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

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, Francisco González-Romero, Ane Nieva-Zuluaga, Mikel Ruiz de Gauna, Naroa Goikoetxea-Usandizaga, Juan Luis García-Rodríguez, Virginia Gutierrez de Juan, Igor Aurrekoetxea, Valle Montalvo-Romeral, Eva M. Novoa, Idoia Martín-Guerrero, Marta Varela-Rey, Sanjay Bhanot, Richard Lee, Jesus M. Banales, Wing-Kin Syn, Guadalupe Sabio, María L. Martínez-Chantar, Rubén Nogueiras and Patricia Aspichueta ()
Additional contact information
Diego Sáenz de Urturi: University of the Basque Country UPV/EHU
Xabier Buqué: University of the Basque Country UPV/EHU
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
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)
Sanjay Bhanot: IONIS Pharmaceuticals
Richard Lee: IONIS Pharmaceuticals
Jesus M. Banales: University of the Basque Country (UPV/EHU)
Wing-Kin Syn: University of the Basque Country UPV/EHU
Guadalupe Sabio: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
María L. Martínez-Chantar: CIC bioGUNE-BRTA (Basque Research & Technology Alliance)
Rubén Nogueiras: University of Santiago de Compostela-Instituto de Investigación Sanitaria
Patricia Aspichueta: University of the Basque Country UPV/EHU

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28749-z

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