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

Adipose Tissue, Brown / metabolism Animals Energy Metabolism Insulin Resistance Liver / metabolism Methionine Adenosyltransferase / genetics Mice NF-E2-Related Factor 2 / genetics Obesity / genetics Oligonucleotides, Antisense / metabolism

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
01 03 2022
Historique:
received: 24 07 2020
accepted: 03 02 2022
entrez: 2 3 2022
pubmed: 3 3 2022
medline: 13 4 2022
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-022-28749-z PMID: 35232994 PMC: PMC8888704
pubmed: 35232994
doi: 10.1038/s41467-022-28749-z
pii: 10.1038/s41467-022-28749-z
pmc: PMC8888704
doi:

Substances chimiques

NF-E2-Related Factor 2 0
Oligonucleotides, Antisense 0
Mat1a protein, mouse EC 2.5.1.6
Methionine Adenosyltransferase EC 2.5.1.6

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1096

Informations de copyright

© 2022. The Author(s).

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Auteurs

Diego Sáenz de Urturi (D)

Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.

Xabier Buqué (X)

Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.
Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.
ORCID: 0000-0002-0911-0033

Begoña Porteiro (B)

Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.

Cintia Folgueira (C)

Myocardial Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
ORCID: 0000-0003-3803-9149

Alfonso Mora (A)

Myocardial Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
ORCID: 0000-0002-6397-4836

Teresa C Delgado (TC)

Liver Disease Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Derio, Spain.
ORCID: 0000-0001-9204-581X

Endika Prieto-Fernández (E)

Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Science and Technology, University of the Basque Country UPV/EHU, Leioa, Spain.
ORCID: 0000-0001-8378-1495

Paula Olaizola (P)

Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute-Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
ORCID: 0000-0002-1358-5429

Beatriz Gómez-Santos (B)

Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.

Maider Apodaka-Biguri (M)

Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.

Francisco González-Romero (F)

Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.

Ane Nieva-Zuluaga (A)

Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.

Mikel Ruiz de Gauna (M)

Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.

Naroa Goikoetxea-Usandizaga (N)

Liver Disease Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Derio, Spain.
ORCID: 0000-0003-4569-028X

Juan Luis García-Rodríguez (JL)

Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.
ORCID: 0000-0002-1818-1781

Virginia Gutierrez de Juan (V)

Liver Disease Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Derio, Spain.

Igor Aurrekoetxea (I)

Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.
Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.

Valle Montalvo-Romeral (V)

Myocardial Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.

Eva M Novoa (EM)

Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.

Idoia Martín-Guerrero (I)

Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Science and Technology, University of the Basque Country UPV/EHU, Leioa, Spain.
ORCID: 0000-0002-0098-1908

Marta Varela-Rey (M)

Liver Disease Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Derio, Spain.
National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain.
Gene Regulatory Control in Disease Laboratory, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
ORCID: 0000-0002-2413-8659

Sanjay Bhanot (S)

IONIS Pharmaceuticals, Carlsbad, CA, USA.

Richard Lee (R)

IONIS Pharmaceuticals, Carlsbad, CA, USA.
ORCID: 0000-0003-1738-1746

Jesus M Banales (JM)

Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute-Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain.
Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.

Wing-Kin Syn (WK)

Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.
Section of Gastroenterology, Ralph H Johnson, VAMC, Charleston, SC, USA.
Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC, USA.

Guadalupe Sabio (G)

Myocardial Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.

María L Martínez-Chantar (ML)

Liver Disease Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Derio, Spain.
National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain.
ORCID: 0000-0002-6446-9911

Rubén Nogueiras (R)

Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
Galician Agency of Investigation, Xunta de Galicia, Spain.
ORCID: 0000-0002-9976-9930

Patricia Aspichueta (P)

Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain. patricia.aspichueta@ehu.eus.
Biocruces Bizkaia Health Research Institute, Barakaldo, Spain. patricia.aspichueta@ehu.eus.
National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain. patricia.aspichueta@ehu.eus.
ORCID: 0000-0002-3553-1755

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Classifications MeSH

questionsmedicales.fr › Tissus › Tissu conjonctif › Tissu adipeux › Tissu adipeux brun › Methionine adenosyltransferase 1a antisense...
questionsmedicales.fr › Eucaryotes › Animaux › Methionine adenosyltransferase 1a antisense...
questionsmedicales.fr › Métabolisme › Métabolisme énergétique › Methionine adenosyltransferase 1a antisense...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Insulinorésistance › Methionine adenosyltransferase 1a antisense...
questionsmedicales.fr › Système digestif › Foie › Methionine adenosyltransferase 1a antisense...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Alkyl et aryl transferases › Methionine adenosyltransferase › Methionine adenosyltransferase 1a antisense...
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