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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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  • Diego Sáenz de Urturi

    (University of the Basque Country UPV/EHU)

  • Xabier Buqué

    (University of the Basque Country UPV/EHU
    Biocruces Bizkaia Health Research Institute)

  • Begoña Porteiro

    (University of Santiago de Compostela-Instituto de Investigación Sanitaria)

  • Cintia Folgueira

    (Centro Nacional de Investigaciones Cardiovasculares (CNIC))

  • Alfonso Mora

    (Centro Nacional de Investigaciones Cardiovasculares (CNIC))

  • Teresa C. Delgado

    (CIC bioGUNE-BRTA (Basque Research & Technology Alliance))

  • Endika Prieto-Fernández

    (University of the Basque Country UPV/EHU)

  • Paula Olaizola

    (University of the Basque Country (UPV/EHU))

  • Beatriz Gómez-Santos

    (University of the Basque Country UPV/EHU)

  • Maider Apodaka-Biguri

    (University of the Basque Country UPV/EHU)

  • Francisco González-Romero

    (University of the Basque Country UPV/EHU)

  • Ane Nieva-Zuluaga

    (University of the Basque Country UPV/EHU)

  • Mikel Ruiz de Gauna

    (University of the Basque Country UPV/EHU)

  • Naroa Goikoetxea-Usandizaga

    (CIC bioGUNE-BRTA (Basque Research & Technology Alliance))

  • Juan Luis García-Rodríguez

    (University of the Basque Country UPV/EHU)

  • Virginia Gutierrez de Juan

    (CIC bioGUNE-BRTA (Basque Research & Technology Alliance))

  • Igor Aurrekoetxea

    (University of the Basque Country UPV/EHU
    Biocruces Bizkaia Health Research Institute)

  • Valle Montalvo-Romeral

    (Centro Nacional de Investigaciones Cardiovasculares (CNIC))

  • Eva M. Novoa

    (University of Santiago de Compostela-Instituto de Investigación Sanitaria)

  • Idoia Martín-Guerrero

    (University of the Basque Country UPV/EHU)

  • Marta Varela-Rey

    (CIC bioGUNE-BRTA (Basque Research & Technology Alliance)
    National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III)
    University of Santiago de Compostela-Instituto de Investigación Sanitaria)

  • Sanjay Bhanot

    (IONIS Pharmaceuticals)

  • Richard Lee

    (IONIS Pharmaceuticals)

  • Jesus M. Banales

    (University of the Basque Country (UPV/EHU)
    National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III)
    Ikerbasque, Basque Foundation for Science
    University of Navarra)

  • Wing-Kin Syn

    (University of the Basque Country UPV/EHU
    Ralph H Johnson, VAMC
    Medical University of South Carolina)

  • Guadalupe Sabio

    (Centro Nacional de Investigaciones Cardiovasculares (CNIC))

  • María L. Martínez-Chantar

    (CIC bioGUNE-BRTA (Basque Research & Technology Alliance)
    National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III))

  • Rubén Nogueiras

    (University of Santiago de Compostela-Instituto de Investigación Sanitaria
    CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)
    Galician Agency of Investigation)

  • Patricia Aspichueta

    (University of the Basque Country UPV/EHU
    Biocruces Bizkaia Health Research Institute
    National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III))

Abstract

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.

Suggested Citation

  • Diego Sáenz de Urturi & Xabier Buqué & Begoña Porteiro & Cintia Folgueira & Alfonso Mora & Teresa C. Delgado & Endika Prieto-Fernández & Paula Olaizola & Beatriz Gómez-Santos & Maider Apodaka-Biguri &, 2022. "Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28749-z
    DOI: 10.1038/s41467-022-28749-z
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    2. Matthew D. Hirschey & Tadahiro Shimazu & Eric Goetzman & Enxuan Jing & Bjoern Schwer & David B. Lombard & Carrie A. Grueter & Charles Harris & Sudha Biddinger & Olga R. Ilkayeva & Robert D. Stevens & , 2010. "SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation," Nature, Nature, vol. 464(7285), pages 121-125, March.
    3. Lucía Barbier-Torres & Karen A. Fortner & Paula Iruzubieta & Teresa C. Delgado & Emily Giddings & Youdinghuan Chen & Devin Champagne & David Fernández-Ramos & Daniela Mestre & Beatriz Gomez-Santos & M, 2020. "Silencing hepatic MCJ attenuates non-alcoholic fatty liver disease (NAFLD) by increasing mitochondrial fatty acid oxidation," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
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