Metabolic and Inflammatory Adaptation of Reactive Astrocytes: Role of PPARs

Molecular Neurobiology

Volumn 54, Issue 4, 2017, Pages 2518-2538

  Iglesias, José ^a   Morales, Ludis ^a   Barreto, George E ^a,b,c  

^a PONTIFICIA UNIVERSIDAD JAVERIANA   (Colombia)

^b UNIVERSIDAD AUTÓNOMA DE CHILE   (Chile)

^c UNIVERSIDAD CIENTÍFICA DEL SUR   (Peru)

Author keywords

Astrogliosis; Fatty acid oxidation; Glutamate; Glycolysis; Ketone bodies; Neuroprotection; PPAR

Indexed keywords

GLUCOSE; GLUTAMIC ACID; GLUTAMINE; LACTIC ACID; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR DELTA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA;

ASTROCYTE; ASTROCYTOSIS; CELL INTERACTION; CELL METABOLISM; CELL STRUCTURE; DEGENERATIVE DISEASE; FATTY ACID METABOLISM; GLIOSIS; GLUTAMATE GLUTAMINE CYCLE; HUMAN; ISCHEMIA; MACROGLIA; MICROGLIA; MODULATION; NERVOUS SYSTEM INFLAMMATION; NONHUMAN; PROTEIN FUNCTION; REVIEW; ANIMAL; BIOLOGICAL MODEL; INFLAMMATION; METABOLISM; PATHOLOGY;

ANIMALS; ASTROCYTES; GLIOSIS; HUMANS; INFLAMMATION; MODELS, BIOLOGICAL; PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS;

EID: 84961213535     PISSN: 08937648     EISSN: 15591182     Source Type: Journal    
DOI: 10.1007/s12035-016-9833-2     Document Type: Review

References (267)

1. Perea G, Sur M, Araque A (2014) Neuron-glia networks: integral gear of brain function. Front Cell Neurosci 8:378. doi:10.3389/fncel.2014.00378
2. Perez-Alvarez A, Araque A (2013) Astrocyte-neuron interaction at tripartite synapses. Curr Drug Targets 14(11):1220–1224
3. Navarrete M, Araque A (2011) Basal synaptic transmission: astrocytes rule! Cell 146(5):675–677. doi:10.1016/j.cell.2011.08.006
4. Perea G, Navarrete M, Araque A (2009) Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 32(8):421–431. doi:10.1016/j.tins.2009.05.001
5. Barreto GE, Gonzalez J, Torres Y, Morales L (2011) Astrocytic-neuronal crosstalk: implications for neuroprotection from brain injury. Neurosci Res 71(2):107–113. doi:10.1016/j.neures.2011.06.004
6. Brown AM, Ransom BR (2007) Astrocyte glycogen and brain energy metabolism. Glia 55(12):1263–1271. doi:10.1002/glia.20557
7. Tekkok SB, Brown AM, Westenbroek R, Pellerin L, Ransom BR (2005) Transfer of glycogen-derived lactate from astrocytes to axons via specific monocarboxylate transporters supports mouse optic nerve activity. J Neurosci Res 81(5):644–652. doi:10.1002/jnr.20573
8. Posada-Duque RA, Barreto GE, Cardona-Gomez GP (2014) Protection after stroke: cellular effectors of neurovascular unit integrity. Front Cell Neurosci 8:231. doi:10.3389/fncel.2014.00231
9. Cabezas R, Avila M, Gonzalez J, El-Bacha RS, Baez E, Garcia-Segura LM, Jurado Coronel JC, Capani F et al (2014) Astrocytic modulation of blood brain barrier: perspectives on Parkinson’s disease. Front Cell Neurosci 8:211. doi:10.3389/fncel.2014.00211
10. Barreto G, White RE, Ouyang Y, Xu L, Giffard RG (2011) Astrocytes: targets for neuroprotection in stroke. Cent Nerv Syst Agents Med Chem 11(2):164–173
11. Cabezas R, El-Bacha RS, Gonzalez J, Barreto GE (2012) Mitochondrial functions in astrocytes: neuroprotective implications from oxidative damage by rotenone. Neurosci Res 74(2):80–90. doi:10.1016/j.neures.2012.07.008
12. Correa F, Mallard C, Nilsson M, Sandberg M (2011) Activated microglia decrease histone acetylation and Nrf2-inducible anti-oxidant defence in astrocytes: restoring effects of inhibitors of HDACs, p38 MAPK and GSK3beta. Neurobiol Dis 44(1):142–151. doi:10.1016/j.nbd.2011.06.016
13. Deng YY, Lu J, Ling EA, Kaur C (2010) Microglia-derived macrophage colony stimulating factor promotes generation of proinflammatory cytokines by astrocytes in the periventricular white matter in the hypoxic neonatal brain. Brain Pathol 20(5):909–925. doi:10.1111/j.1750-3639.2010.00387.x
14. Chen SH, Oyarzabal EA, Sung YF, Chu CH, Wang Q, Chen SL, Lu RB, Hong JS (2015) Microglial regulation of immunological and neuroprotective functions of astroglia. Glia 63(1):118–131. doi:10.1002/glia.22738
15. Drew PD, Xu J, Storer PD, Chavis JA, Racke MK (2006) Peroxisome proliferator-activated receptor agonist regulation of glial activation: relevance to CNS inflammatory disorders. Neurochem Int 49(2):183–189. doi:10.1016/j.neuint.2006.04.003
16. Verkhratsky ABA (2013) Glial physiology and pathophysiology. Wiley, Hoboken, pp 453–504
17. Schitine C, Nogaroli L, Costa MR, Hedin-Pereira C (2015) Astrocyte heterogeneity in the brain: from development to disease. Front Cell Neurosci 9:76. doi:10.3389/fncel.2015.00076
18. Pekny M, Pekna M (2014) Astrocyte reactivity and reactive astrogliosis: costs and benefits. Physiol Rev 94(4):1077–1098. doi:10.1152/physrev.00041.2013
19. Barreto GE, White RE, Xu L, Palm CJ, Giffard RG (2012) Effects of heat shock protein 72 (Hsp72) on evolution of astrocyte activation following stroke in the mouse. Exp Neurol 238(2):284–296. doi:10.1016/j.expneurol.2012.08.015
20. Barreto GE, Sun X, Xu L, Giffard RG (2011) Astrocyte proliferation following stroke in the mouse depends on distance from the infarct. PLoS One 6(11), e27881. doi:10.1371/journal.pone.0027881
21. Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, Xing Y, Lubischer JL et al (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28(1):264–278. doi:10.1523/JNEUROSCI.4178-07.2008
22. Bachoo RM, Kim RS, Ligon KL, Maher EA, Brennan C, Billings N, Chan S, Li C et al (2004) Molecular diversity of astrocytes with implications for neurological disorders. Proc Natl Acad Sci U S A 101(22):8384–8389. doi:10.1073/pnas.0402140101
23. Höft S, Griemsmann S, Seifert G, Steinhäuser C (2014) Heterogeneity in expression of functional ionotropic glutamate and GABA receptors in astrocytes across brain regions: insights from the thalamus. Philos Trans R Soc Lond B Biol Sci 369(1654):20130602. doi:10.1098/rstb.2013.0602
24. Burda JE, Sofroniew MV (2014) Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 81(2):229–248. doi:10.1016/j.neuron.2013.12.034
25. Barreto GE, Black JA (2014) Introduction. Astrocytes in the injured brain: is gliosis adaptive or maladaptive? Neurosci Lett 565:1. doi:10.1016/j.neulet.2014.01.052
26. Romero J, Muniz J, Logica Tornatore T, Holubiec M, Gonzalez J, Barreto GE, Guelman L, Lillig CH et al (2014) Dual role of astrocytes in perinatal asphyxia injury and neuroprotection. Neurosci Lett 565:42–46. doi:10.1016/j.neulet.2013.10.046
27. Barreto G, Santos-Galindo M, Diz-Chaves Y, Pernia O, Carrero P, Azcoitia I, Garcia-Segura LM (2009) Selective estrogen receptor modulators decrease reactive astrogliosis in the injured brain: effects of aging and prolonged depletion of ovarian hormones. Endocrinology 150(11):5010–5015. doi:10.1210/en.2009-0352
28. Barreto G, Veiga S, Azcoitia I, Garcia-Segura LM, Garcia-Ovejero D (2007) Testosterone decreases reactive astroglia and reactive microglia after brain injury in male rats: role of its metabolites, oestradiol and dihydrotestosterone. Eur J Neurosci 25(10):3039–3046. doi:10.1111/j.1460-9568.2007.05563.x
29. Koyama Y (2014) Signaling molecules regulating phenotypic conversions of astrocytes and glial scar formation in damaged nerve tissues. Neurochem Int 78:35–42. doi:10.1016/j.neuint.2014.08.005
30. Wanner IB, Anderson MA, Song B, Levine J, Fernandez A, Gray-Thompson Z, Ao Y, Sofroniew MV (2013) Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury. J Neurosci 33(31):12870–12886. doi:10.1523/JNEUROSCI.2121-13.2013
31. Li H, Zhang N, Lin HY, Yu Y, Cai QY, Ma L, Ding S (2014) Histological, cellular and behavioral assessments of stroke outcomes after photothrombosis-induced ischemia in adult mice. BMC Neurosci 15:58. doi:10.1186/1471-2202-15-58
32. Ding S (2014) Dynamic reactive astrocytes after focal ischemia. Neural Regen Res 9(23):2048–2052. doi:10.4103/1673-5374.147929
33. Li CY, Li X, Liu SF, Qu WS, Wang W, Tian DS (2015) Inhibition of mTOR pathway restrains astrocyte proliferation, migration and production of inflammatory mediators after oxygen-glucose deprivation and reoxygenation. Neurochem Int 83–84:9–18. doi:10.1016/j.neuint.2015.03.001
34. Bardehle S, Krüger M, Buggenthin F, Schwausch J, Ninkovic J, Clevers H, Snippert HJ, Theis FJ et al (2013) Live imaging of astrocyte responses to acute injury reveals selective juxtavascular proliferation. Nat Neurosci 16(5):580–586. doi:10.1038/nn.3371
35. Anderson MA, Ao Y, Sofroniew MV (2014) Heterogeneity of reactive astrocytes. Neurosci Lett 565:23–29. doi:10.1016/j.neulet.2013.12.030
36. Burda JE, Bernstein AM, Sofroniew MV (2015) Astrocyte roles in traumatic brain injury. Exp Neurol. doi:10.1016/j.expneurol.2015.03.020
37. Franke H, Illes P (2014) Nucleotide signaling in astrogliosis. Neurosci Lett 565:14–22. doi:10.1016/j.neulet.2013.09.056
38. Joiner TE, Lewinsohn PM, Seeley JR (2002) The core of loneliness: lack of pleasurable engagement—more so than painful disconnection—predicts social impairment, depression onset, and recovery from depressive disorders among adolescents. J Pers Assess 79(3):472–491. doi:10.1207/S15327752JPA7903_05
39. 2+ signal alterations in astrocytes from Niemann-Pick type C mice. PLoS One 8(8), e71361. doi:10.1371/journal.pone.0071361
40. Hamby ME, Coppola G, Ao Y, Geschwind DH, Khakh BS, Sofroniew MV (2012) Inflammatory mediators alter the astrocyte transcriptome and calcium signaling elicited by multiple G-protein-coupled receptors. J Neurosci 32(42):14489–14510. doi:10.1523/JNEUROSCI.1256-12.2012
41. Hol EM, Pekny M (2015) Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system. Curr Opin Cell Biol 32:121–130. doi:10.1016/j.ceb.2015.02.004
42. Middeldorp J, Hol EM (2011) GFAP in health and disease. Prog Neurobiol 93(3):421–443. doi:10.1016/j.pneurobio.2011.01.005
43. Bramanti V, Tomassoni D, Avitabile M, Amenta F, Avola R (2010) Biomarkers of glial cell proliferation and differentiation in culture. Front Biosci (Schol Ed) 2:558–570
44. Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, Barres BA (2012) Genomic analysis of reactive astrogliosis. J Neurosci 32(18):6391–6410. doi:10.1523/JNEUROSCI.6221-11.2012
45. Jha MK, Seo M, Kim JH, Kim BG, Cho JY, Suk K (2013) The secretome signature of reactive glial cells and its pathological implications. Biochim Biophys Acta 1834(11):2418–2428. doi:10.1016/j.bbapap.2012.12.006
46. Cabezas R, Avila-Rodriguez M, Vega-Vela NE, Echeverria V, Gonzalez J, Hidalgo OA, Santos AB, Aliev G, Barreto GE (2015) Growth factors and astrocytic metabolism: possible roles for platelet derived growth factor. Med Chem
47. Wilhelmsson U, Li L, Pekna M, Berthold CH, Blom S, Eliasson C, Renner O, Bushong E et al (2004) Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. J Neurosci 24(21):5016–5021. doi:10.1523/JNEUROSCI.0820-04.2004
48. Properzi F, Carulli D, Asher RA, Muir E, Camargo LM, van Kuppevelt TH, ten Dam GB, Furukawa Y et al (2005) Chondroitin 6-sulphate synthesis is up-regulated in injured CNS, induced by injury-related cytokines and enhanced in axon-growth inhibitory glia. Eur J Neurosci 21(2):378–390. doi:10.1111/j.1460-9568.2005.03876.x
49. Laabs TL, Wang H, Katagiri Y, McCann T, Fawcett JW, Geller HM (2007) Inhibiting glycosaminoglycan chain polymerization decreases the inhibitory activity of astrocyte-derived chondroitin sulfate proteoglycans. J Neurosci 27(52):14494–14501. doi:10.1523/JNEUROSCI.2807-07.2007
50. Kwok JC, Heller JP, Zhao RR, Fawcett JW (2014) Targeting inhibitory chondroitin sulphate proteoglycans to promote plasticity after injury. Methods Mol Biol 1162:127–138. doi:10.1007/978-1-4939-0777-9_10
51. Vorobyov V, Kwok JC, Fawcett JW, Sengpiel F (2013) Effects of digesting chondroitin sulfate proteoglycans on plasticity in cat primary visual cortex. J Neurosci 33(1):234–243. doi:10.1523/JNEUROSCI.2283-12.2013
52. Ashwell K (1990) Microglia and cell death in the developing mouse cerebellum. Brain Res Dev Brain Res 55(2):219–230
53. Ellison JA, de Vellis J (1995) Amoeboid microglia expressing GD3 ganglioside are concentrated in regions of oligodendrogenesis during development of the rat corpus callosum. Glia 14(2):123–132. doi:10.1002/glia.440140207
54. Innocenti GM, Clarke S, Koppel H (1983) Transitory macrophages in the white matter of the developing visual cortex. II. Development and relations with axonal pathways. Brain Res 313(1):55–66
55. Giulian D, Young DG, Woodward J, Brown DC, Lachman LB (1988) Interleukin-1 is an astroglial growth factor in the developing brain. J Neurosci 8(2):709–714
56. Aloisi F (2001) Immune function of microglia. Glia 36(2):165–179
57. Becher B, Prat A, Antel JP (2000) Brain-immune connection: immuno-regulatory properties of CNS-resident cells. Glia 29(4):293–304
58. Inoue K (2002) Microglial activation by purines and pyrimidines. Glia 40(2):156–163. doi:10.1002/glia.10150
59. Khanna R, Roy L, Zhu X, Schlichter LC (2001) K+ channels and the microglial respiratory burst. Am J Physiol Cell Physiol 280(4):C796–C806
60. Klein MA, Moller JC, Jones LL, Bluethmann H, Kreutzberg GW, Raivich G (1997) Impaired neuroglial activation in interleukin-6 deficient mice. Glia 19(3):227–233
61. Moller T, Hanisch UK, Ransom BR (2000) Thrombin-induced activation of cultured rodent microglia. J Neurochem 75(4):1539–1547
62. Moller T, Nolte C, Burger R, Verkhratsky A, Kettenmann H (1997) Mechanisms of C5a and C3a complement fragment-induced [Ca2+]i signaling in mouse microglia. J Neurosci 17(2):615–624
63. Del Río-Hortega P (1919) El tercer elemento de los centros nerviosos. Bol Soc Esp Biol 9:69–120
64. Del Río-Hortega P (1920) La microglía y su transformación en células en bastoncito y cuerpos gránulo-adiposos. Trab Lab Invest Biol 18:37–82
65. Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39(1):151–170
66. Finsen BR, Jorgensen MB, Diemer NH, Zimmer J (1993) Microglial MHC antigen expression after ischemic and kainic acid lesions of the adult rat hippocampus. Glia 7(1):41–49. doi:10.1002/glia.440070109
67. Jensen MB, Finsen B, Zimmer J (1997) Morphological and immunophenotypic microglial changes in the denervated fascia dentata of adult rats: correlation with blood–brain barrier damage and astroglial reactions. Exp Neurol 143(1):103–116. doi:10.1006/exnr.1996.6337
68. Jorgensen MB, Finsen BR, Jensen MB, Castellano B, Diemer NH, Zimmer J (1993) Microglial and astroglial reactions to ischemic and kainic acid-induced lesions of the adult rat hippocampus. Exp Neurol 120(1):70–88. doi:10.1006/exnr.1993.1041
69. Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19(8):312–318
70. Barreto GE, Santos-Galindo M, Garcia-Segura LM (2014) Selective estrogen receptor modulators regulate reactive microglia after penetrating brain injury. Front Aging Neurosci 6:132. doi:10.3389/fnagi.2014.00132
71. Simard AR, Rivest S (2007) Neuroprotective effects of resident microglia following acute brain injury. J Comp Neurol 504(6):716–729. doi:10.1002/cne.21469
72. Polazzi E, Contestabile A (2002) Reciprocal interactions between microglia and neurons: from survival to neuropathology. Rev Neurosci 13(3):221–242
73. Polazzi E, Gianni T, Contestabile A (2001) Microglial cells protect cerebellar granule neurons from apoptosis: evidence for reciprocal signaling. Glia 36(3):271–280
74. Zhao W, Xie W, Xiao Q, Beers DR, Appel SH (2006) Protective effects of an anti-inflammatory cytokine, interleukin-4, on motoneuron toxicity induced by activated microglia. J Neurochem 99(4):1176–1187. doi:10.1111/j.1471-4159.2006.04172.x
75. Mason JL, Suzuki K, Chaplin DD, Matsushima GK (2001) Interleukin-1beta promotes repair of the CNS. J Neurosci 21(18):7046–7052
76. Chamak B, Morandi V, Mallat M (1994) Brain macrophages stimulate neurite growth and regeneration by secreting thrombospondin. J Neurosci Res 38(2):221–233. doi:10.1002/jnr.490380213
77. Heumann R, Lindholm D, Bandtlow C, Meyer M, Radeke MJ, Misko TP, Shooter E, Thoenen H (1987) Differential regulation of mRNA encoding nerve growth factor and its receptor in rat sciatic nerve during development, degeneration, and regeneration: role of macrophages. Proc Natl Acad Sci U S A 84(23):8735–8739
78. Lai AY, Todd KG (2008) Differential regulation of trophic and proinflammatory microglial effectors is dependent on severity of neuronal injury. Glia 56(3):259–270. doi:10.1002/glia.20610
79. Wang P, Rothwell NJ, Pinteaux E, Brough D (2008) Neuronal injury induces the release of pro-interleukin-1beta from activated microglia in vitro. Brain Res 1236:1–7. doi:10.1016/j.brainres.2008.08.001
80. Xiong X, Barreto GE, Xu L, Ouyang YB, Xie X, Giffard RG (2011) Increased brain injury and worsened neurological outcome in interleukin-4 knockout mice after transient focal cerebral ischemia. Stroke 42(7):2026–2032. doi:10.1161/STROKEAHA.110.593772
81. Xiong X, Xu L, Wei L, White RE, Ouyang YB, Giffard RG (2015) IL-4 is required for sex differences in vulnerability to focal ischemia in mice. Stroke. doi:10.1161/STROKEAHA.115.008897
82. Bruce-Keller AJ (1999) Microglial-neuronal interactions in synaptic damage and recovery. J Neurosci Res 58(1):191–201
83. Juliet PA, Mao X, Del Bigio MR (2008) Proinflammatory cytokine production by cultured neonatal rat microglia after exposure to blood products. Brain Res 1210:230–239. doi:10.1016/j.brainres.2008.02.099
84. Sawada M, Suzumura A, Marunouchi T (1995) Cytokine network in the central nervous system and its roles in growth and differentiation of glial and neuronal cells. Int J Dev Neurosci 13(3–4):253–264
85. Cheng B, Christakos S, Mattson MP (1994) Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis. Neuron 12(1):139–153
86. Minghetti L, Levi G (1998) Microglia as effector cells in brain damage and repair: focus on prostanoids and nitric oxide. Prog Neurobiol 54(1):99–125
87. Prewitt CM, Niesman IR, Kane CJ, Houle JD (1997) Activated macrophage/microglial cells can promote the regeneration of sensory axons into the injured spinal cord. Exp Neurol 148(2):433–443. doi:10.1006/exnr.1997.6694
88. Cadelli DS, Bandtlow CE, Schwab ME (1992) Oligodendrocyte- and myelin-associated inhibitors of neurite outgrowth: their involvement in the lack of CNS regeneration. Exp Neurol 115(1):189–192
89. Frisen J, Haegerstrand A, Fried K, Piehl F, Cullheim S, Risling M (1994) Adhesive/repulsive properties in the injured spinal cord: relation to myelin phagocytosis by invading macrophages. Exp Neurol 129(2):183–193. doi:10.1006/exnr.1994.1160
90. Lotan M, Solomon A, Ben-Bassat S, Schwartz M (1994) Cytokines modulate the inflammatory response and change permissiveness to neuronal adhesion in injured mammalian central nervous system. Exp Neurol 126(2):284–290. doi:10.1006/exnr.1994.1066
91. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P et al (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21(3):383–421
92. McGeer PL, McGeer EG (2001) Inflammation, autotoxicity and Alzheimer disease. Neurobiol Aging 22(6):799–809
93. Streit WJ (2002) Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40(2):133–139. doi:10.1002/glia.10154
94. Streit WJ, Sammons NW, Kuhns AJ, Sparks DL (2004) Dystrophic microglia in the aging human brain. Glia 45(2):208–212. doi:10.1002/glia.10319
95. Banati RB, Gehrmann J, Schubert P, Kreutzberg GW (1993) Cytotoxicity of microglia. Glia 7(1):111–118. doi:10.1002/glia.440070117
96. Giulian D, Vaca K, Noonan CA (1990) Secretion of neurotoxins by mononuclear phagocytes infected with HIV-1. Science 250(4987):1593–1596
97. Nakajima K, Tohyama Y, Maeda S, Kohsaka S, Kurihara T (2007) Neuronal regulation by which microglia enhance the production of neurotrophic factors for GABAergic, catecholaminergic, and cholinergic neurons. Neurochem Int 50(6):807–820. doi:10.1016/j.neuint.2007.02.006
98. Yawata I, Takeuchi H, Doi Y, Liang J, Mizuno T, Suzumura A (2008) Macrophage-induced neurotoxicity is mediated by glutamate and attenuated by glutaminase inhibitors and gap junction inhibitors. Life Sci 82(21–22):1111–1116. doi:10.1016/j.lfs.2008.03.010
99. Skripuletz T, Hackstette D, Bauer K, Gudi V, Pul R, Voss E, Berger K, Kipp M et al (2013) Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination. Brain: J Neurol 136(Pt 1):147–167. doi:10.1093/brain/aws262
100. Xu J, Drew PD (2007) Peroxisome proliferator-activated receptor-gamma agonists suppress the production of IL-12 family cytokines by activated glia. J Immunol 178(3):1904–1913
101. Tsacopoulos M, Veuthey AL, Saravelos SG, Perrottet P, Tsoupras G (1994) Glial cells transform glucose to alanine, which fuels the neurons in the honeybee retina. J Neurosci 14(3 Pt 1):1339–1351
102. Walz W, Mukerji S (1988) Lactate release from cultured astrocytes and neurons: a comparison. Glia 1(6):366–370. doi:10.1002/glia.440010603
103. Allaman I, Bélanger M, Magistretti PJ (2015) Methylglyoxal, the dark side of glycolysis. Front Neurosci 9:23. doi:10.3389/fnins.2015.00023
104. Chuquet J, Quilichini P, Nimchinsky EA, Buzsáki G (2010) Predominant enhancement of glucose uptake in astrocytes versus neurons during activation of the somatosensory cortex. J Neurosci 30(45):15298–15303. doi:10.1523/JNEUROSCI.0762-10.2010
105. Hertz L, Peng L, Dienel GA (2007) Energy metabolism in astrocytes: high rate of oxidative metabolism and spatiotemporal dependence on glycolysis/glycogenolysis. J Cereb Blood Flow Metab 27(2):219–249. doi:10.1038/sj.jcbfm.9600343
106. Nehlig A, Wittendorp-Rechenmann E, Lam CD (2004) Selective uptake of [14C]2-deoxyglucose by neurons and astrocytes: high-resolution microautoradiographic imaging by cellular 14C-trajectography combined with immunohistochemistry. J Cereb Blood Flow Metab 24(9):1004–1014. doi:10.1097/01.WCB.0000128533.84196.D8
107. Barros LF, Deitmer JW (2010) Glucose and lactate supply to the synapse. Brain Res Rev 63(1–2):149–159. doi:10.1016/j.brainresrev.2009.10.002
108. Benarroch EE (2014) Brain glucose transporters: implications for neurologic disease. Neurology 82(15):1374–1379. doi:10.1212/WNL.0000000000000328
109. Cunnane S, Nugent S, Roy M, Courchesne-Loyer A, Croteau E, Tremblay S, Castellano A, Pifferi F et al (2011) Brain fuel metabolism, aging, and Alzheimer’s disease. Nutrition 27(1):3–20. doi:10.1016/j.nut.2010.07.021
110. García M, Millán C, Balmaceda-Aguilera C, Castro T, Pastor P, Montecinos H, Reinicke K, Zúñiga F et al (2003) Hypothalamic ependymal-glial cells express the glucose transporter GLUT2, a protein involved in glucose sensing. J Neurochem 86(3):709–724
111. Thorens B (2015) GLUT2, glucose sensing and glucose homeostasis. Diabetologia 58(2):221–232. doi:10.1007/s00125-014-3451-1
112. Berkich DA, Ola MS, Cole J, Sweatt AJ, Hutson SM, LaNoue KF (2007) Mitochondrial transport proteins of the brain. J Neurosci Res 85(15):3367–3377. doi:10.1002/jnr.21500
113. Bouzier-Sore AK, Pellerin L (2013) Unraveling the complex metabolic nature of astrocytes. Front Cell Neurosci 7:179. doi:10.3389/fncel.2013.00179
114. Sun X, Voloboueva LA, Stary CM, Giffard RG (2015) Physiologically normal 5% O supports neuronal differentiation and resistance to inflammatory injury in neural stem cell cultures. J Neurosci Res. doi:10.1002/jnr.23615
115. Pellerin L, Magistretti PJ (2012) Sweet sixteen for ANLS. J Cereb Blood Flow Metab 32(7):1152–1166. doi:10.1038/jcbfm.2011.149
116. DiNuzzo M, Maraviglia B, Giove F (2011) Why does the brain (not) have glycogen? Bioessays 33(5):319–326. doi:10.1002/bies.201000151
117. DiNuzzo M, Mangia S, Maraviglia B, Giove F (2013) Regulatory mechanisms for glycogenolysis and K+ uptake in brain astrocytes. Neurochem Int 63(5):458–464. doi:10.1016/j.neuint.2013.08.004
118. Amaral AI, Teixeira AP, Håkonsen BI, Sonnewald U, Alves PM (2011) A comprehensive metabolic profile of cultured astrocytes using isotopic transient metabolic flux analysis and C-labeled glucose. Front Neuroenerg 3:5. doi:10.3389/fnene.2011.00005
119. Dienel GA (2013) Astrocytic energetics during excitatory neurotransmission: what are contributions of glutamate oxidation and glycolysis? Neurochem Int 63(4):244–258. doi:10.1016/j.neuint.2013.06.015
120. Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65(1):1–105
121. Nakagawa T, Kaneko S (2013) SLC1 glutamate transporters and diseases: psychiatric diseases and pathological pain. Curr Mol Pharmacol 6(2):66–73
122. Martinez-Hernandez A, Bell KP, Norenberg MD (1977) Glutamine synthetase: glial localization in brain. Science 195(4284):1356–1358
123. Morken TS, Brekke E, Håberg A, Widerøe M, Brubakk AM, Sonnewald U (2014) Neuron-astrocyte interactions, pyruvate carboxylation and the pentose phosphate pathway in the neonatal rat brain. Neurochem Res 39(3):556–569. doi:10.1007/s11064-013-1014-3
124. Pardo B, Contreras L, Satrústegui J (2013) De novo synthesis of glial glutamate and glutamine in young mice requires aspartate provided by the neuronal mitochondrial aspartate-glutamate carrier Aralar/AGC1. Front Endocrinol (Lausanne) 4:149. doi:10.3389/fendo.2013.00149
125. McKenna MC, Sonnewald U, Huang X, Stevenson J, Zielke HR (1996) Exogenous glutamate concentration regulates the metabolic fate of glutamate in astrocytes. J Neurochem 66(1):386–393
126. Frigerio F, Karaca M, De Roo M, Mlynárik V, Skytt DM, Carobbio S, Pajęcka K, Waagepetersen HS et al (2012) Deletion of glutamate dehydrogenase 1 (Glud1) in the central nervous system affects glutamate handling without altering synaptic transmission. J Neurochem 123(3):342–348. doi:10.1111/j.1471-4159.2012.07933.x
127. Shank RP, Bennett GS, Freytag SO, Campbell GL (1985) Pyruvate carboxylase: an astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools. Brain Res 329(1–2):364–367
128. Waagepetersen HS, Qu H, Schousboe A, Sonnewald U (2001) Elucidation of the quantitative significance of pyruvate carboxylation in cultured cerebellar neurons and astrocytes. J Neurosci Res 66(5):763–770
129. Pardo B, Rodrigues TB, Contreras L, Garzón M, Llorente-Folch I, Kobayashi K, Saheki T, Cerdan S et al (2011) Brain glutamine synthesis requires neuronal-born aspartate as amino donor for glial glutamate formation. J Cereb Blood Flow Metab 31(1):90–101. doi:10.1038/jcbfm.2010.146
130. Murín R, Mohammadi G, Leibfritz D, Hamprecht B (2009) Glial metabolism of isoleucine. Neurochem Res 34(1):194–204. doi:10.1007/s11064-008-9840-4
131. Murín R, Mohammadi G, Leibfritz D, Hamprecht B (2009) Glial metabolism of valine. Neurochem Res 34(7):1195–1203. doi:10.1007/s11064-008-9895-2
132. Yudkoff M (1997) Brain metabolism of branched-chain amino acids. Glia 21(1):92–98
133. Ebert D, Haller RG, Walton ME (2003) Energy contribution of octanoate to intact rat brain metabolism measured by 13C nuclear magnetic resonance spectroscopy. J Neurosci 23(13):5928–5935
134. Halim ND, McFate T, Mohyeldin A, Okagaki P, Korotchkina LG, Patel MS, Jeoung NH, Harris RA et al (2010) Phosphorylation status of pyruvate dehydrogenase distinguishes metabolic phenotypes of cultured rat brain astrocytes and neurons. Glia 58(10):1168–1176. doi:10.1002/glia.20996
135. Itoh Y, Esaki T, Shimoji K, Cook M, Law MJ, Kaufman E, Sokoloff L (2003) Dichloroacetate effects on glucose and lactate oxidation by neurons and astroglia in vitro and on glucose utilization by brain in vivo. Proc Natl Acad Sci U S A 100(8):4879–4884. doi:10.1073/pnas.0831078100
136. Auestad N, Korsak RA, Morrow JW, Edmond J (1991) Fatty acid oxidation and ketogenesis by astrocytes in primary culture. J Neurochem 56(4):1376–1386
137. Guzmán M, Blázquez C (2001) Is there an astrocyte-neuron ketone body shuttle? Trends Endocrinol Metab 12(4):169–173
138. Blázquez C, Woods A, de Ceballos ML, Carling D, Guzmán M (1999) The AMP-activated protein kinase is involved in the regulation of ketone body production by astrocytes. J Neurochem 73(4):1674–1682
139. Deitmer JW (2000) Glial strategy for metabolic shuttling and neuronal function. Bioessays 22(8):747–752. doi:10.1002/1521-1878(200008)22:8<747::AID-BIES8>3.0.CO;2-0
140. Amaral AI (2013) Effects of hypoglycaemia on neuronal metabolism in the adult brain: role of alternative substrates to glucose. J Inherit Metab Dis 36(4):621–634. doi:10.1007/s10545-012-9553-3
141. Murín R, Hamprecht B (2008) Metabolic and regulatory roles of leucine in neural cells. Neurochem Res 33(2):279–284. doi:10.1007/s11064-007-9444-4
142. Taïb B, Bouyakdan K, Hryhorczuk C, Rodaros D, Fulton S, Alquier T (2013) Glucose regulates hypothalamic long-chain fatty acid metabolism via AMP-activated kinase (AMPK) in neurons and astrocytes. J Biol Chem 288(52):37216–37229. doi:10.1074/jbc.M113.506238
143. Allaman I, Gavillet M, Bélanger M, Laroche T, Viertl D, Lashuel HA, Magistretti PJ (2010) Amyloid-beta aggregates cause alterations of astrocytic metabolic phenotype: impact on neuronal viability. J Neurosci 30(9):3326–3338. doi:10.1523/JNEUROSCI.5098-09.2010
144. Lee YJ, Han SB, Nam SY, Oh KW, Hong JT (2010) Inflammation and Alzheimer’s disease. Arch Pharm Res 33(10):1539–1556. doi:10.1007/s12272-010-1006-7
145. Nagele RG, D’Andrea MR, Lee H, Venkataraman V, Wang HY (2003) Astrocytes accumulate A beta 42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res 971(2):197–209
146. Phatnani H, Maniatis T (2015) Astrocytes in neurodegenerative disease. Cold Spring Harb Perspect Biol 7 (6). doi:10.1101/cshperspect.a020628
147. Fu W, Jhamandas JH (2014) Role of astrocytic glycolytic metabolism in Alzheimer’s disease pathogenesis. Biogerontology 15(6):579–586. doi:10.1007/s10522-014-9525-0
148. Bigl M, Apelt J, Eschrich K, Schliebs R (2003) Cortical glucose metabolism is altered in aged transgenic Tg2576 mice that demonstrate Alzheimer plaque pathology. J Neural Transm 110(1):77–94. doi:10.1007/s00702-002-0772-x
149. Fu W, Shi D, Westaway D, Jhamandas JH (2015) Bioenergetic mechanisms in astrocytes may contribute to amyloid plaque deposition and toxicity. J Biol Chem 290(20):12504–12513. doi:10.1074/jbc.M114.618157
150. El Kadmiri N, Slassi I, El Moutawakil B, Nadifi S, Tadevosyan A, Hachem A, Soukri A (2014) Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Alzheimer’s disease. Pathol Biol (Paris) 62(6):333–336. doi:10.1016/j.patbio.2014.08.002
151. Mazzola JL, Sirover MA (2001) Reduction of glyceraldehyde-3-phosphate dehydrogenase activity in Alzheimer’s disease and in Huntington’s disease fibroblasts. J Neurochem 76(2):442–449
152. Amaral AI, Teixeira AP, Martens S, Bernal V, Sousa MF, Alves PM (2010) Metabolic alterations induced by ischemia in primary cultures of astrocytes: merging 13C NMR spectroscopy and metabolic flux analysis. J Neurochem 113(3):735–748. doi:10.1111/j.1471-4159.2010.06636.x
153. Vannucci SJ, Reinhart R, Maher F, Bondy CA, Lee WH, Vannucci RC, Simpson IA (1998) Alterations in GLUT1 and GLUT3 glucose transporter gene expression following unilateral hypoxia-ischemia in the immature rat brain. Brain Res Dev Brain Res 107(2):255–264
154. Shen Y, Tian Y, Yang J, Shi X, Ouyang L, Gao J, Lu J (2014) Dual effects of carnosine on energy metabolism of cultured cortical astrocytes under normal and ischemic conditions. Regul Pept 192–193:45–52. doi:10.1016/j.regpep.2014.08.005
155. Torrente D, Avila MF, Cabezas R, Morales L, Gonzalez J, Samudio I, Barreto GE (2014) Paracrine factors of human mesenchymal stem cells increase wound closure and reduce reactive oxygen species production in a traumatic brain injury in vitro model. Hum Exp Toxicol 33(7):673–684. doi:10.1177/0960327113509659
156. Avila Rodriguez M, Garcia-Segura LM, Cabezas R, Torrente D, Capani F, Gonzalez J, Barreto GE (2014) Tibolone protects T98G cells from glucose deprivation. J Steroid Biochem Mol Biol 144(Pt B):294–303. doi:10.1016/j.jsbmb.2014.07.009
157. Carpenter KL, Jalloh I, Hutchinson PJ (2015) Glycolysis and the significance of lactate in traumatic brain injury. Front Neurosci 9:112. doi:10.3389/fnins.2015.00112
158. Bigl M, Brückner MK, Arendt T, Bigl V, Eschrich K (1999) Activities of key glycolytic enzymes in the brains of patients with Alzheimer’s disease. J Neural Transm 106(5–6):499–511
159. Thoren AE, Helps SC, Nilsson M, Sims NR (2006) The metabolism of C-glucose by neurons and astrocytes in brain subregions following focal cerebral ischemia in rats. J Neurochem 97(4):968–978. doi:10.1111/j.1471-4159.2006.03778.x
160. Choi JW, Shin CY, Yoo BK, Choi MS, Lee WJ, Han BH, Kim WK, Kim HC et al (2004) Glucose deprivation increases hydrogen peroxide level in immunostimulated rat primary astrocytes. J Neurosci Res 75(5):722–731. doi:10.1002/jnr.20009
161. Liao SL, Ou YC, Chang CY, Chen WY, Kuan YH, Wang WY, Pan HC, Chen CJ (2013) Diethylmaleate and iodoacetate in combination caused profound cell death in astrocytes. J Neurochem 127(2):271–282. doi:10.1111/jnc.12291
162. Bartnik BL, Sutton RL, Fukushima M, Harris NG, Hovda DA, Lee SM (2005) Upregulation of pentose phosphate pathway and preservation of tricarboxylic acid cycle flux after experimental brain injury. J Neurotrauma 22(10):1052–1065. doi:10.1089/neu.2005.22.1052
163. Brekke EM, Morken TS, Widerøe M, Håberg AK, Brubakk AM, Sonnewald U (2014) The pentose phosphate pathway and pyruvate carboxylation after neonatal hypoxic-ischemic brain injury. J Cereb Blood Flow Metab 34(4):724–734. doi:10.1038/jcbfm.2014.8
164. Boneva NB, Kaplamadzhiev DB, Sahara S, Kikuchi H, Pyko IV, Kikuchi M, Tonchev AB, Yamashima T (2011) Expression of fatty acid-binding proteins in adult hippocampal neurogenic niche of postischemic monkeys. Hippocampus 21(2):162–171. doi:10.1002/hipo.20732
165. Gibbs ME, Gibbs Z, Hertz L (2009) Rescue of Abeta(1–42)-induced memory impairment in day-old chick by facilitation of astrocytic oxidative metabolism: implications for Alzheimer’s disease. J Neurochem 109(Suppl 1):230–236. doi:10.1111/j.1471-4159.2009.05800.x
166. Korenić A, Andjus P, Radenović L, Spasojević I (2015) The role of autophagy and lipolysis in survival of astrocytes under nutrient deprivation. Neurosci Lett 595:128–133. doi:10.1016/j.neulet.2015.04.020
167. Cabodevilla AG, Sánchez-Caballero L, Nintou E, Boiadjieva VG, Picatoste F, Gubern A, Claro E (2013) Cell survival during complete nutrient deprivation depends on lipid droplet-fueled β-oxidation of fatty acids. J Biol Chem 288(39):27777–27788. doi:10.1074/jbc.M113.466656
168. Ding F, Yao J, Rettberg JR, Chen S, Brinton RD (2013) Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer’s mouse brain: implication for bioenergetic intervention. PLoS One 8(11), e79977. doi:10.1371/journal.pone.0079977
169. Yao J, Rettberg JR, Klosinski LP, Cadenas E, Brinton RD (2011) Shift in brain metabolism in late onset Alzheimer’s disease: implications for biomarkers and therapeutic interventions. Mol Aspects Med 32(4–6):247–257. doi:10.1016/j.mam.2011.10.005
170. Barros LF (2013) Metabolic signaling by lactate in the brain. Trends Neurosci 36(7):396–404. doi:10.1016/j.tins.2013.04.002
171. Suzuki A, Stern SA, Bozdagi O, Huntley GW, Walker RH, Magistretti PJ, Alberini CM (2011) Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144(5):810–823. doi:10.1016/j.cell.2011.02.018
172. Bezzi P, Volterra A (2011) Astrocytes: powering memory. Cell 144(5):644–645. doi:10.1016/j.cell.2011.02.027
173. Hihi AKML, Wahli W (2002) PPARs: transcriptional effectors of fatty acids and their derivatives. Cell Mol Life Sci 59(5):790–798
174. Diradourian C, Girard J, Pégorier JP (2005) Phosphorylation of PPARs: from molecular characterization to physiological relevance. Biochimie 87(1):33–38. doi:10.1016/j.biochi.2004.11.010
175. Floyd ZE, Stephens JM (2012) Controlling a master switch of adipocyte development and insulin sensitivity: covalent modifications of PPARγ. Biochim Biophys Acta 1822(7):1090–1095. doi:10.1016/j.bbadis.2012.03.014
176. Kim TH, Kim MY, Jo SH, Park JM, Ahn YH (2013) Modulation of the transcriptional activity of peroxisome proliferator-activated receptor gamma by protein-protein interactions and post-translational modifications. Yonsei Med J 54(3):545–559. doi:10.3349/ymj.2013.54.3.545
177. Anbalagan M, Huderson B, Murphy L, Rowan BG (2012) Post-translational modifications of nuclear receptors and human disease. Nucl Recept Signal 10, e001. doi:10.1621/nrs.10001
178. Wadosky KM, Willis MS (2012) The story so far: post-translational regulation of peroxisome proliferator-activated receptors by ubiquitination and SUMOylation. Am J Physiol Heart Circ Physiol 302(3):H515–H526. doi:10.1152/ajpheart.00703.2011
179. Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, Evans RM (2013) PPARγ signaling and metabolism: the good, the bad and the future. Nat Med 19(5):557–566. doi:10.1038/nm.3159
180. Wahli W, Michalik L (2012) PPARs at the crossroads of lipid signaling and inflammation. Trends Endocrinol Metab 23(7):351–363. doi:10.1016/j.tem.2012.05.001
181. Yessoufou A, Wahli W (2010) Multifaceted roles of peroxisome proliferator-activated receptors (PPARs) at the cellular and whole organism levels. Swiss Med Wkly 140:w13071. doi:10.4414/smw.2010.13071
182. Montagner A, Rando G, Degueurce G, Leuenberger N, Michalik L, Wahli W (2011) New insights into the role of PPARs. Prostaglandins Leukot Essent Fatty Acids 85(5):235–243. doi:10.1016/j.plefa.2011.04.016
183. Michalik L, Wahli W (2007) Peroxisome proliferator-activated receptors (PPARs) in skin health, repair and disease. Biochim Biophys Acta 1771(8):991–998. doi:10.1016/j.bbalip.2007.02.004
184. Gupta M, Mahajan VK, Mehta KS, Chauhan PS, Rawat R (2015) Peroxisome proliferator-activated receptors (PPARs) and PPAR agonists: the ‘future’ in dermatology therapeutics? Arch Dermatol Res. doi:10.1007/s00403-015-1571-1
185. Iglesias J, Barg S, Vallois D, Lahiri S, Roger C, Yessoufou A, Pradevand S, McDonald A et al (2012) PPARβ/δ affects pancreatic β cell mass and insulin secretion in mice. J Clin Invest 122(11):4105–4117. doi:10.1172/JCI42127
186. Michalik L, Wahli W (2008) PPARs mediate lipid signaling in inflammation and cancer. PPAR Res 2008:134059. doi:10.1155/2008/134059
187. Sahebkar A, Chew GT, Watts GF (2014) New peroxisome proliferator-activated receptor agonists: potential treatments for atherogenic dyslipidemia and non-alcoholic fatty liver disease. Expert Opin Pharmacother 15(4):493–503. doi:10.1517/14656566.2014.876992
188. Ding Y, Yang KD, Yang Q (2014) The role of PPARδ signaling in the cardiovascular system. Prog Mol Biol Transl Sci 121:451–473. doi:10.1016/B978-0-12-800101-1.00014-4
189. Grygiel-Górniak B (2014) Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications—a review. Nutr J 13:17. doi:10.1186/1475-2891-13-17
190. Nadra K, Anghel SI, Joye E, Tan NS, Basu-Modak S, Trono D, Wahli W, Desvergne B (2006) Differentiation of trophoblast giant cells and their metabolic functions are dependent on peroxisome proliferator-activated receptor beta/delta. Mol Cell Biol 26(8):3266–3281. doi:10.1128/MCB.26.8.3266-3281.2006
191. Varnat F, Heggeler BB, Grisel P, Boucard N, Corthésy-Theulaz I, Wahli W, Desvergne B (2006) PPARbeta/delta regulates paneth cell differentiation via controlling the hedgehog signaling pathway. Gastroenterology 131(2):538–553. doi:10.1053/j.gastro.2006.05.004
192. Pelton P (2006) GW-501516 GlaxoSmithKline/Ligand. Curr Opin Investig Drugs 7(4):360–370
193. Wang YX, Zhang CL, Yu RT, Cho HK, Nelson MC, Bayuga-Ocampo CR, Ham J, Kang H et al (2004) Regulation of muscle fiber type and running endurance by PPARdelta. PLoS Biol 2(10), e294. doi:10.1371/journal.pbio.0020294
194. Kostadinova R, Montagner A, Gouranton E, Fleury S, Guillou H, Dombrowicz D, Desreumaux P, Wahli W (2012) GW501516-activated PPARβ/δ promotes liver fibrosis via p38-JNK MAPK-induced hepatic stellate cell proliferation. Cell Biosci 2(1):34. doi:10.1186/2045-3701-2-34
195. Barish GD, Atkins AR, Downes M, Olson P, Chong LW, Nelson M, Zou Y, Hwang H et al (2008) PPARdelta regulates multiple proinflammatory pathways to suppress atherosclerosis. Proc Natl Acad Sci U S A 105(11):4271–4276. doi:10.1073/pnas.0711875105
196. Montagner A, Wahli W (2013) Contributions of peroxisome proliferator-activated receptor β/δ to skin health and disease. Biomol Concepts 4(1):53–64. doi:10.1515/bmc-2012-0035
197. Cristiano L, Bernardo A, Cerù MP (2001) Peroxisome proliferator-activated receptors (PPARs) and peroxisomes in rat cortical and cerebellar astrocytes. J Neurocytol 30(8):671–683
198. Woods JW, Tanen M, Figueroa DJ, Biswas C, Zycband E, Moller DE, Austin CP, Berger JP (2003) Localization of PPARdelta in murine central nervous system: expression in oligodendrocytes and neurons. Brain Res 975(1–2):10–21
199. Cimini A, Benedetti E, Cristiano L, Sebastiani P, D’Amico MA, D’Angelo B, Di Loreto S (2005) Expression of peroxisome proliferator-activated receptors (PPARs) and retinoic acid receptors (RXRs) in rat cortical neurons. Neuroscience 130(2):325–337. doi:10.1016/j.neuroscience.2004.09.043
200. Lleo A, Galea E, Sastre M (2007) Molecular targets of non-steroidal anti-inflammatory drugs in neurodegenerative diseases. Cell Mol Life Sci 64(11):1403–1418. doi:10.1007/s00018-007-6516-1
201. Dill J, Patel AR, Yang XL, Bachoo R, Powell CM, Li S (2010) A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons. J Neurosci 30(3):963–972. doi:10.1523/JNEUROSCI.5045-09.2010
202. Sastre M, Dewachter I, Landreth GE, Willson TM, Klockgether T, van Leuven F, Heneka MT (2003) Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. J Neurosci 23(30):9796–9804
203. Sastre M, Walter J, Gentleman SM (2008) Interactions between APP secretases and inflammatory mediators. J Neuroinflammation 5:25. doi:10.1186/1742-2094-5-25
204. Sato T, Hanyu H, Hirao K, Kanetaka H, Sakurai H, Iwamoto T (2011) Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging 32(9):1626–1633. doi:10.1016/j.neurobiolaging.2009.10.009
205. Mandrekar-Colucci S, Karlo JC, Landreth GE (2012) Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer’s disease. J Neurosci 32(30):10117–10128. doi:10.1523/JNEUROSCI.5268-11.2012
206. Wang HM, Zhao YX, Zhang S, Liu GD, Kang WY, Tang HD, Ding JQ, Chen SD (2010) PPARgamma agonist curcumin reduces the amyloid-beta-stimulated inflammatory responses in primary astrocytes. J Alzheimers Dis 20(4):1189–1199. doi:10.3233/JAD-2010-091336
207. Aguirre-Rueda D, Guerra-Ojeda S, Aldasoro M, Iradi A, Obrador E, Ortega A, Mauricio MD, Vila JM et al (2015) Astrocytes protect neurons from Aβ1-42 peptide-induced neurotoxicity increasing TFAM and PGC-1 and decreasing PPAR-γ and SIRT-1. Int J Med Sci 12(1):48–56. doi:10.7150/ijms.10035
208. Hong S, Xin Y, HaiQin W, GuiLian Z, Ru Z, ShuQin Z, HuQing W, Li Y et al (2012) The PPARγ agonist rosiglitazone prevents cognitive impairment by inhibiting astrocyte activation and oxidative stress following pilocarpine-induced status epilepticus. Neurol Sci 33(3):559–566. doi:10.1007/s10072-011-0774-2
209. Ching J, Amiridis S, Stylli SS, Morokoff AP, O’Brien TJ, Kaye AH (2015) A novel treatment strategy for glioblastoma multiforme and glioma associated seizures: increasing glutamate uptake with PPARγ agonists. J Clin Neurosci 22(1):21–28. doi:10.1016/j.jocn.2014.09.001
210. Tian GX, Zhu XQ, Chen Y, Wu GC, Wang J (2013) Huperzine A inhibits CCL2 production in experimental autoimmune encephalomyelitis mice and in cultured astrocyte. Int J Immunopathol Pharmacol 26(3):757–764
211. Kumari R, Willing LB, Patel SD, Krady JK, Zavadoski WJ, Gibbs EM, Vannucci SJ, Simpson IA (2010) The PPAR-gamma agonist, darglitazone, restores acute inflammatory responses to cerebral hypoxia-ischemia in the diabetic ob/ob mouse. J Cereb Blood Flow Metab 30(2):352–360. doi:10.1038/jcbfm.2009.221
212. Lee CH, Park OK, Yoo KY, Byun K, Lee B, Choi JH, Hwang IK, Kim YM et al (2011) The role of peroxisome proliferator-activated receptor γ, and effects of its agonist, rosiglitazone, on transient cerebral ischemic damage. J Neurol Sci 300(1–2):120–129. doi:10.1016/j.jns.2010.09.005
213. Sayan-Ozacmak H, Ozacmak VH, Barut F, Jakubowska-Dogru E (2011) Neuroprotective efficacy of the peroxisome proliferator-activated receptor-γ ligand in chronic cerebral hypoperfusion. Curr Neurovasc Res 8(3):190–199
214. Sergeeva MG, Aleshin SE, Grabeklis S, Reiser G (2010) PPAR activation has dichotomous control on the expression levels of cytosolic and secretory phospholipase A2 in astrocytes; inhibition in naïve, untreated cells and enhancement in LPS-stimulated cells. J Neurochem 115(2):399–410. doi:10.1111/j.1471-4159.2010.06931.x
215. Sun GY, Xu J, Jensen MD, Simonyi A (2004) Phospholipase A2 in the central nervous system: implications for neurodegenerative diseases. J Lipid Res 45(2):205–213. doi:10.1194/jlr.R300016-JLR200
216. Peters-Golden M, Henderson WR (2007) Leukotrienes. N Engl J Med 357(18):1841–1854. doi:10.1056/NEJMra071371
217. Di Cesare ML, Zanardelli M, Micheli L, Ghelardini C (2014) PPAR- γ impairment alters peroxisome functionality in primary astrocyte cell cultures. Biomed Res Int 2014:546453. doi:10.1155/2014/546453
218. Aguirre-Rueda D, Guerra-Ojeda S, Aldasoro M, Iradi A, Obrador E, Mauricio MD, Vila JM, Marchio P et al (2015) WIN 55,212-2, agonist of cannabinoid receptors, prevents amyloid β1-42 effects on astrocytes in primary culture. PLoS One 10(4), e0122843. doi:10.1371/journal.pone.0122843
219. Xu J, Storer PD, Chavis JA, Racke MK, Drew PD (2005) Agonists for the peroxisome proliferator-activated receptor-alpha and the retinoid X receptor inhibit inflammatory responses of microglia. J Neurosci Res 81(3):403–411. doi:10.1002/jnr.20518
220. Xu J, Racke MK, Drew PD (2007) Peroxisome proliferator-activated receptor-alpha agonist fenofibrate regulates IL-12 family cytokine expression in the CNS: relevance to multiple sclerosis. J Neurochem 103(5):1801–1810. doi:10.1111/j.1471-4159.2007.04875.x
221. Lovett-Racke AE, Hussain RZ, Northrop S, Choy J, Rocchini A, Matthes L, Chavis JA, Diab A et al (2004) Peroxisome proliferator-activated receptor alpha agonists as therapy for autoimmune disease. J Immunol 172(9):5790–5798
222. Esposito E, Impellizzeri D, Mazzon E, Paterniti I, Cuzzocrea S (2012) Neuroprotective activities of palmitoylethanolamide in an animal model of Parkinson’s disease. PLoS One 7(8), e41880. doi:10.1371/journal.pone.0041880
223. Raso GM, Esposito E, Vitiello S, Iacono A, Santoro A, D’Agostino G, Sasso O, Russo R et al (2011) Palmitoylethanolamide stimulation induces allopregnanolone synthesis in C6 cells and primary astrocytes: involvement of peroxisome-proliferator activated receptor-α. J Neuroendocrinol 23(7):591–600. doi:10.1111/j.1365-2826.2011.02152.x
224. Wang G, Namura S (2011) Effects of chronic systemic treatment with peroxisome proliferator-activated receptor α activators on neuroinflammation induced by intracerebral injection of lipopolysaccharide in adult mice. Neurosci Res 70(2):230–237. doi:10.1016/j.neures.2011.02.001
225. Fandel D, Wasmuht D, Avila-Martín G, Taylor JS, Galán-Arriero I, Mey J (2013) Spinal cord injury induced changes of nuclear receptors PPARα and LXRβ and modulation with oleic acid/albumin treatment. Brain Res 1535:89–105. doi:10.1016/j.brainres.2013.08.022
226. Cristiano L, Cimini A, Moreno S, Ragnelli AM, Paola Cerù M (2005) Peroxisome proliferator-activated receptors (PPARs) and related transcription factors in differentiating astrocyte cultures. Neuroscience 131(3):577–587. doi:10.1016/j.neuroscience.2004.11.008
227. Cimini A, Cerù MP (2008) Emerging roles of peroxisome proliferator-activated receptors (PPARs) in the regulation of neural stem cells proliferation and differentiation. Stem Cell Rev 4(4):293–303. doi:10.1007/s12015-008-9024-2
228. Polak PE, Kalinin S, Dello Russo C, Gavrilyuk V, Sharp A, Peters JM, Richardson J, Willson TM et al (2005) Protective effects of a peroxisome proliferator-activated receptor-beta/delta agonist in experimental autoimmune encephalomyelitis. J Neuroimmunol 168(1–2):65–75. doi:10.1016/j.jneuroim.2005.07.006
229. Vittoria Simonini M, Polak PE, Boullerne AI, Peters JM, Richardson JC, Feinstein DL (2010) Regulation of oligodendrocyte progenitor cell maturation by PPARδ: effects on bone morphogenetic proteins. ASN Neuro 2(1), e00025. doi:10.1042/AN20090033
230. Defaux A, Zurich MG, Braissant O, Honegger P, Monnet-Tschudi F (2009) Effects of the PPAR-beta agonist GW501516 in an in vitro model of brain inflammation and antibody-induced demyelination. J Neuroinflammation 6:15. doi:10.1186/1742-2094-6-15
231. Schnegg CI, Greene-Schloesser D, Kooshki M, Payne VS, Hsu FC, Robbins ME (2013) The PPARδ agonist GW0742 inhibits neuroinflammation, but does not restore neurogenesis or prevent early delayed hippocampal-dependent cognitive impairment after whole-brain irradiation. Free Radic Biol Med 61:1–9. doi:10.1016/j.freeradbiomed.2013.03.002
232. Sartoris DJ, Resnick D (1990) Radiologic evaluation of midfoot injuries: test of interpretation and clinical knowledge. J Foot Surg 29(3):292–297
233. Martin HL, Mounsey RB, Sathe K, Mustafa S, Nelson MC, Evans RM, Teismann P (2013) A peroxisome proliferator-activated receptor-δ agonist provides neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. Neuroscience 240:191–203. doi:10.1016/j.neuroscience.2013.02.058
234. Chistyakov DV, Aleshin SE, Astakhova AA, Sergeeva MG, Reiser G (2015) Regulation of peroxisome proliferator-activated receptors (PPAR) α and -γ of rat brain astrocytes in the course of activation by toll-like receptor agonists. J Neurochem. doi:10.1111/jnc.13101
235. Cheong SJ, Lee CM, Kim EM, Lim ST, Sohn MH, Jeong HJ (2015) The effect of PPAR-γ agonist on (18)F-FDG PET imaging for differentiating tumors and inflammation lesions. Nucl Med Biol 42(2):85–91. doi:10.1016/j.nucmedbio.2014.08.013
236. Festuccia WT, Blanchard PG, Turcotte V, Laplante M, Sariahmetoglu M, Brindley DN, Deshaies Y (2009) Depot-specific effects of the PPARgamma agonist rosiglitazone on adipose tissue glucose uptake and metabolism. J Lipid Res 50(6):1185–1194. doi:10.1194/jlr.M800620-JLR200
237. Badeau RM, Honka MJ, Lautamäki R, Stewart M, Kangas AJ, Soininen P, Ala-Korpela M, Nuutila P (2014) Systemic metabolic markers and myocardial glucose uptake in type 2 diabetic and coronary artery disease patients treated for 16 weeks with rosiglitazone, a PPARγ agonist. Ann Med 46(1):18–23. doi:10.3109/07853890.2013.853369
238. Tsukahara T, Haniu H, Matsuda Y (2013) Effect of alkyl glycerophosphate on the activation of peroxisome proliferator-activated receptor gamma and glucose uptake in C2C12 cells. Biochem Biophys Res Commun 433(3):281–285. doi:10.1016/j.bbrc.2013.02.101
239. Tabernero A, Medina JM, Giaume C (2006) Glucose metabolism and proliferation in glia: role of astrocytic gap junctions. J Neurochem 99(4):1049–1061. doi:10.1111/j.1471-4159.2006.04088.x
240. Dello Russo C, Gavrilyuk V, Weinberg G, Almeida A, Bolanos JP, Palmer J, Pelligrino D, Galea E et al (2003) Peroxisome proliferator-activated receptor gamma thiazolidinedione agonists increase glucose metabolism in astrocytes. J Biol Chem 278(8):5828–5836. doi:10.1074/jbc.M208132200
241. Izawa Y, Takahashi S, Suzuki N (2009) Pioglitazone enhances pyruvate and lactate oxidation in cultured neurons but not in cultured astroglia. Brain Res 1305:64–73. doi:10.1016/j.brainres.2009.09.098
242. Spagnolo A, Grant EN, Glick R, Lichtor T, Feinstein DL (2007) Differential effects of PPARgamma agonists on the metabolic properties of gliomas and astrocytes. Neurosci Lett 417(1):72–77. doi:10.1016/j.neulet.2007.02.036
243. Gao C, Zhou L, Zhu W, Wang H, Wang R, He Y, Li Z (2015) Monocarboxylate transporter-dependent mechanism confers resistance to oxygen- and glucose-deprivation injury in astrocyte-neuron co-cultures. Neurosci Lett 594:99–104. doi:10.1016/j.neulet.2015.03.062
244. Atsumi T, Nishio T, Niwa H, Takeuchi J, Bando H, Shimizu C, Yoshioka N, Bucala R et al (2005) Expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase/PFKFB3 isoforms in adipocytes and their potential role in glycolytic regulation. Diabetes 54(12):3349–3357
245. Nielsen R, Pedersen TA, Hagenbeek D, Moulos P, Siersbaek R, Megens E, Denissov S, Børgesen M et al (2008) Genome-wide profiling of PPARgamma:RXR and RNA polymerase II occupancy reveals temporal activation of distinct metabolic pathways and changes in RXR dimer composition during adipogenesis. Genes Dev 22(21):2953–2967. doi:10.1101/gad.501108
246. Guo X, Xu K, Zhang J, Li H, Zhang W, Wang H, Lange AJ, Chen YE et al (2010) Involvement of inducible 6-phosphofructo-2-kinase in the anti-diabetic effect of peroxisome proliferator-activated receptor gamma activation in mice. J Biol Chem 285(31):23711–23720. doi:10.1074/jbc.M110.123174
247. Verma R, Mishra V, Gupta K, Sasmal D, Raghubir R (2011) Neuroprotection by rosiglitazone in transient focal cerebral ischemia might not be mediated by glutamate transporter-1. J Neurosci Res 89(11):1849–1858. doi:10.1002/jnr.22710
248. García-Bueno B, Caso JR, Pérez-Nievas BG, Lorenzo P, Leza JC (2007) Effects of peroxisome proliferator-activated receptor gamma agonists on brain glucose and glutamate transporters after stress in rats. Neuropsychopharmacology 32(6):1251–1260. doi:10.1038/sj.npp.1301252
249. Romera C, Hurtado O, Mallolas J, Pereira MP, Morales JR, Romera A, Serena J, Vivancos J et al (2007) Ischemic preconditioning reveals that GLT1/EAAT2 glutamate transporter is a novel PPARgamma target gene involved in neuroprotection. J Cereb Blood Flow Metab 27(7):1327–1338. doi:10.1038/sj.jcbfm.9600438
250. Escartin C, Brouillet E, Gubellini P, Trioulier Y, Jacquard C, Smadja C, Knott GW, Kerkerian-Le Goff L et al (2006) Ciliary neurotrophic factor activates astrocytes, redistributes their glutamate transporters GLAST and GLT-1 to raft microdomains, and improves glutamate handling in vivo. J Neurosci 26(22):5978–5989. doi:10.1523/JNEUROSCI.0302-06.2006
251. Beurrier C, Faideau M, Bennouar KE, Escartin C, Kerkerian-Le Goff L, Bonvento G, Gubellini P (2010) Ciliary neurotrophic factor protects striatal neurons against excitotoxicity by enhancing glial glutamate uptake. PLoS One 5(1), e8550. doi:10.1371/journal.pone.0008550
252. Paintlia MK, Paintlia AS, Singh AK, Singh I (2013) S-nitrosoglutathione induces ciliary neurotrophic factor expression in astrocytes, which has implications to protect the central nervous system under pathological conditions. J Biol Chem 288(6):3831–3843. doi:10.1074/jbc.M112.405654
253. Haemmerle G, Moustafa T, Woelkart G, Büttner S, Schmidt A, van de Weijer T, Hesselink M, Jaeger D et al (2011) ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-α and PGC-1. Nat Med 17(9):1076–1085. doi:10.1038/nm.2439
254. 2 receptors. Br J Pharmacol 166(4):1474–1489. doi:10.1111/j.1476-5381.2012.01889.x
255. Touriño C, Oveisi F, Lockney J, Piomelli D, Maldonado R (2010) FAAH deficiency promotes energy storage and enhances the motivation for food. Int J O bes (Lond) 34(3):557–568. doi:10.1038/ijo.2009.262
256. Zhao S, Mugabo Y, Ballentine G, Attane C, Iglesias J, Poursharifi P, Zhang D, Anne Nguyen T, Erb H, Prentki R, Peyot M-L, Joly E, Tobin S, Fulton S, Brown JM, Madiraju SRM, Prentki M (2016) a/b-Hydrolase domain-6 deletion induces adipose browning and prevents obesity and type-2 diabetes. Cell Rep
257. Chen R, Zhang J, Wu Y, Wang D, Feng G, Tang YP, Teng Z, Chen C (2012) Monoacylglycerol lipase is a therapeutic target for Alzheimer’s disease. Cell Rep 2(5):1329–1339. doi:10.1016/j.celrep.2012.09.030
258. Cullingford TE (2004) The ketogenic diet; fatty acids, fatty acid-activated receptors and neurological disorders. Prostaglandins Leukot Essent Fatty Acids 70(3):253–264. doi:10.1016/j.plefa.2003.09.008
259. Cullingford TE, Dolphin CT, Sato H (2002) The peroxisome proliferator-activated receptor alpha-selective activator ciprofibrate upregulates expression of genes encoding fatty acid oxidation and ketogenesis enzymes in rat brain. Neuropharmacology 42(5):724–730
260. König B, Koch A, Giggel K, Dordschbal B, Eder K, Stangl GI (2008) Monocarboxylate transporter (MCT)-1 is up-regulated by PPARalpha. Biochim Biophys Acta 1780(6):899–904. doi:10.1016/j.bbagen.2008.03.002
261. Porta N, Vallée L, Lecointe C, Bouchaert E, Staels B, Bordet R, Auvin S (2009) Fenofibrate, a peroxisome proliferator-activated receptor-alpha agonist, exerts anticonvulsive properties. Epilepsia 50(4):943–948. doi:10.1111/j.1528-1167.2008.01901.x
262. Nałecz KA, Miecz D, Berezowski V, Cecchelli R (2004) Carnitine: transport and physiological functions in the brain. Mol Aspects Med 25(5–6):551–567. doi:10.1016/j.mam.2004.06.001
263. Januszewicz E, Pajak B, Gajkowska B, Samluk L, Djavadian RL, Hinton BT, Nałecz KA (2009) Organic cation/carnitine transporter OCTN3 is present in astrocytes and is up-regulated by peroxisome proliferators-activator receptor agonist. Int J Biochem Cell Biol 41(12):2599–2609. doi:10.1016/j.biocel.2009.08.020
264. Khatchadourian A, Bourque SD, Richard VR, Titorenko VI, Maysinger D (2012) Dynamics and regulation of lipid droplet formation in lipopolysaccharide (LPS)-stimulated microglia. Biochim Biophys Acta 1821(4):607–617. doi:10.1016/j.bbalip.2012.01.007
265. Gubern A, Barceló-Torns M, Barneda D, López JM, Masgrau R, Picatoste F, Chalfant CE, Balsinde J et al (2009) JNK and ceramide kinase govern the biogenesis of lipid droplets through activation of group IVA phospholipase A2. J Biol Chem 284(47):32359–32369. doi:10.1074/jbc.M109.061515
266. Aleshin S, Reiser G (2014) Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) protects against ceramide-induced cellular toxicity in rat brain astrocytes and neurons by activation of ceramide kinase. Mol Cell Neurosci 59:127–134. doi:10.1016/j.mcn.2014.01.008
267. Targett-Adams P, McElwee MJ, Ehrenborg E, Gustafsson MC, Palmer CN, McLauchlan J (2005) A PPAR response element regulates transcription of the gene for human adipose differentiation-related protein. Biochim Biophys Acta 1728(1–2):95–104. doi:10.1016/j.bbaexp.2005.01.017