dc.creator | Lorenzo, Petra I. | es |
dc.creator | Martín Vázquez, Eugenia | es |
dc.creator | López-Noriega, Livia | es |
dc.creator | Fuente-Martín, Esther | es |
dc.creator | Mellado-Gil, José M. | es |
dc.creator | Franco, Jaime M. | es |
dc.creator | Rivero Canalejo, Sabrina | es |
dc.creator | Pozo Pérez, David | es |
dc.creator | Gauthier, Benoit R. | es |
dc.date.accessioned | 2022-10-31T16:43:55Z | |
dc.date.available | 2022-10-31T16:43:55Z | |
dc.date.issued | 2021 | |
dc.identifier.citation | Lorenzo, P.I., Martín Vázquez, E., López-Noriega, L., Fuente-Martín, E., Mellado-Gil, J.M., Franco, J.M.,...,Gauthier, B.R. (2021). The metabesity factor HMG20A potentiates astrocyte survival and reactive astrogliosis preserving neuronal integrity. Theranostics, 11 (14), 6983-7004. https://doi.org/10.7150/thno.57237. | |
dc.identifier.issn | 1838-7640 | es |
dc.identifier.uri | https://hdl.handle.net/11441/138552 | |
dc.description.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 ORY1001, 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. | es |
dc.format | application/pdf | es |
dc.format.extent | 22 p. | es |
dc.language.iso | eng | es |
dc.publisher | IVYSPRING INT PUBL | es |
dc.relation.ispartof | Theranostics, 11 (14), 6983-7004. | |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject | HMG20A | es |
dc.subject | Metabolism | es |
dc.subject | Metabesity | es |
dc.subject | Astrocytes | es |
dc.subject | Inflammation | es |
dc.subject | ORY1001 | es |
dc.title | The metabesity factor HMG20A potentiates astrocyte survival and reactive astrogliosis preserving neuronal integrity | es |
dc.type | info:eu-repo/semantics/article | es |
dcterms.identifier | https://ror.org/03yxnpp24 | |
dc.type.version | info:eu-repo/semantics/publishedVersion | es |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | es |
dc.contributor.affiliation | Universidad de Sevilla. Departamento de Citología e Histología Normal y Patológica | es |
dc.contributor.affiliation | Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología | es |
dc.relation.projectID | PI-0727-2010 | es |
dc.relation.projectID | PI-0001-2020 | es |
dc.relation.projectID | P10.CTS.6359 | es |
dc.relation.projectID | PI10/00871 | es |
dc.relation.projectID | PI13/00593 | es |
dc.relation.projectID | IJCI-2015-26238 | es |
dc.relation.projectID | RH-0070-2013 | es |
dc.relation.publisherversion | https://www.thno.org/v11p6983.htm | es |
dc.identifier.doi | 10.7150/thno.57237 | es |
dc.journaltitle | Theranostics | es |
dc.publication.volumen | 11 | es |
dc.publication.issue | 14 | es |
dc.publication.initialPage | 6983 | es |
dc.publication.endPage | 7004 | es |
dc.contributor.funder | Consejería de Salud, Fundación Pública Andaluza Progreso y Salud, Junta de Andalucía | es |
dc.contributor.funder | Consejería de Economía, Innovación y Ciencia | es |
dc.contributor.funder | Ministerio de Economía y Competitividad co-funded by Fondos FEDER | es |
dc.contributor.funder | Ministerio de Economía y Competitividad | es |
dc.contributor.funder | Consejería de Salud, Junta de Andalucía | es |