Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis.

Sáenz de Urturi, Diego; Buqué, Xabier; Porteiro, Begoña; Folgueira, Cintia; Mora, Alfonso; Delgado, Teresa C; Prieto-Fernández, Endika; Olaizola, Paula; Gómez-Santos, Beatriz; Apodaka-Biguri, Maider; González-Romero, Francisco; Nieva-Zuluaga, Ane; Ruiz de Gauna, Mikel; Goikoetxea-Usandizaga, Naroa; García-Rodríguez, Juan Luis; Gutierrez de Juan, Virginia; Aurrekoetxea, Igor; Montalvo-Romeral, Valle; Novoa, Eva M; Martín-Guerrero, Idoia; Varela-Rey, Marta; Bhanot, Sanjay; Lee, Richard; Banales, Jesus M; Syn, Wing-Kin; Sabio, Guadalupe; Martínez-Chantar, María L; Nogueiras, Rubén; Aspichueta, Patricia

Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis.

Altered methionine metabolism is associated with weight gain in obesity. The methionine adenosyltransferase (MAT), catalyzing the first reaction of the methionine cycle, plays an important role regulating lipid metabolism. However, its role in obesity, when a plethora of metabolic diseases occurs, i...

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Autores:	Sáenz de Urturi, Diego, Buqué, Xabier, Porteiro, Begoña, Folgueira, Cintia, Mora, Alfonso, Delgado, Teresa C, Prieto-Fernández, Endika, Olaizola, Paula, Gómez-Santos, Beatriz, Apodaka-Biguri, Maider, González-Romero, Francisco, Nieva-Zuluaga, Ane, Ruiz de Gauna, Mikel, Goikoetxea-Usandizaga, Naroa, García-Rodríguez, Juan Luis, Gutierrez de Juan, Virginia, Aurrekoetxea, Igor, Montalvo-Romeral, Valle, Novoa, Eva M, Martín-Guerrero, Idoia, Varela-Rey, Marta, Bhanot, Sanjay, Lee, Richard, Banales, Jesus M, Syn, Wing-Kin, Sabio, Guadalupe, Martínez-Chantar, María L, Nogueiras, Rubén, Aspichueta, Patricia
Tipo de recurso:	artículo
Fecha de publicación:	2022
País:	España
Institución:	Instituto de Salud Carlos III (ISCIII)
Repositorio:	Repisalud
Idioma:	inglés
OAI Identifier:	oai:repisalud.isciii.es:20.500.12105/15706
Acceso en línea:	http://hdl.handle.net/20.500.12105/15706
Access Level:	acceso abierto
Palabra clave:	Adipose Tissue, Brown Insulin Resistance Methionine Adenosyltransferase Obesity Oligonucleotides, Antisense Animals Energy Metabolism Liver Mice NF-E2-Related Factor 2

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spelling	Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis.Sáenz de Urturi, DiegoBuqué, XabierPorteiro, BegoñaFolgueira, CintiaMora, AlfonsoDelgado, Teresa CPrieto-Fernández, EndikaOlaizola, PaulaGómez-Santos, BeatrizApodaka-Biguri, MaiderGonzález-Romero, FranciscoNieva-Zuluaga, AneRuiz de Gauna, MikelGoikoetxea-Usandizaga, NaroaGarcía-Rodríguez, Juan LuisGutierrez de Juan, VirginiaAurrekoetxea, IgorMontalvo-Romeral, ValleNovoa, Eva MMartín-Guerrero, IdoiaVarela-Rey, MartaBhanot, SanjayLee, RichardBanales, Jesus MSyn, Wing-KinSabio, GuadalupeMartínez-Chantar, María LNogueiras, RubénAspichueta, PatriciaAdipose Tissue, BrownInsulin ResistanceMethionine AdenosyltransferaseObesityOligonucleotides, AntisenseAnimalsEnergy MetabolismLiverMiceNF-E2-Related Factor 2Altered methionine metabolism is associated with weight gain in obesity. The methionine adenosyltransferase (MAT), catalyzing the first reaction of the methionine cycle, plays an important role regulating lipid metabolism. However, its role in obesity, when a plethora of metabolic diseases occurs, is still unknown. By using antisense oligonucleotides (ASO) and genetic depletion of Mat1a, here, we demonstrate that Mat1a deficiency in diet-induce obese or genetically obese mice prevented and reversed obesity and obesity-associated insulin resistance and hepatosteatosis by increasing energy expenditure in a hepatocyte FGF21 dependent fashion. The increased NRF2-mediated FGF21 secretion induced by targeting Mat1a, mobilized plasma lipids towards the BAT to be catabolized, induced thermogenesis and reduced body weight, inhibiting hepatic de novo lipogenesis. The beneficial effects of Mat1a ASO were abolished following FGF21 depletion in hepatocytes. Thus, targeting Mat1a activates the liver-BAT axis by increasing NRF2-mediated FGF21 secretion, which prevents obesity, insulin resistance and hepatosteatosis.Nature Publishing GroupAgencia Estatal de Investigación (España)Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)Fundación LillyAsociación Española Contra el CáncerComunidad de Madrid (España)Fundación La CaixaMinisterio de Economía, Innovación y Competitividad (España)Fundación BBVAXunta de Galicia (España)20232023-03-2720222022-03-0120222022-03-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/15706reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/157062026-06-12T12:43:37Z
dc.title.none.fl_str_mv	Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis.
title	Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis.
spellingShingle	Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis. Sáenz de Urturi, Diego Adipose Tissue, Brown Insulin Resistance Methionine Adenosyltransferase Obesity Oligonucleotides, Antisense Animals Energy Metabolism Liver Mice NF-E2-Related Factor 2
title_short	Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis.
title_full	Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis.
title_fullStr	Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis.
title_full_unstemmed	Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis.
title_sort	Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis.
dc.creator.none.fl_str_mv	Sáenz de Urturi, Diego Buqué, Xabier Porteiro, Begoña Folgueira, Cintia Mora, Alfonso Delgado, Teresa C Prieto-Fernández, Endika Olaizola, Paula Gómez-Santos, Beatriz Apodaka-Biguri, Maider González-Romero, Francisco Nieva-Zuluaga, Ane Ruiz de Gauna, Mikel Goikoetxea-Usandizaga, Naroa García-Rodríguez, Juan Luis Gutierrez de Juan, Virginia Aurrekoetxea, Igor Montalvo-Romeral, Valle Novoa, Eva M Martín-Guerrero, Idoia Varela-Rey, Marta Bhanot, Sanjay Lee, Richard Banales, Jesus M Syn, Wing-Kin Sabio, Guadalupe Martínez-Chantar, María L Nogueiras, Rubén Aspichueta, Patricia
author	Sáenz de Urturi, Diego
author_facet	Sáenz de Urturi, Diego Buqué, Xabier Porteiro, Begoña Folgueira, Cintia Mora, Alfonso Delgado, Teresa C Prieto-Fernández, Endika Olaizola, Paula Gómez-Santos, Beatriz Apodaka-Biguri, Maider González-Romero, Francisco Nieva-Zuluaga, Ane Ruiz de Gauna, Mikel Goikoetxea-Usandizaga, Naroa García-Rodríguez, Juan Luis Gutierrez de Juan, Virginia Aurrekoetxea, Igor Montalvo-Romeral, Valle Novoa, Eva M Martín-Guerrero, Idoia Varela-Rey, Marta Bhanot, Sanjay Lee, Richard Banales, Jesus M Syn, Wing-Kin Sabio, Guadalupe Martínez-Chantar, María L Nogueiras, Rubén Aspichueta, Patricia
author_role	author
author2	Buqué, Xabier Porteiro, Begoña Folgueira, Cintia Mora, Alfonso Delgado, Teresa C Prieto-Fernández, Endika Olaizola, Paula Gómez-Santos, Beatriz Apodaka-Biguri, Maider González-Romero, Francisco Nieva-Zuluaga, Ane Ruiz de Gauna, Mikel Goikoetxea-Usandizaga, Naroa García-Rodríguez, Juan Luis Gutierrez de Juan, Virginia Aurrekoetxea, Igor Montalvo-Romeral, Valle Novoa, Eva M Martín-Guerrero, Idoia Varela-Rey, Marta Bhanot, Sanjay Lee, Richard Banales, Jesus M Syn, Wing-Kin Sabio, Guadalupe Martínez-Chantar, María L Nogueiras, Rubén Aspichueta, Patricia
author2_role	author author author author author author author author author author author author author author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Agencia Estatal de Investigación (España) Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) Fundación Lilly Asociación Española Contra el Cáncer Comunidad de Madrid (España) Fundación La Caixa Ministerio de Economía, Innovación y Competitividad (España) Fundación BBVA Xunta de Galicia (España)
dc.subject.none.fl_str_mv	Adipose Tissue, Brown Insulin Resistance Methionine Adenosyltransferase Obesity Oligonucleotides, Antisense Animals Energy Metabolism Liver Mice NF-E2-Related Factor 2
topic	Adipose Tissue, Brown Insulin Resistance Methionine Adenosyltransferase Obesity Oligonucleotides, Antisense Animals Energy Metabolism Liver Mice NF-E2-Related Factor 2
description	Altered methionine metabolism is associated with weight gain in obesity. The methionine adenosyltransferase (MAT), catalyzing the first reaction of the methionine cycle, plays an important role regulating lipid metabolism. However, its role in obesity, when a plethora of metabolic diseases occurs, is still unknown. By using antisense oligonucleotides (ASO) and genetic depletion of Mat1a, here, we demonstrate that Mat1a deficiency in diet-induce obese or genetically obese mice prevented and reversed obesity and obesity-associated insulin resistance and hepatosteatosis by increasing energy expenditure in a hepatocyte FGF21 dependent fashion. The increased NRF2-mediated FGF21 secretion induced by targeting Mat1a, mobilized plasma lipids towards the BAT to be catabolized, induced thermogenesis and reduced body weight, inhibiting hepatic de novo lipogenesis. The beneficial effects of Mat1a ASO were abolished following FGF21 depletion in hepatocytes. Thus, targeting Mat1a activates the liver-BAT axis by increasing NRF2-mediated FGF21 secretion, which prevents obesity, insulin resistance and hepatosteatosis.
publishDate	2022
dc.date.none.fl_str_mv	2022 2022-03-01 2022 2022-03-01 2023 2023-03-27
dc.type.none.fl_str_mv	journal article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	http://hdl.handle.net/20.500.12105/15706
url	http://hdl.handle.net/20.500.12105/15706
dc.language.none.fl_str_mv	Inglés eng
language_invalid_str_mv	Inglés
language	eng
dc.rights.none.fl_str_mv	open access http://purl.org/coar/access_right/c_abf2 Atribución 4.0 Internacional http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	open access http://purl.org/coar/access_right/c_abf2 Atribución 4.0 Internacional http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	Nature Publishing Group
publisher.none.fl_str_mv	Nature Publishing Group
dc.source.none.fl_str_mv	reponame:Repisalud instname:Instituto de Salud Carlos III (ISCIII)
instname_str	Instituto de Salud Carlos III (ISCIII)
reponame_str	Repisalud
collection	Repisalud
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Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis.

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