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Blood-Borne Metabolic Factors in Obesity Exacerbate Injury-Induced Gliosis

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Abstract

Reactive gliosis, a sign of neuroinflammation, has been observed in mice with adult-onset obesity as well as CNS injury. The hypothesis that obesity-derived metabolic factors exacerbate reactive gliosis in response to mechanical injury was tested here on cultured primary glial cells subjected to a well-established model of scratch wound injury. Cells treated with serum from mice with diet-induced obesity (DIO) showed higher immunoreactivity of CD11b (marker for microglia) and GFAP (marker for astrocytes), with morphological changes at both the injury border and areas away from the injury. The effect of DIO serum was greater than that of scratch injury alone. Leptin was almost as effective as DIO serum in inducing microgliosis and astrogliosis in a dose-response manner. By contrast, C-reactive protein (CRP) mainly induced microgliosis in noninjured cells; injury-induced factors appeared to attenuate this effect. The effect of CRP also differed from the effect of the antibiotic minocycline. Minocycline attenuated the microgliosis and to a lesser extent astrogliosis, particularly in CRP-treated cells, thus serving as a negative control. We conclude that blood-borne proinflammatory metabolic factors in obesity increase reactive gliosis and probably exacerbate CNS injury.

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References

  • Ahima RS, Osei SY (2004) Leptin signaling. Physiol Behav 81:223–241

    Article  PubMed  CAS  Google Scholar 

  • Banks WA (2001) Leptin transport across the blood-brain barrier: implications for the cause and treatment of obesity. Curr Pharm Des 7:125–133

    Article  PubMed  CAS  Google Scholar 

  • Banks WA, Kastin AJ, Huang W, Jaspan JB, Maness LM (1996) Leptin enters the brain by a saturable system independent of insulin. Peptides 17:305–311

    Article  PubMed  CAS  Google Scholar 

  • Chen X, Pi R, Liu M, Ma X, Jiang Y, Liu Y, Mao X, Hu X (2010) Combination of methylprednisolone and minocycline synergistically improves experimental autoimmune encephalomyelitis in C57 BL/6 mice. J Neuroimmunol 226:104–109

    Article  PubMed  CAS  Google Scholar 

  • Eng LF, Vanderhaeghen JJ, Bignami A, Gerstl B (1971) An acidic protein isolated from fibrous astrocytes. Brain Res 28:351–354

    Article  PubMed  CAS  Google Scholar 

  • Eng LF, Ghirnikar RS, Lee YL (2000) Glial fibrillary acidic protein: GFAP-thirty-one years (1969-2000). Neurochem Res 25:1439–1451

    Article  PubMed  CAS  Google Scholar 

  • Farr SA, Banks WA, Morley JE (2006) Effects of leptin on memory processing. Peptides 27:1420–1425

    Article  PubMed  CAS  Google Scholar 

  • Farr SA, Yamada KA, Butterfield DA, Abdul HM, Xu L, Miller NE, Banks WA, Morley JE (2008) Obesity and hypertriglyceridemia produce cognitive impairment. Endocrinology 149:2628–2636

    Article  PubMed  CAS  Google Scholar 

  • He Y, Kastin AJ, Hsuchou H, Pan W (2009) The Cdk5/p35 kinases modulate leptin-induced STAT3 signaling. J Mol Neurosci 39:49–58

    Article  PubMed  CAS  Google Scholar 

  • Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, Sheridan JF, Godbout JP (2008) Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflammation 5:15

    Article  PubMed  Google Scholar 

  • Hoane MR, Swan AA, Heck SE (2011) The effects of a high-fat sucrose diet on functional outcome following cortical contusion injury in the rat. Behav Brain Res 223:119–124

    Article  PubMed  CAS  Google Scholar 

  • Hosoi T, Okuma Y, Wada S, Nomura Y (2003) Inhibition of leptin-induced IL-1beta expression by glucocorticoids in the brain. Brain Res 969:95–101

    Article  PubMed  CAS  Google Scholar 

  • Hsuchou H, He Y, Kastin AJ, Tu H, Markadakis EN, Rogers RC, Fossier PB, Pan W (2009a) Obesity induces functional astrocytic leptin receptors in hypothalamus. Brain 132:889–902

    Article  PubMed  Google Scholar 

  • Hsuchou H, Pan W, Barnes MJ, Kastin AJ (2009b) Leptin receptor mRNA in rat brain astrocytes. Peptides 30:2275–2280

    Article  PubMed  CAS  Google Scholar 

  • Hwang LL, Wang CH, Li TL, Chang SD, Lin LC, Chen CP, Chen CT, Liang KC, Ho IK, Yang WS, Chiou LC (2010) Sex differences in high-fat diet-induced obesity, metabolic alterations and learning, and synaptic plasticity deficits in mice. Obes Silver Spring 18:463–469

    Article  CAS  Google Scholar 

  • Kanoski SE, Davidson TL (2011) Western diet consumption and cognitive impairment: links to hippocampal dysfunction and obesity. Physiol Behav 103:59–68

    Article  PubMed  CAS  Google Scholar 

  • Kanoski SE, Zhang Y, Zheng W, Davidson TL (2010) The effects of a high-energy diet on hippocampal function and blood-brain barrier integrity in the rat. J Alzheimers Dis 21:207–219

    PubMed  CAS  Google Scholar 

  • Kastin AJ, Pan W (2003) Feeding peptides interact in several ways with the blood-brain barrier. Curr Pharm Des 9:789–794

    Article  PubMed  CAS  Google Scholar 

  • Kastin AJ, Pan W (2006) Intranasal leptin: blood-brain barrier bypass (BBBB) for obesity? Endocrinol 147:2086–2087

    Article  CAS  Google Scholar 

  • Kastin AJ, Pan W (2008) Blood-brain barrier and feeding: regulatory roles of saturable transport systems for ingestive peptides. Curr Pharm Des 14:1615–1619

    Article  PubMed  CAS  Google Scholar 

  • Kastin AJ, Akerstrom V, Pan W (2001) Validity of multiple-time regression analysis in measurement of tritiated and iodinated leptin crossing the blood-brain barrier: meaningful controls. Peptides 22:2127–2136

    Article  PubMed  CAS  Google Scholar 

  • Katano H, Fujita K, Kato T, Asai K, Kawamura Y, Masago A, Yamada K (1999) Traumatic injury in vitro induces IEG mRNAs in cultured glial cells, suppressed by co-culture with neurons. NeuroReport 10:2439–2448

    Article  PubMed  CAS  Google Scholar 

  • Kibayashi E, Urakaze M, Kobashi C, Kishida M, Takata M, Sato A, Yamazaki K, Kobayashi M (2005) Inhibitory effect of pitavastatin (NK-104) on the C-reactive-protein-induced interleukin-8 production in human aortic endothelial cells. Clin Sci Lond 108:515–521

    Article  PubMed  CAS  Google Scholar 

  • Kornyei Z, Czirok A, Vicsek T, Madarasz E (2000) Proliferative and migratory responses of astrocytes to in vitro injury. J Neurosci Res 61:421–429

    Article  PubMed  CAS  Google Scholar 

  • Lafrance V, Inoue W, Kan B, Luheshi GN (2010) Leptin modulates cell morphology and cytokine release in microglia. Brain Behav Immun 24:358–365

    Article  PubMed  CAS  Google Scholar 

  • Langdon KD, Clarke J, Corbett D (2011) Long-term exposure to high fat diet is bad for your brain: exacerbation of focal ischemic brain injury. Neuroscience 182:82–87

    Article  PubMed  CAS  Google Scholar 

  • Lau LT, Yu AC (2001) Astrocytes produce and release interleukin-1, interleukin-6, tumor necrosis factor alpha and interferon-gamma following traumatic and metabolic injury. J Neurotrauma 18:351–359

    Article  PubMed  CAS  Google Scholar 

  • Lavin DN, Joesting JJ, Chiu GS, Moon ML, Meng J, Dilger RN, Freund GG (2011) Fasting induces an anti-inflammatory effect on the neuroimmune system which a high-fat diet prevents. Obes Silver Spring 19:1586–1594

    Article  CAS  Google Scholar 

  • Magdalena J, Millard TH, Etienne-Manneville S, Launay S, Warwick HK, Machesky LM (2003) Involvement of the Arp2/3 complex and Scar2 in Golgi polarity in scratch wound models. Mol Biol Cell 14:670–684

    Article  PubMed  CAS  Google Scholar 

  • Mahajan N, Bahl A, Dhawan V (2010) C-reactive protein (CRP) up-regulates expression of receptor for advanced glycation end products (RAGE) and its inflammatory ligand EN-RAGE in THP-1 cells: inhibitory effects of atorvastatin. Int J Cardiol 142:273–278

    Article  PubMed  Google Scholar 

  • Malhotra SK, Luong LT, Bhatnagar R, Shnitka TK (1997) Up-regulation of reactive astrogliosis in the rat glioma 9L cell line by combined mechanical and chemical injuries. Cytobios 89:115–134

    PubMed  CAS  Google Scholar 

  • Marnell L, Mold C, Du Clos TW (2005) C-reactive protein: ligands, receptors and role in inflammation. Clin Immunol 117:104–111

    Article  PubMed  CAS  Google Scholar 

  • Mattace RG, Esposito E, Iacono A, Pacilio M, Coppola A, Bianco G, Diano S, Di Carlo R, Meli R (2006) Leptin induces nitric oxide synthase type II in C6 glioma cells. Role for nuclear factor-kappaB in hormone effect. Neurosci Lett 396:121–126

    Article  Google Scholar 

  • Ohnishi S, Maeda S, Nishiguchi S, Arao T, Shimada K (1988) Structure of the mouse C-reactive protein gene. Biochem Biophys Res Commun 156:814–822

    Article  PubMed  CAS  Google Scholar 

  • Pan W, Kastin AJ (2007) Adipokines and the blood-brain barrier. Peptides 28:1317–1330

    Article  PubMed  CAS  Google Scholar 

  • Pan W, Tu H, Hsuchou H, Daniel J, Kastin AJ (2007) Unexpected amplification of leptin-induced Stat3 signaling by urocortin: implications for obesity. J Mol Neurosci 33:232–238

    Article  PubMed  CAS  Google Scholar 

  • Pan W, Hsuchou H, He Y, Sakharkar A, Cain C, Yu C, Kastin AJ (2008) Astrocyte leptin receptor (ObR) and leptin transport in adult-onset obese mice. Endocrinology 149:2798–2806

    Article  PubMed  CAS  Google Scholar 

  • Pan W, Hsuchou H, He Y, Kastin AJ (2011) Glial leptin receptors and obesity. In: Preedy VR (ed) Modern insights into disease from molecules to man: Adipokines. Science Publishers, Enfield, pp 185–196

    Google Scholar 

  • Pan W, Hsuchou H, Jayaram B, Khan RS, Huang EYK, Wu X, Chen C, Kastin AJ (2012) Leptin action on non-neuronal cells in the CNS: potential clinical implications. Ann N Y Acad Sci. In press

  • Peisajovich A, Marnell L, Mold C, Du Clos TW (2008) C-reactive protein at the interface between innate immunity and inflammation. Expert Rev Clin Immunol 4:379–390

    Article  PubMed  CAS  Google Scholar 

  • Pepys MB (1981) C-reactive protein fifty years on. Lancet 1:653–657

    Article  PubMed  CAS  Google Scholar 

  • Pinteaux E, Inoue W, Schmidt L, Molina-Holgado F, Rothwell NJ, Luheshi GN (2007) Leptin induces interleukin-1beta release from rat microglial cells through a caspase 1 independent mechanism. J Neurochem 102:826–833

    Article  PubMed  CAS  Google Scholar 

  • Raji CA, Ho AJ, Parikshak NN, Becker JT, Lopez OL, Kuller LH, Hua X, Leow AD, Toga AW, Thompson PM (2010) Brain structure and obesity. Hum Brain Mapp 31:353–364

    PubMed  Google Scholar 

  • Streit WJ (2002) Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40:133–139

    Article  PubMed  Google Scholar 

  • Tang H, Fu WY, Ip NY (2000) Altered expression of tissue-type plasminogen activator and type 1 inhibitor in astrocytes of mouse cortex following scratch injury in culture. Neurosci Lett 285:143–146

    Article  PubMed  CAS  Google Scholar 

  • Tang CH, Lu DY, Yang RS, Tsai HY, Kao MC, Fu WM, Chen YF (2007) Leptin-induced IL-6 production is mediated by leptin receptor, insulin receptor substrate-1, phosphatidylinositol 3-kinase, Akt, NF-kappaB, and p300 pathway in microglia. J Immunol 179:1292–1302

    PubMed  CAS  Google Scholar 

  • Tapanainen P, Leinonen E, Ruokonen A, Knip M (2001) Leptin concentrations are elevated in newborn infants of diabetic mothers. Horm Res 55:185–190

    Article  PubMed  CAS  Google Scholar 

  • Tikka TM, Koistinaho JE (2001) Minocycline provides neuroprotection against N-methyl-d-aspartate neurotoxicity by inhibiting microglia. J Immunol 166:7527–7533

    PubMed  CAS  Google Scholar 

  • Walther K, Birdsill AC, Glisky EL, Ryan L (2010) Structural brain differences and cognitive functioning related to body mass index in older females. Hum Brain Mapp 31:1052–1064

    Article  PubMed  Google Scholar 

  • Wu X, Kastin AJ, He Y, Hsuchou H, Rood JC, Pan W (2010) Essential role of interleukin-15 receptor in normal anxiety behavior. Brain Behav Immun 24:1340–1346

    Article  PubMed  CAS  Google Scholar 

  • Yang H, Cheng XP, Li JW, Yao Q, Ju G (2009) De-differentiation response of cultured astrocytes to injury induced by scratch or conditioned culture medium of scratch-insulted astrocytes. Cell Mol Neurobiol 29:455–473

    Article  PubMed  Google Scholar 

  • Yu AC, Lee YL, Eng LF (1993) Astrogliosis in culture: I. The model and the effect of antisense oligonucleotides on glial fibrillary acidic protein synthesis. J Neurosci Res 34:295–303

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Wu X, He Y, Kastin AJ, Hsuchou H, Rosenblum CI, Pan W (2009) Melanocortin potentiates leptin-induced STAT3 signaling via MAPK pathway. J Neurochem 110:390–399

    Article  PubMed  CAS  Google Scholar 

  • Zhang D, Hu X, Qian L, O'Callaghan JP, Hong JS (2010) Astrogliosis in CNS pathologies: is there a role for microglia? Mol Neurobiol 41:232–241

    Article  PubMed  Google Scholar 

  • Zhao XQ, Zhang MW, Wang F, Zhao YX, Li JJ, Wang XP, Bu PL, Yang JM, Liu XL, Zhang MX, Gao F, Zhang C, Zhang Y (2011) CRP enhances soluble LOX-1 release from macrophages by activating TNF-alpha converting enzyme. J Lipid Res 52:923–933

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Grant support was provided by NIH (DK54880 and DK92245 to AJK and NS62291 to WP.

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  1. Blood-Brain Barrier Group, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA, 70808, USA

    Hung Hsuchou, Abba J. Kastin & Weihong Pan

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  1. Hung Hsuchou
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  2. Abba J. Kastin
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  3. Weihong Pan
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Correspondence to Abba J. Kastin.

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Hsuchou, H., Kastin, A.J. & Pan, W. Blood-Borne Metabolic Factors in Obesity Exacerbate Injury-Induced Gliosis. J Mol Neurosci 47, 267–277 (2012). https://doi.org/10.1007/s12031-012-9734-4

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  • DOI: https://doi.org/10.1007/s12031-012-9734-4

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