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-GuerreroMarta Varela-Rey, Sanjay Bhanot, Richard Lee, Jesus M. Banales, Wing Kin Syn, Guadalupe Sabio, María L. Martínez-Chantar, Rubén Nogueiras, Patricia Aspichueta*

*Corresponding author af dette arbejde

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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.

OriginalsprogEngelsk
Artikelnummer1096
TidsskriftNature Communications
Vol/bind13
Nummer1
Antal sider19
ISSN2041-1723
DOI
StatusUdgivet - dec. 2022
Udgivet eksterntJa

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