) in the development of obesity and how peripheral hormonal signals modulate CNS regulation of energy homeostasis. In this article, we address how obesity affects the structure and function of the blood-brain barrier (BBB), the impact of obesity on Alzheimer’s disease, the effects of obesity on circulating proteins and their transport into the brain, and how these changes can potentially be reversed by weight loss.

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References

  1. Kopelman PG. Obesity as a medical problem. Nature. 2000;404(6778):635–43.

    CAS  PubMed  Google Scholar 

  2. Trogdon JG, Finkelstein EA, Feagan CW, Cohen JW. State- and payer-specific estimates of annual medical expenditures attributable to obesity. Obesity. 2012;20(1):214–20.

    Article  PubMed  Google Scholar 

  3. Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature. 2000;404(6778):661–71.

    CAS  PubMed  Google Scholar 

  4. Banks WA. Peptides and the blood-brain barrier. Peptides. 2015;72:16–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7(1):41–53.

    Article  CAS  PubMed  Google Scholar 

  6. Moraes JC, Coope A, Morari J, Cintra DE, Roman EA, Pauli JR, et al. High-fat diet induces apoptosis of hypothalamic neurons. PLoS One. 2009;4(4):e5045.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Kim DW, Glendining KA, Grattan DR, Jasoni CL. Maternal obesity in the mouse compromises the blood-brain barrier in the arcuate nucleus of offspring. Endocrinology. 2016;157(6):2229–42.

    Article  CAS  PubMed  Google Scholar 

  8. Baufeld C, Osterloh A, Prokop S, Miller KR, Heppner FL. High-fat diet-induced brain region-specific phenotypic spectrum of CNS resident microglia. Acta Neuropathol. 2016;132:361–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Thaler JP, Guyenet SJ, Dorfman MD, Wisse BE, Schwartz MW. Hypothalamic inflammation: marker or mechanism of obesity pathogenesis? Diabetes. 2013;62(8):2629–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Prickett C, Brennan L, Stolwyk R. Examining the relationship between obesity and cognitive function: a systematic literature review. Obesity Research & Clinical Practice. 2015;9(2):93–113.

    Article  Google Scholar 

  11. Morris MC, Evans DA, Bienias JL, Tangney CC, Wilson RS. Dietary fat intake and 6-year cognitive change in an older biracial community population. Neurology. 2004;62(9):1573–9.

    Article  CAS  PubMed  Google Scholar 

  12. Farr SA, Yamada KA, Butterfield DA, Abdul HM, Xu L, Miller NE, et al. Obesity and hypertriglyceridemia produce cognitive impairment. Endocrinology. 2008;149(5):2628–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Walker JM, Dixit S, Saulsberry AC, May JM, Harrison FE. Reversal of high fat diet-induced obesity improves glucose tolerance, inflammatory response, beta-amyloid accumulation and cognitive decline in the APP/PSEN1 mouse model of Alzheimer’s disease. Neurobiol Dis. 2017.

  14. Wang X, Michaelis EK. Selective neuronal vulnerability to oxidative stress in the brain. Front Aging Neurosci. 2010;2:12.

    PubMed  PubMed Central  Google Scholar 

  15. Granholm A-C, Bimonte-Nelson HA, Moore AB, Nelson ME, Freeman LR, Sambamurti K. Effects of a saturated fat and high cholesterol diet on memory and hippocampal morphology in the middle-aged rat. Journal of Alzheimer's disease : JAD. 2008;14(2):133–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Stranahan AM, Norman ED, Lee K, Cutler RG, Telljohann R, Egan JM, et al. Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle-aged rats. Hippocampus. 2008;18(11):1085–8.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Persidsky Y, Ramirez SH, Haorah J, Kanmogne GD. Blood–brain barrier: structural components and function under physiologic and pathologic conditions. J NeuroImmune Pharmacol. 2006;1(3):223–36.

    Article  PubMed  Google Scholar 

  18. Gustafson DR, Karlsson C, Skoog I, Rosengren L, Lissner L, Blennow K. Mid-life adiposity factors relate to blood–brain barrier integrity in late life. J Intern Med. 2007;262(6):643–50.

    Article  CAS  PubMed  Google Scholar 

  19. Ghribi O, Golovko MY, Larsen B, Schrag M, Murphy EJ. Deposition of iron and β-amyloid plaques is associated with cortical cellular damage in rabbits fed with long-term cholesterol-enriched diets. J Neurochem. 2006;99(2):438–49.

    Article  CAS  PubMed  Google Scholar 

  20. Kanoski SE, Zhang Y, Zheng W, Davidson TL. The effects of a high-energy diet on hippocampal function and blood-brain barrier integrity in the rat. J Alzheimers Dis. 2010;21(1):207–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ouyang S, Hsuchou H, Kastin AJ, Wang Y, Yu C, Pan W. Diet-induced obesity suppresses expression of many proteins at the blood–brain barrier. J Cereb Blood Flow Metab. 2014;34(1):43–51.

    Article  CAS  PubMed  Google Scholar 

  22. Bondia-Pons I, Boque N, Paternain L, Santamaria E, Fernandez J, Campion J, et al. Liver proteome changes induced by a short-term high-fat sucrose diet in wistar rats. J Nutrigenet Nutrigenomics. 2011;4(6):344–53.

    Article  CAS  PubMed  Google Scholar 

  23. Cruz-Topete D, List EO, Okada S, Kelder B, Kopchick JJ. Proteomic changes in the heart of diet-induced pre-diabetic mice. J Proteome. 2011;74(5):716–27.

    Article  CAS  Google Scholar 

  24. Sarria AJ, Panini SR, Evans RM. A functional role for vimentin intermediate filaments in the metabolism of lipoprotein-derived cholesterol in human SW-13 cells. J Biol Chem. 1992;267(27):19455–63.

    CAS  PubMed  Google Scholar 

  25. Winkler EA, Nishida Y, Sagare AP, Rege SV, Bell RD, Perlmutter D, et al. GLUT1 reductions exacerbate Alzheimer’s disease vasculo-neuronal dysfunction and degeneration. Nat Neurosci. 2015;18(4):521–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fukuda AM, Badaut J. Aquaporin 4: a player in cerebral edema and neuroinflammation. J Neuroinflammation. 2012;9:279.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tomassoni D, Tayebati SK, Cognigni MF, Amenta F. Obesity-related blood brain barrier changes in obese Zucker rats. 2015.

  28. Lutz TA, Woods SC. Overview of animal models of obesity. In: Enna SJ, et al. editor. Current protocols in pharmacology / editorial board. 2012. CHAPTER:Unit5.61-Unit5.

  29. Banks WA, Gray AM, Erickson MA, Salameh TS, Damodarasamy M, Sheibani N, et al. Lipopolysaccharide-induced blood-brain barrier disruption: roles of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit. J Neuroinflammation. 2015;12(1):223.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Price TO, Eranki V, Banks WA, Ercal N, Shah GN. Topiramate treatment protects blood-brain barrier pericytes from hyperglycemia-induced oxidative damage in diabetic mice. Endocrinology. 2012;153(1):362–72.

    Article  CAS  PubMed  Google Scholar 

  31. Price TO, Farr SA, Niehoff ML, Ercal N, Morley JE, Shah GN. Protective effect of topiramate on hyperglycemia-induced cerebral oxidative stress, pericyte loss and learning behavior in diabetic mice. Int Libr Diabetes Metab. 2015;1(1):6–12.

    PubMed  PubMed Central  Google Scholar 

  32. Roh H-T, Cho S-Y, So W-Y. Obesity promotes oxidative stress and exacerbates blood-brain barrier disruption after high-intensity exercise. J Sport Health Sci. 2016.

  33. Tucsek Z, Toth P, Sosnowska D, Gautam T, Mitschelen M, Koller A, et al. Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation, and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer’s disease. J Gerontol A Biol Sci Med Sci. 2014;69(10):1212–26.

    Article  CAS  PubMed  Google Scholar 

  34. Dorfman MD, Thaler JP. Hypothalamic inflammation and gliosis in obesity. Curr Opin Endocrinol Diabetes Obes. 2015;22(5):325–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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(10):4192–9.

    Article  CAS  PubMed  Google Scholar 

  36. Sobesky JL, Barrientos RM, De May HS, Thompson BM, Weber MD, Watkins LR, et al. High-fat diet consumption disrupts memory and primes elevations in hippocampal IL-1beta, an effect that can be prevented with dietary reversal or IL-1 receptor antagonism. Brain Behav Immun. 2014;42:22–32.

    Article  CAS  PubMed  Google Scholar 

  37. Zhang X, Dong F, Ren J, Driscoll MJ, Culver B. High dietary fat induces NADPH oxidase-associated oxidative stress and inflammation in rat cerebral cortex. Exp Neurol. 2005;191(2):318–25.

    Article  CAS  PubMed  Google Scholar 

  38. Stranahan AM, Hao S, Dey A, Yu X, Baban B. Blood-brain barrier breakdown promotes macrophage infiltration and cognitive impairment in leptin receptor-deficient mice. J Cereb Blood Flow Metab. 2016;36(12):2108–21.

    Article  PubMed  Google Scholar 

  39. Banks WA, Kastin AJ, Broadwell RD. Passage of cytokines across the blood-brain barrier. Neuroimmunomodulation. 1995;2(4):241–8.

    Article  CAS  PubMed  Google Scholar 

  40. Jung UJ, Choi MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci. 2014;15(4):6184–223.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Banks WA, Kastin AJ, Gutierrez EG. Penetration of interleukin-6 across the murine blood-brain barrier. Neurosci Lett. 1994;179(1–2):53–6.

    Article  CAS  PubMed  Google Scholar 

  42. Pan W, Kastin AJ. TNFalpha transport across the blood-brain barrier is abolished in receptor knockout mice. Exp Neurol. 2002;174(2):193–200.

    Article  CAS  PubMed  Google Scholar 

  43. Williams K, Alvarez X, Lackner AA. Central nervous system perivascular cells are immunoregulatory cells that connect the CNS with the peripheral immune system. Glia. 2001;36(2):156–64.

    Article  CAS  PubMed  Google Scholar 

  44. Jais A, Solas M, Backes H, Chaurasia B, Kleinridders A, Theurich S, et al. Myeloid-cell-derived VEGF maintains brain glucose uptake and limits cognitive impairment in obesity. Cell. 2016;165(4):882–95.

    Article  CAS  PubMed  Google Scholar 

  45. Verma S, Nakaoke R, Dohgu S, Banks WA. Release of cytokines by brain endothelial cells: a polarized response to lipopolysaccharide. Brain Behav Immun. 2006;20(5):449–55.

    Article  CAS  PubMed  Google Scholar 

  46. Banks WA, Niehoff ML, Ponzio NM, Erickson MA, Zalcman SS. Pharmacokinetics and modeling of immune cell trafficking: quantifying differential influences of target tissues versus lymphocytes in SJL and lipopolysaccharide-treated mice. J Neuroinflammation. 2012;9:231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Engelhardt B. Molecular mechanisms involved in T cell migration across the blood-brain barrier. J Neural Transm (Vienna). 2006;113(4):477–85.

    Article  CAS  Google Scholar 

  48. Buckman LB, Thompson MM, Lippert RN, Blackwell TS, Yull FE, Ellacott KL. Evidence for a novel functional role of astrocytes in the acute homeostatic response to high-fat diet intake in mice. Mol Metab. 2015;4(1):58–63.

    Article  CAS  PubMed  Google Scholar 

  49. O'Carroll SJ, Kho DT, Wiltshire R, Nelson V, Rotimi O, Johnson R, et al. Pro-inflammatory TNFalpha and IL-1beta differentially regulate the inflammatory phenotype of brain microvascular endothelial cells. J Neuroinflammation. 2015;12:131.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Etienne-Manneville S, Manneville JB, Adamson P, Wilbourn B, Greenwood J, Couraud PO. ICAM-1-coupled cytoskeletal rearrangements and transendothelial lymphocyte migration involve intracellular calcium signaling in brain endothelial cell lines. J Immunol. 2000;165(6):3375–83.

    Article  CAS  PubMed  Google Scholar 

  51. Nerurkar PV, Johns LM, Buesa LM, Kipyakwai G, Volper E, Sato R, et al. Momordica charantia (bitter melon) attenuates high-fat diet-associated oxidative stress and neuroinflammation. J Neuroinflammation. 2011;8:64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol. 2011;10(9):819–28.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Julien C, Tremblay C, Phivilay A, Berthiaume L, Emond V, Julien P, et al. High-fat diet aggravates amyloid-beta and tau pathologies in the 3xTg-AD mouse model. Neurobiol Aging. 2010;31(9):1516–31.

    Article  CAS  PubMed  Google Scholar 

  54. Levin-Allerhand JA, Lominska CE, Smith JD. Increased amyloid- levels in APPSWE transgenic mice treated chronically with a physiological high-fat high-cholesterol diet. J Nutr Health Aging. 2002;6(5):315–9.

    CAS  PubMed  Google Scholar 

  55. Hanson AJ, Bayer JL, Baker LD, Cholerton B, VanFossen B, Trittschuh E, et al. Differential effects of meal challenges on cognition, metabolism, and biomarkers for apolipoprotein E varepsilon4 carriers and adults with mild cognitive impairment. J Alzheimers Dis. 2015;48(1):205–18.

    Article  CAS  PubMed  Google Scholar 

  56. Takechi R, Galloway S, Pallebage-Gamarallage MM, Lam V, Mamo JC. Dietary fats, cerebrovasculature integrity and Alzheimer’s disease risk. Prog Lipid Res. 2010;49(2):159–70.

    Article  CAS  PubMed  Google Scholar 

  57. Pugazhenthi S, Qin L, Reddy PH. Common neurodegenerative pathways in obesity, diabetes, and Alzheimer’s disease. Biochim Biophys Acta. 2016.

  58. Erickson MA, Hartvigson PE, Morofuji Y, Owen JB, Butterfield DA, Banks WA. Lipopolysaccharide impairs amyloid beta efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood-brain barrier. J Neuroinflammation. 2012;9:150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Miller MC, Tavares R, Johanson CE, Hovanesian V, Donahue JE, Gonzalez L, et al. Hippocampal RAGE immunoreactivity in early and advanced Alzheimer’s disease. Brain Res. 2008;1230:273–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Song F, Hurtado del Pozo C, Rosario R, Zou YS, Ananthakrishnan R, Xu X, et al. RAGE regulates the metabolic and inflammatory response to high-fat feeding in mice. Diabetes. 2014;63(6):1948–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wang M, Norman JE, Srinivasan VJ, Rutledge JC. Metabolic, inflammatory, and microvascular determinants of white matter disease and cognitive decline. American journal of neurodegenerative disease. 2016;5(5):171–7.

    PubMed  PubMed Central  Google Scholar 

  62. Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9(2):106–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Hanson AJ, Bayer-Carter JL, Green PS, Montine TJ, Wilkinson CW, Baker LD, et al. Effect of apolipoprotein E genotype and diet on apolipoprotein E lipidation and amyloid peptides: randomized clinical trial. JAMA Neurol. 2013;1–9.

  64. Elliott DA, Weickert CS, Garner B. Apolipoproteins in the brain: implications for neurological and psychiatric disorders. Clinical lipidology. 2010;51(4):555–73.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Shayo M, McLay RN, Kastin AJ, Banks WA. The putative blood-brain barrier transporter for the β-amyloid binding protein apolipoprotein J is saturated at physiological concentrations. Life Sci. 1996;60:L115–L8.

    Google Scholar 

  66. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes. 2001;50(4):707–9.

    Article  CAS  PubMed  Google Scholar 

  68. Bagdade JD. Basal insulin and obesity. Lancet. 1968;2(7568):630–1.

    Article  CAS  PubMed  Google Scholar 

  69. Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet. 1996;348(9021):159–61.

    Article  CAS  PubMed  Google Scholar 

  70. Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte Jr D. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat Med. 1996;2(5):589–93.

    Article  CAS  PubMed  Google Scholar 

  71. Adam CL, Findlay PA. Decreased blood-brain leptin transfer in an ovine model of obesity and weight loss: resolving the cause of leptin resistance. Int J Obes. 2010;34(6):980–8.

    Article  CAS  Google Scholar 

  72. Banks WA, DiPalma CR, Farrell CL. Impaired transport of leptin across the blood-brain barrier in obesity. Peptides. 1999;20(11):1341–5.

    Article  CAS  PubMed  Google Scholar 

  73. Kern W, Benedict C, Schultes B, Plohr F, Moser A, Born J, et al. Low cerebrospinal fluid insulin levels in obese humans. Diabetologia. 2006;49(11):2790–2.

    Article  CAS  PubMed  Google Scholar 

  74. Kaiyala KJ, Prigeon RL, Kahn SE, Woods SC, Schwartz MW. Obesity induced by a high-fat diet is associated with reduced brain insulin transport in dogs. Diabetes. 2000;49(9):1525–33.

    Article  CAS  PubMed  Google Scholar 

  75. Baskin DG, Stein LJ, Ikeda H, Woods SC, Figlewicz DP, Porte Jr D, et al. Genetically obese Zucker rats have abnormally low brain insulin content. Life Sci. 1985;36(7):627–33.

    Article  CAS  PubMed  Google Scholar 

  76. Urayama A, Banks WA. Starvation and triglycerides reverse the obesity-induced impairment of insulin transport at the blood-brain barrier. Endocrinology. 2008;149(7):3592–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Spranger J, Verma S, Gohring I, Bobbert T, Seifert J, Sindler AL, et al. Adiponectin does not cross the blood-brain barrier but modifies cytokine expression of brain endothelial cells. Diabetes. 2006;55(1):141–7.

    Article  CAS  PubMed  Google Scholar 

  78. Pan W, Tu H, Kastin AJ. Differential BBB interactions of three ingestive peptides: obestatin, ghrelin, and adiponectin. Peptides. 2006;27(4):911–6.

    Article  CAS  PubMed  Google Scholar 

  79. Banks WA, Burney BO, Robinson SM. Effects of triglycerides, obesity, and starvation on ghrelin transport across the blood-brain barrier. Peptides. 2008;29(11):2061–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Karmi A, Iozzo P, Viljanen A, Hirvonen J, Fielding BA, Virtanen K, et al. Increased brain fatty acid uptake in metabolic syndrome. Diabetes. 2010;59(9):2171–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 1998;395(6704):763–70.

    Article  CAS  PubMed  Google Scholar 

  82. Banks WA, Kastin AJ, Huang W, Jaspan JB, Maness LM. Leptin enters the brain by a saturable system independent of insulin. Peptides. 1996;17(2):305–11.

    Article  CAS  PubMed  Google Scholar 

  83. Banks WA, Clever CM, Farrell CL. Partial saturation and regional variation in the blood-to-brain transport of leptin in normal weight mice. Am J Physiol Endocrinol Metab. 2000;278(6):E1158–65.

    CAS  PubMed  Google Scholar 

  84. Van Heek M, Compton DS, France CF, Tedesco RP, Fawzi AB, Graziano MP, et al. Diet-induced obese mice develop peripheral, but not central, resistance to leptin. J Clin Invest. 1997;99(3):385–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Halaas JL, Boozer C, Blair-West J, Fidahusein N, Denton DA, Friedman JM. Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc Natl Acad Sci U S A. 1997;94(16):8878–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Banks WA, Niehoff ML, Martin D, Farrell CL. Leptin transport across the blood-brain barrier of the Koletsky rat is not mediated by a product of the leptin receptor gene. Brain Res. 2002;950(1–2):130–6.

    Article  CAS  PubMed  Google Scholar 

  87. Maness LM, Banks WA, Kastin AJ. Persistence of blood-to-brain transport of leptin in obese leptin-deficient and leptin receptor-deficient mice. Brain Res. 2000;873(1):165–7.

    Article  CAS  PubMed  Google Scholar 

  88. Banks WA, Coon AB, Robinson SM, Moinuddin A, Shultz JM, Nakaoke R, et al. Triglycerides induce leptin resistance at the blood-brain barrier. Diabetes. 2004;53(5):1253–60.

    Article  CAS  PubMed  Google Scholar 

  89. Kastin AJ, Akerstrom V. Glucose and insulin increase the transport of leptin through the blood-brain barrier in normal mice but not in streptozotocin-diabetic mice. Neuroendocrinology. 2001;73(4):237–42.

    Article  CAS  PubMed  Google Scholar 

  90. Yi X, Yuan D, Farr SA, Banks WA, Poon CD, Kabanov AV. Pluronic modified leptin with increased systemic circulation, brain uptake and efficacy for treatment of obesity. J Control Release. 2014;191:34–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Banks WA, Gertler A, Solomon G, Niv-Spector L, Shpilman M, Yi X, et al. Principles of strategic drug delivery to the brain (SDDB): development of anorectic and orexigenic analogs of leptin. Physiol Behav. 2011;105(1):145–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Qi Y, Takahashi N, Hileman SM, Patel HR, Berg AH, Pajvani UB, et al. Adiponectin acts in the brain to decrease body weight. Nat Med. 2004;10(5):524–9.

    Article  CAS  PubMed  Google Scholar 

  93. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun. 1999;257(1):79–83.

    Article  CAS  PubMed  Google Scholar 

  94. Neumeier M, Weigert J, Buettner R, Wanninger J, Schaffler A, Muller AM, et al. Detection of adiponectin in cerebrospinal fluid in humans. Am J Physiol Endocrinol Metab. 2007;293(4):E965–9.

    Article  CAS  PubMed  Google Scholar 

  95. Vachharajani V, Cunningham C, Yoza B, Carson Jr J, Vachharajani TJ, McCall C. Adiponectin-deficiency exaggerates sepsis-induced microvascular dysfunction in the mouse brain. Obesity (Silver Spring). 2012;20(3):498–504.

    Article  CAS  Google Scholar 

  96. Stephan F, Reville P, Thierry R, Schlienger JL. Correlations between plasma insulin and body weight in obesity, anorexia nervosa and diabetes mellitus. Diabetologia. 1972;8(3):196–201.

    Article  CAS  PubMed  Google Scholar 

  97. Woods SC, Seeley RJ, Baskin DG, Schwartz MW. Insulin and the blood-brain barrier. Curr Pharm Des. 2003;9(10):795–800.

    Article  CAS  PubMed  Google Scholar 

  98. Cangiano C, Cardelli-Cangiano P, Cascino A, Patrizi MA, Barberini F, Rossi Fanelli F, et al. On the stimulation by insulin of tryptophan transport across the blood-brain barrier. Biochem Int. 1983;7(5):617–27.

    CAS  PubMed  Google Scholar 

  99. Banks WA, Kastin AJ. Differential permeability of the blood-brain barrier to two pancreatic peptides: insulin and amylin. Peptides. 1998;19(5):883–9.

    Article  CAS  PubMed  Google Scholar 

  100. Roth JD, Roland BL, Cole RL, Trevaskis JL, Weyer C, Koda JE, et al. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc Natl Acad Sci U S A. 2008;105(20):7257–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Uchida A, Zechner JF, Mani BK, Park WM, Aguirre V, Zigman JM. Altered ghrelin secretion in mice in response to diet-induced obesity and Roux-en-Y gastric bypass. Mol Metab. 2014;3(7):717–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Lamers D, Famulla S, Wronkowitz N, Hartwig S, Lehr S, Ouwens DM, et al. Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes. 2011;60(7):1917–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Tanaka S, Kanazawa I, Notsu M, Sugimoto T. Visceral fat obesity increases serum DPP-4 levels in men with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2016;116:1–6.

    Article  CAS  PubMed  Google Scholar 

  104. Kieffer TJ, McIntosh CH, Pederson RA. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology. 1995;136(8):3585–96.

    Article  CAS  PubMed  Google Scholar 

  105. Kastin AJ, Akerstrom V, Pan W. Interactions of glucagon-like peptide-1 (GLP-1) with the blood-brain barrier. J Mol Neurosci. 2002;18(1–2):7–14.

    Article  CAS  PubMed  Google Scholar 

  106. Rohrborn D, Wronkowitz N, Eckel J. DPP4 in diabetes. Front Immunol. 2015;6:386.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Pocai A, Lam TK, Obici S, Gutierrez-Juarez R, Muse ED, Arduini A, et al. Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats. J Clin Invest. 2006;116(4):1081–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Obici S, Feng Z, Morgan K, Stein D, Karkanias G, Rossetti L. Central administration of oleic acid inhibits glucose production and food intake. Diabetes. 2002;51(2):271–5.

    Article  CAS  PubMed  Google Scholar 

  109. Boden G. Obesity and free fatty acids. Endocrinol Metab Clin N Am. 2008;37(3):635–46. viii-ix

    Article  CAS  Google Scholar 

  110. Guiducci L, Gronroos T, Jarvisalo MJ, Kiss J, Viljanen A, Naum AG, et al. Biodistribution of the fatty acid analogue 18F-FTHA: plasma and tissue partitioning between lipid pools during fasting and hyperinsulinemia. J Nucl Med. 2007;48(3):455–62.

    CAS  PubMed  Google Scholar 

  111. Arai T, Wakabayashi S, Channing MA, Dunn BB, Der MG, Bell JM, et al. Incorporation of [1-carbon-11]palmitate in monkey brain using PET. J Nucl Med. 1995;36(12):2261–7.

    CAS  PubMed  Google Scholar 

  112. Kimes AS, Sweeney D, London ED, Rapoport SI. Palmitate incorporation into different brain regions in the awake rat. Brain Res. 1983;274(2):291–301.

    Article  CAS  PubMed  Google Scholar 

  113. Vendelbo J, Olesen RH, Lauridsen JK, Rungby J, Kleinman JE, Hyde TM, et al. Increasing BMI is associated with reduced expression of P-glycoprotein (ABCB1 gene) in the human brain with a stronger association in African Americans than Caucasians. Pharmacogenomics J. 2016.

  114. Veronese N, Facchini S, Stubbs B, Luchini C, Solmi M, Manzato E, et al. Weight loss is associated with improvements in cognitive function among overweight and obese people: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2017;72:87–94.

    Article  PubMed  Google Scholar 

  115. Jeong SK, Nam HS, Son MH, Son EJ, Cho KH. Interactive effect of obesity indexes on cognition. Dement Geriatr Cogn Disord. 2005;19(2–3):91–6.

    Article  PubMed  Google Scholar 

  116. Dahl A, Hassing LB, Fransson E, Berg S, Gatz M, Reynolds CA, et al. Being overweight in midlife is associated with lower cognitive ability and steeper cognitive decline in late life. J Gerontol A Biol Sci Med Sci. 2010;65(1):57–62.

    Article  PubMed  Google Scholar 

  117. Hassing LB, Dahl AK, Pedersen NL, Johansson B. Overweight in midlife is related to lower cognitive function 30 years later: a prospective study with longitudinal assessments. Dement Geriatr Cogn Disord. 2010;29(6):543–52.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Banks WA, Farrell CL. Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible. Am J Physiol Endocrinol Metab. 2003;285(1):E10–5.

    Article  CAS  PubMed  Google Scholar 

  119. Begg DP, Mul JD, Liu M, Reedy BM, D'Alessio DA, Seeley RJ, et al. Reversal of diet-induced obesity increases insulin transport into cerebrospinal fluid and restores sensitivity to the anorexic action of central insulin in male rats. Endocrinology. 2013;154(3):1047–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest. 1996;97(11):2601–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Ziccardi P, Nappo F, Giugliano G, Esposito K, Marfella R, Cioffi M, et al. Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation. 2002;105(7):804–9.

    Article  CAS  PubMed  Google Scholar 

  122. Bigornia SJ, Mott MM, Hess DT, Apovian CM, McDonnell ME, Duess MA, et al. Long-term successful weight loss improves vascular endothelial function in severely obese individuals. Obesity (Silver Spring). 2010;18(4):754–9.

    Article  Google Scholar 

  123. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science. 1996;271(5249):665–8.

    Article  CAS  PubMed  Google Scholar 

  124. Xaio H, Banks WA, Niehoff ML, Morley JE. Effect of LPS on the permeability of the blood-brain barrier to insulin. Brain Res. 2001;896(1–2):36–42.

    Article  CAS  PubMed  Google Scholar 

  125. Park S, Park NY, Valacchi G, Lim Y. Calorie restriction with a high-fat diet effectively attenuated inflammatory response and oxidative stress-related markers in obese tissues of the high diet fed rats. Mediat Inflamm. 2012;2012:984643.

    Article  CAS  Google Scholar 

  126. Giugliano G, Nicoletti G, Grella E, Giugliano F, Esposito K, Scuderi N, et al. Effect of liposuction on insulin resistance and vascular inflammatory markers in obese women. Br J Plast Surg. 2004;57(3):190–4.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by numerous grants from the National Institute of Health. EMR is supported by T32-AG000057. TSS, along with WAB, is supported by R21-NS093368-01A1. WAB is also supported by RO1-AG046619, along with MAE. AFL is supported by T32-AG052354-01. AJH is supported by K23-AG047978-01. This article results from work supported by resources from the Veterans Affairs Puget Sound Health Care System, Seattle, Washington.

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Authors and Affiliations

  1. Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA

    Elizabeth M. Rhea, Therese S. Salameh, Aric F. Logsdon, Angela J. Hanson, Michelle A. Erickson & William A. Banks

  2. Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, 810A/Bldg 1, 1660 S Columbian Way, Seattle, Washington, 98108, USA

    Elizabeth M. Rhea, Therese S. Salameh, Aric F. Logsdon, Angela J. Hanson, Michelle A. Erickson & William A. Banks

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  1. Elizabeth M. Rhea
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  2. Therese S. Salameh
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  3. Aric F. Logsdon
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  4. Angela J. Hanson
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Correspondence to Elizabeth M. Rhea.

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Guest Editors: Marilyn E. Morris and Jean-Michel Scherrmann

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Rhea, E.M., Salameh, T.S., Logsdon, A.F. et al. Blood-Brain Barriers in Obesity. AAPS J 19, 921–930 (2017). https://doi.org/10.1208/s12248-017-0079-3

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