https://doi.org/10.4081/ejh.2023.3691
High glucose inhibits neural differentiation by excessive autophagy via peroxisome proliferator-activated receptor gamma
Submitted: 22 February 2023
Accepted: 24 April 2023
Published: 11 May 2023
Accepted: 24 April 2023
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
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The high prevalence of prediabetes and diabetes globally has led to the widespread occurrence of severe complications, such as diabetic neuropathy, which is a result of chronic hyperglycemia. Studies have demonstrated that maternal diabetes can lead to neural tube defects by suppressing neurogenesis during neuroepithelium development. While aberrant autophagy has been associated with abnormal neuronal differentiation, the mechanism by which high glucose suppresses neural differentiation in stem cells remains unclear. Therefore, we developed a neuronal cell differentiation model of retinoic acid induced P19 cells to investigate the impact of high glucose on neuronal differentiation in vitro. Our findings indicate that high glucose (HG) hinders neuronal differentiation and triggers excessive. Furthermore, HG treatment significantly reduces the expression of markers for neurons (Tuj1) and glia (GFAP), while enhancing autophagic activity mediated by peroxisome proliferator-activated receptor gamma (PPARγ). By manipulating PPARγ activity through pharmacological approaches and genetically knocking it down using shRNA, we discovered that altering PPARγ activity affects the differentiation of neural stem cells exposed to HG. Our study reveals that PPARγ acts as a downstream mediator in high glucose-suppressed neural stem cell differentiation and that refining autophagic activity via PPARγ at an appropriate level could improve neuronal differentiation efficiency. Our data provide novel insights and potential therapeutic targets for the clinical management of gestational diabetes mellitus.
Alexopoulos AS, Blair R, Peters AL. Management of preexisting diabetes in pregnancy: a review. JAMA 2019;321:1811-9.
DOI: https://doi.org/10.1001/jama.2019.4981
Feghali MN, Umans JG, Catalano PM. Drugs to control diabetes during pregnancy. Clin Perinatol 2019;46:257-72.
DOI: https://doi.org/10.1016/j.clp.2019.02.005
Kapur A, McIntyre HD, Hod M. Type 2 diabetes in pregnancy. Endocrinol Metab Clin North Am 2019;48:511-31.
DOI: https://doi.org/10.1016/j.ecl.2019.05.009
Ringholm L, Damm P, Mathiesen ER. Improving pregnancy outcomes in women with diabetes mellitus: modern management. Nat Rev Endocrinol 2019;15:406-16.
DOI: https://doi.org/10.1038/s41574-019-0197-3
Etchegoyen M, Nobile MH, Baez F, Posesorski B, Gonzalez J, Lago N, et al. Metabolic syndrome and neuroprotection. Front Neurosci 2018;12:196.
DOI: https://doi.org/10.3389/fnins.2018.00196
Papanas N, Ziegler D. Risk factors and comorbidities in diabetic neuropathy: An update 2015. Rev Diabet Stud 2015;12:48-62.
DOI: https://doi.org/10.1900/RDS.2015.12.48
Oh J. Clinical spectrum and diagnosis of diabetic neuropathies. Korean J Intern Med 2020;35:1059-69.
DOI: https://doi.org/10.3904/kjim.2020.202
Sasaki H, Kawamura N, Dyck PJ, Dyck PJB, Kihara M, Low PA. Spectrum of diabetic neuropathies. Diabetol Int 2020;11:87-96.
DOI: https://doi.org/10.1007/s13340-019-00424-7
Caruso I, Marrano N, Biondi G, Genchi VA, D'Oria R, Sorice GP, et al. Glucagon in type 2 diabetes: Friend or foe? Diabetes Metab Res Rev 2023:e3609.
DOI: https://doi.org/10.1002/dmrr.3609
Malik RA. Diabetic neuropathy: A focus on small fibres. Diabetes Metab Res Rev 2020;36:e3255.
DOI: https://doi.org/10.1002/dmrr.3255
Feldman EL, Callaghan BC, Pop-Busui R, Zochodne DW, Wright DE, Bennett DL, et al. Diabetic neuropathy. Nat Rev Dis Primers 2019;5:41.
DOI: https://doi.org/10.1038/s41572-019-0092-1
Zhang M, Zhou M, Cai X, Zhou Y, Jiang X, Luo Y, et al. VEGF promotes diabetic retinopathy by upregulating the PKC/ET/NF-kappaB/ICAM-1 signaling pathway. Eur J Histochem 2022;66:3522.
DOI: https://doi.org/10.4081/ejh.2022.3522
Bloomgarden ZT. Neuropathy, womens' health, and socioeconomic aspects of diabetes. Diabetes Care 2002;25:1085-94.
DOI: https://doi.org/10.2337/diacare.25.6.1085
Levine B, Kroemer G. Biological functions of autophagy genes: a disease perspective. Cell 2019;176:11-42.
DOI: https://doi.org/10.1016/j.cell.2018.09.048
Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science 2000;290:1717-21.
DOI: https://doi.org/10.1126/science.290.5497.1717
Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006;124:471-84.
DOI: https://doi.org/10.1016/j.cell.2006.01.016
Lum JJ, DeBerardinis RJ, Thompson CB. Autophagy in metazoans: cell survival in the land of plenty. Nat Rev Mol Cell Biol 2005;6:439-48.
DOI: https://doi.org/10.1038/nrm1660
Noda T, Ohsumi Y. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem 1998;273:3963-6.
DOI: https://doi.org/10.1074/jbc.273.7.3963
Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol 2010;221:3-12.
DOI: https://doi.org/10.1002/path.2697
Geng J, Klionsky DJ. The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. 'Protein modifications: beyond the usual suspects' review series. EMBO Rep 2008;9:859-64.
DOI: https://doi.org/10.1038/embor.2008.163
Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell 2011;147:728-41.
DOI: https://doi.org/10.1016/j.cell.2011.10.026
Johansen T, Lamark T. Selective autophagy: ATG8 family proteins, LIR motifs and cargo receptors. J Mol Biol 2020;432:80-103.
DOI: https://doi.org/10.1016/j.jmb.2019.07.016
Stavoe AKH, Holzbaur ELF. Autophagy in neurons. Annu Rev Cell Dev Biol 2019;35:477-500.
DOI: https://doi.org/10.1146/annurev-cellbio-100818-125242
Walls KC, Ghosh AP, Franklin AV, Klocke BJ, Ballestas M, Shacka JJ, et al. Lysosome dysfunction triggers Atg7-dependent neural apoptosis. J Biol Chem 2010;285:10497-507.
DOI: https://doi.org/10.1074/jbc.M110.103747
Benito-Cuesta I, Diez H, Ordonez L, Wandosell F. Assessment of autophagy in neurons and brain tissue. Cells 2017;6:25.
DOI: https://doi.org/10.3390/cells6030025
Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K, et al. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol 2001;152:657-68.
DOI: https://doi.org/10.1083/jcb.152.4.657
Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA 2003;100:15077-82.
DOI: https://doi.org/10.1073/pnas.2436255100
Fimia GM, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S, Nardacci R, et al. Ambra1 regulates autophagy and development of the nervous system. Nature 2007;447:1121-5.
DOI: https://doi.org/10.1038/nature05925
Evans RM, Mangelsdorf DJ. Nuclear receptors, RXR, and the Big Bang. Cell 2014;157:255-66.
DOI: https://doi.org/10.1016/j.cell.2014.03.012
Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology 1996;137:354-66.
DOI: https://doi.org/10.1210/endo.137.1.8536636
Huin C, Corriveau L, Bianchi A, Keller JM, Collet P, Kremarik-Bouillaud P, et al. Differential expression of peroxisome proliferator-activated receptors (PPARs) in the developing human fetal digestive tract. J Histochem Cytochem 2000;48:603-11.
DOI: https://doi.org/10.1177/002215540004800504
Barger PM, Browning AC, Garner AN, Kelly DP. p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor alpha: a potential role in the cardiac metabolic stress response. J Biol Chem 2001;276:44495-501.
DOI: https://doi.org/10.1074/jbc.M105945200
Moreno S, Farioli-Vecchioli S, Ceru MP. Immunolocalization of peroxisome proliferator-activated receptors and retinoid X receptors in the adult rat CNS. Neuroscience 2004;123:131-45.
DOI: https://doi.org/10.1016/j.neuroscience.2003.08.064
Rolland B, Bordet R. The first theme issue on PPARs for brain disorders. Curr Drug Targets 2013;14:723.
DOI: https://doi.org/10.2174/1389450111314070001
Heneka MT, Landreth GE. PPARs in the brain. Biochim Biophys Acta 2007;1771:1031-45.
DOI: https://doi.org/10.1016/j.bbalip.2007.04.016
Kalinin S, Richardson JC, Feinstein DL. A PPARdelta agonist reduces amyloid burden and brain inflammation in a transgenic mouse model of Alzheimer's disease. Curr Alzheimer Res 2009;6:431-7.
DOI: https://doi.org/10.2174/156720509789207949
Schnegg CI, Robbins ME. Neuroprotective mechanisms of PPARdelta: modulation of oxidative stress and inflammatory processes. PPAR Res 2011;2011:373560.
DOI: https://doi.org/10.1155/2011/373560
Heneka MT, Reyes-Irisarri E, Hull M, Kummer MP. Impact and therapeutic potential of PPARs in Alzheimer's disease. Curr Neuropharmacol 2011;9:643-50.
DOI: https://doi.org/10.2174/157015911798376325
Barroso E, del Valle J, Porquet D, Vieira Santos AM, Salvado L, Rodriguez-Rodriguez R, et al. Tau hyperphosphorylation and increased BACE1 and RAGE levels in the cortex of PPARbeta/delta-null mice. Biochim Biophys Acta 2013;1832:1241-8.
DOI: https://doi.org/10.1016/j.bbadis.2013.03.006
Benedetti E, D'Angelo B, Cristiano L, Di Giacomo E, Fanelli F, Moreno S, et al. Involvement of peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) in BDNF signaling during aging and in Alzheimer disease: possible role of 4-hydroxynonenal (4-HNE). Cell Cycle 2014;13:1335-44.
DOI: https://doi.org/10.4161/cc.28295
Corbett GT, Gonzalez FJ, Pahan K. Activation of peroxisome proliferator-activated receptor alpha stimulates ADAM10-mediated proteolysis of APP. Proc Natl Acad Sci USA 2015;112:8445-50.
DOI: https://doi.org/10.1073/pnas.1504890112
Skerrett R, Pellegrino MP, Casali BT, Taraboanta L, Landreth GE. Combined liver X receptor/peroxisome proliferator-activated receptor gamma agonist treatment reduces amyloid beta levels and improves behavior in amyloid precursor protein/presenilin 1 mice. J Biol Chem 2015;290:21591-602.
DOI: https://doi.org/10.1074/jbc.M115.652008
Li X, Xue Y, Pang L, Len B, Lin Z, Huang J, et al. Agaricus bisporus-derived beta-glucan prevents obesity through PPAR gamma downregulation and autophagy induction in zebrafish fed by chicken egg yolk. Int J Biol Macromol 2019;125:820-8.
DOI: https://doi.org/10.1016/j.ijbiomac.2018.12.122
Lu X, Liu T, Chen K, Xia Y, Dai W, Xu S, et al. Isorhamnetin: A hepatoprotective flavonoid inhibits apoptosis and autophagy via P38/PPAR-alpha pathway in mice. Biomed Pharmacother 2018;103:800-11.
DOI: https://doi.org/10.1016/j.biopha.2018.04.016
Gonzalez-Blanco L, Bermejo-Millo JC, Oliveira G, Potes Y, Antuna E, Menendez-Valle I, et al. Neurogenic potential of the 18-kDa mitochondrial translocator protein (TSPO) in pluripotent P19 stem cells. Cells 2021;10:2784.
DOI: https://doi.org/10.3390/cells10102784
Prasad R, Jung H, Tan A, Song Y, Moon S, Shaker MR, et al. Hypermethylation of Mest promoter causes aberrant Wnt signaling in patients with Alzheimer's disease. Sci Rep 2021;11:20075.
DOI: https://doi.org/10.1038/s41598-021-99562-9
Rudnicki MA, Ruben M, McBurney MW. Regulated expression of a transfected human cardiac actin gene during differentiation of multipotential murine embryonal carcinoma cells. Mol Cell Biol 1988;8:406-17.
DOI: https://doi.org/10.1128/MCB.8.1.406
Berardo C, Siciliano V, Di Pasqua LG, Richelmi P, Vairetti M, Ferrigno A. Comparison between lipofectamine RNAiMAX and GenMute transfection agents in two cellular models of human hepatoma. Eur J Histochem 2019;63:3048.
DOI: https://doi.org/10.4081/ejh.2019.3048
Anji A, Anderson B, Akhtar F, Meekins DA, Ito T, Mummidi S, et al. Exosomes induce neurogenesis of pluripotent P19 cells. Stem Cell Rev Rep 2023. Online Ahead of Print.
DOI: https://doi.org/10.1007/s12015-023-10512-6
50. Liu H, Cai X, Liu J, Zhang F, He A, Li R. The MEG3 lncRNA promotes trophoblastic cell growth and invasiveness in preeclampsia by acting as a sponge for miR-21, which regulates BMPR2 levels. Eur J Histochem 2021;65:3323.
DOI: https://doi.org/10.4081/ejh.2021.3323
Voronova A, Fischer A, Ryan T, Al Madhoun A, Skerjanc IS. Ascl1/Mash1 is a novel target of Gli2 during Gli2-induced neurogenesis in P19 EC cells. PLoS One 2011;6:e19174.
DOI: https://doi.org/10.1371/journal.pone.0019174
Fu F, Li LS, Li R, Deng Q, Yu QX, Yang X, et al. All-trans-retinoid acid induces the differentiation of P19 cells into neurons involved in the PI3K/Akt/GSK3beta signaling pathway. J Cell Biochem 2020;121:4386-96.
DOI: https://doi.org/10.1002/jcb.29659
Moazeny M, Dehbashi M, Hojati Z, Esmaeili F. Investigating neural differentiation of mouse P19 embryonic stem cells in a time-dependent manner by bioinformatic, microscopic and transcriptional analyses. Mol Biol Rep 2022;50:2183-94.
DOI: https://doi.org/10.1007/s11033-022-08166-7
Faghfouri AH, Khajebishak Y, Payahoo L, Faghfuri E, Alivand M. PPAR-gamma agonists: Potential modulators of autophagy in obesity. Eur J Pharmacol 2021;912:174562.
DOI: https://doi.org/10.1016/j.ejphar.2021.174562
Ziegler D, Keller J, Maier C, Pannek J. Diabetic neuropathy. Exp Clin Endocrinol Diabetes 2023;131:72-83.
DOI: https://doi.org/10.1055/a-1946-3813
Hackett RA, Steptoe A. Type 2 diabetes mellitus and psychological stress - a modifiable risk factor. Nat Rev Endocrinol 2017;13:547-60.
DOI: https://doi.org/10.1038/nrendo.2017.64
Gabbay-Benziv R, Reece EA, Wang F, Yang P. Birth defects in pregestational diabetes: Defect range, glycemic threshold and pathogenesis. World J Diabetes 2015;6:481-8.
DOI: https://doi.org/10.4239/wjd.v6.i3.481
Lee SY, Papanna R, Farmer D, Tsao K. Fetal repair of neural tube defects. Clin Perinatol 2022;49:835-48.
DOI: https://doi.org/10.1016/j.clp.2022.06.004
Ocal O, Ocal FD, Sinaci S, Daglar Z, Secen AE, Divanlioglu D, et al. Maternal serum and fetal cord blood concentrations of thiol/disulfide and ischemia-modified albumin as predictors of neural tube defects. Turk Neurosurg 2023;33:134-9.
DOI: https://doi.org/10.5137/1019-5149.JTN.40096-22.3
Hong CJ, Park H, Yu SW. Autophagy for the quality control of adult hippocampal neural stem cells. Brain Res 2016;1649:166-72.
DOI: https://doi.org/10.1016/j.brainres.2016.02.048
Qi Y, Zhang M, Li H, Frank JA, Dai L, Liu H, et al. Autophagy inhibition by sustained overproduction of IL6 contributes to arsenic carcinogenesis. Cancer Res 2014;74:3740-52.
DOI: https://doi.org/10.1158/0008-5472.CAN-13-3182
Strand DW, Jiang M, Murphy TA, Yi Y, Konvinse KC, Franco OE, et al. PPARgamma isoforms differentially regulate metabolic networks to mediate mouse prostatic epithelial differentiation. Cell Death Dis 2012;3:e361.
DOI: https://doi.org/10.1038/cddis.2012.99
Corona JC, de Souza SC, Duchen MR. PPARgamma activation rescues mitochondrial function from inhibition of complex I and loss of PINK1. Exp Neurol 2014;253:16-27.
DOI: https://doi.org/10.1016/j.expneurol.2013.12.012
Liu Y, Wang J, Luo S, Zhan Y, Lu Q. The roles of PPARgamma and its agonists in autoimmune diseases: A comprehensive review. J Autoimmun 2020;113:102510.
DOI: https://doi.org/10.1016/j.jaut.2020.102510
Ethics Approval
This study received approval from the Ethics Committee of Jinan University (approval no. 20210826-25; Guangzhou, China)How to Cite
Pan, Y., Qiu, D., Chen, S., Han, X., & Li, R. (2023). High glucose inhibits neural differentiation by excessive autophagy <em>via</em> peroxisome proliferator-activated receptor gamma. European Journal of Histochemistry, 67(2). https://doi.org/10.4081/ejh.2023.3691
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