1. The metabesity factor HMG20A potentiates astrocyte survival and reactive astrogliosis preserving neuronal integrity
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Antonio Campos-Caro, Eduardo García Fuentes, Francisco Javier Bermúdez-Silva, Nadia Cobo-Vuilleumier, Petra I. Lorenzo, Christian Claude Lachaud, Benoit R. Gauthier, Valentine Comaills, Esther Fuente-Martin, Jose C. Reyes, Alejandro Martin-Montalvo, Alejandra Crespo Barreda, José A Guerrero Martínez, Sabrina Rivero Canalejo, Jesús Ángel Pérez-Cabello, Franz Martín, Manuel Álvarez Dolado, José Manuel Mellado-Gil, Eugenia Martin Vázquez, Gemma Rojo-Martínez, Silvana Y. Romero-Zerbo, David Pozo, Jaime M. Franco, Manuel Aguilar-Diosdado, Livia López-Noriega, Junta de Andalucía, European Commission, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación Vencer el Cancer, Fundación DiabetesCERO, Juvenile Diabetes Research Foundation, Instituto de Salud Carlos III, Asociación Española Contra el Cáncer, [Lorenzo,PI, Martin Vazquez,E, López-Noriega,L, Fuente-Martín,E, Mellado-Gil,JM, Franco,JM, Cobo-Vuilleumier,N, Guerrero Martínez,JA, Perez-Cabello,JA, Lachaud,CC, Crespo Barreda,A, Martin-Montalvo,A, Álvarez Dolado,M, Martin,F, Comaills,V, Reyes,JC, Gauthier,BR] Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain. [Romero-Zerbo,SY, Rojo-Martinez,G, Bérmudez-Silva,FJ] Unidad de Gestión Clínica Intercentros de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Spain. [Rivero Canalejo,S] Department of Normal and Pathological Histology and Cytology, University of Seville School of Medicine, Seville, Spain. University Hospital 'Puerta del Mar', Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Cádiz, Spain. [Campos-Caro,A, Aguilar-Diosdado,M] Department of Normal and Pathological Histology and Cytology, University of Seville School of Medicine, Seville, Spain. 4. University Hospital 'Puerta del Mar', Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Cádiz, Spain. [Aguilar-Diosdado,M] Endocrinology and Metabolism Department, University Hospital 'Puerta del Mar', Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Cádiz, Spain. [García Fuentes,E] Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Spain. [Martín,F, Rojo-Martínez,G, Bérmudez-Silva,FJ, Gauthier,BR] Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain., The authors are supported by grants from the Consejería de Salud, Fundación Pública Andaluza Progreso y Salud, Junta de Andalucía (PI-0727-2010 and PI-0001-2020 to B.R.G., PI-0085-2013 to P.I.L., PI-0006-2016 to E.F.M., PI-0574-2012 to S.Y.R.Z, PI-0247-2016 to F.J.B.S.), the Consejería de Economía, Innovación y Ciencia (P10.CTS.6359 to B.R.G., CTS.8081 to E.G.F.), the Ministerio de Economía y Competitividad co-funded by Fondos FEDER (PI10/00871, PI13/00593 and BFU2017-83588-P to B.R.G., PRE2018-084907 to M.E.M.V.G., PI13/00309, PI17/01004 to F.J.B.S., BFU2014-5343-P to J.C.R., and and AGL2017-86927-R to F.M.), Vencer el Cancer (B.R.G), DiabetesCero (B.R.G.) and the Juvenile Diabetes Research Foundation (17-2013-372 and 2-SRA-2019-837-S-B to B.R.G.). E.F.M. was a recipient of a Juan de la Cierva Incorporación Fellowship from the Ministerio de Economía y Competitividad (IJCI-2015-26238). S.Y.R.Z is a recipient of a postdoctoral fellowship from Consejería de Salud, Junta de Andalucía (RH-0070-2013). L.L.N. is supported by a Consejeria de Economia, Conocimiento, Empresas y Universidad postdoctoral fellowship (DOC_00652). F.J.B.S. and E.G.F. are recipients of 'Nicolás Monardes' research contracts from Consejería de Salud Junta de Andalucía, (C-0070-2012 and C-0031-2016). A.M.M. is supported by CPII19/00023 and PI18/01590 from the Instituto de Salud Carlos III co-funded by Fondos FEDER. CIBERDEM is an initiative of the Instituto de Salud Carlos III. V.C. is supported by a AECC investigator award.
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Astrocitos ,Male ,Interleukin-1beta ,Medicine (miscellaneous) ,Adipose tissue ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,Mice ,ORY1001 ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Nerve Tissue Proteins [Medical Subject Headings] ,Organisms::Eukaryota::Animals [Medical Subject Headings] ,Glucose homeostasis ,Gliosis ,RNA-Seq ,RNA, Small Interfering ,Anatomy::Nervous System::Neurons [Medical Subject Headings] ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Metabolismo ,Histone Demethylases ,Neurons ,Chemicals and Drugs::Carbohydrates::Glycosides::Glucosides [Medical Subject Headings] ,High Mobility Group Proteins ,metabesity ,Middle Aged ,Mitochondria ,Astrogliosis ,medicine.anatomical_structure ,Adipose Tissue ,Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Oxidoreductases::Oxidoreductases Acting on CH-NH Group Donors::Oxidoreductases, N-Demethylating::Histone Demethylases [Medical Subject Headings] ,Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Diabetes Mellitus::Diabetes Mellitus, Type 2 [Medical Subject Headings] ,medicine.symptom ,Co-Repressor Proteins ,Research Paper ,Astrocyte ,Adult ,medicine.medical_specialty ,Cell Survival ,Anatomy::Nervous System::Neuroglia::Astrocytes [Medical Subject Headings] ,Hypothalamus ,Nerve Tissue Proteins ,Inflammation ,Biology ,Diet, High-Fat ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Nuclear Proteins::Chromosomal Proteins, Non-Histone::High Mobility Group Proteins [Medical Subject Headings] ,Phenomena and Processes::Physiological Phenomena::Nutritional Physiological Phenomena::Diet::Diet, High-Fat [Medical Subject Headings] ,Insulin resistance ,Downregulation and upregulation ,Internal medicine ,Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Survival [Medical Subject Headings] ,Glial Fibrillary Acidic Protein ,medicine ,Animals ,Humans ,Obesity ,Metabesity ,Persons::Persons::Age Groups::Adult [Medical Subject Headings] ,Inflamación ,astrocytes ,Persons::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings] ,Anatomy::Nervous System::Central Nervous System::Brain::Limbic System::Hypothalamus [Medical Subject Headings] ,Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Gliosis [Medical Subject Headings] ,medicine.disease ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription Factors::Repressor Proteins::Co-Repressor Proteins [Medical Subject Headings] ,Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::Obesity [Medical Subject Headings] ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Interleukins::Interleukin-1::Interleukin-1beta [Medical Subject Headings] ,Mice, Inbred C57BL ,Metabolism ,Glucose ,Endocrinology ,Diabetes Mellitus, Type 2 ,inflammation ,Astrocytes ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Inbred Strains [Medical Subject Headings] ,HMG20A ,Neuron ,metabolism - Abstract
Rationale: We recently demonstrated that the Metabesity factor HMG20A regulates islet beta-cell functional maturity and adaptation to physiological stress such as pregnancy and pre-diabetes. HMG20A also dictates central nervous system (CNS) development via inhibition of the LSD1-CoREST complex but its expression pattern and function in adult brain remains unknown. Herein we sought to determine whether HMG20A is expressed in the adult CNS, specifically in hypothalamic astrocytes that are key in glucose homeostasis and whether similar to islets, HMG20A potentiates astrocyte function in response to environmental cues. Methods: HMG20A expression profile was assessed by quantitative PCR (QT-PCR), Western blotting and/or immunofluorescence in: 1) the hypothalamus of mice exposed or not to either a high-fat diet or a high-fat high-sucrose regimen, 2) human blood leukocytes and adipose tissue obtained from healthy or diabetic individuals and 3) primary mouse hypothalamic astrocytes exposed to either high glucose or palmitate. RNA-seq and cell metabolic parameters were performed on astrocytes treated or not with a siHMG20A. Astrocyte-mediated neuronal survival was evaluated using conditioned media from siHMG20A-Treated astrocytes. The impact of ORY100. An Inhibitor Of The LSD1-CoREST Complex, On Hmg20a Expression, Reactive Astrogliosis And Glucose Metabolism Was Evaluated In Vitro And In Vivo In High-Fat High-Sucrose Fed Mice. Results: We Show That Hmg20a Is Predominantly Expressed In Hypothalamic Astrocytes, The Main Nutrient-Sensing Cell Type Of The Brain. Hmg20a Expression Was Upregulated In Diet-Induced Obesity And Glucose Intolerant Mice, Correlating With Increased Transcript Levels Of Gfap And Il1b Indicative Of Inflammation And Reactive Astrogliosis. Hmg20a Transcript Levels Were Also Increased In Adipose Tissue Of Obese Non-Diabetic Individuals As Compared To Obese Diabetic Patients. Hmg20a Silencing In Astrocytes Resulted In Repression Of Inflammatory, Cholesterol Biogenesis And Epithelial-To-Mesenchymal Transition Pathways Which Are Hallmarks Of Reactive Astrogliosis. Accordingly, Hmg20a Depleted Astrocytes Exhibited Reduced Mitochondrial Bioenergetics And Increased Susceptibility To Apoptosis. Neuron Viability Was Also Hindered In HMG20A-Depleted Astrocyte-Derived Conditioned Media. Ory1001 Treatment Rescued Expression Of Reactive Astrogliosis-Linked Genes In Hmg20a Ablated Astrocytes While Enhancing Cell Surface Area, Gfap Intensity And Stat3 Expression In Healthy Astrocytes, Mimicking The Effect Of Hmg20a. Furthermore, Ory1001 Treatment Protected Against Obesity-Associated Glucose Intolerance In Mice Correlating With A Regression Of Hypothalamic Hmg20a Expression, Indicative Of Reactive Astrogliosis Attenuation With Improved Health Status. Conclusion: Hmg20a Coordinates The Astrocyte Polarization State. Under Physiological Pressure Such As Obesity And Insulin Resistance That Induces Low Grade Inflammation, Hmg20a Expression Is Increased To Induce Reactive Astrogliosis In An Attempt To Preserve The Neuronal Network And Re-Establish Glucose Homeostasis. Nonetheless, A Chronic Metabesity State Or Functional Mutations Will Result In Lower Levels Of Hmg20a, Failure To Promote Reactive Astrogliosis And Increase Susceptibility Of Neurons To Stress-Induced Apoptosis. Such Effects Could Be Reversed By Ory1001 Treatment Both In Vitro And In Vivo, Paving The Way For A New Therapeutic Approach For Type 2 Diabetes Mellitus., The authors are supported by grants from the Consejería de Salud, Fundación Pública Andaluza Progreso y Salud, Junta de Andalucía (PI-0727-2010 and PI-0001-2020 to B.R.G.; PI-0085-2013 to P.I.L.; PI-0006-2016 to E.F.M.; PI-0574-2012 to S.Y.R.Z; PI-0247-2016 to F.J.B.S.), the Consejería de Economía, Innovación y Ciencia (P10.CTS.6359 to B.R.G.; CTS.8081 to E.G.F.), the Ministerio de Economía y Competitividad co-funded by Fondos FEDER (PI10/00871, PI13/00593 and BFU2017-83588-P to B.R.G.; PRE2018-084907 to M.E.M.V.G.; PI13/00309; PI17/01004 to F.J.B.S.; BFU2014-5343-P to J.C.R.; and AGL2017-86927-R to F.M.), Vencer el Cancer (B.R.G), DiabetesCero (B.R.G.) and the Juvenile Diabetes Research Foundation (17-2013-372 and 2-SRA-2019-837-S-B to B.R.G.). E.F.M. was a recipient of a Juan de la Cierva Incorporación Fellowship from the Ministerio de Economía y Competitividad (IJCI-2015-26238). S.Y.R.Z is a recipient of a postdoctoral fellowship from Consejería de Salud, Junta de Andalucía (RH-0070-2013). L.L.N. is supported by a Consejeria de Economia, Conocimiento, Empresas y Universidad postdoctoral fellowship (DOC_00652). F.J.B.S. and E.G.F. are recipients of "Nicolás Monardes" research contracts from Consejería de Salud Junta de Andalucía, (C-0070-2012 and C-0031-2016). A.M.M. is supported by CPII19/00023 and PI18/01590 from the Instituto de Salud Carlos III co-funded by Fondos FEDER. CIBERDEM is an initiative of the Instituto de Salud Carlos III. V.C. is supported by a AECC investigator award.
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- 2021
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