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


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.

SUBMITTER: Saenz de Urturi D 

PROVIDER: S-EPMC8888704 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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

Sáenz de Urturi Diego D   Buqué Xabier X   Porteiro Begoña B   Folgueira Cintia C   Mora Alfonso A   Delgado Teresa C TC   Prieto-Fernández Endika E   Olaizola Paula P   Gómez-Santos Beatriz B   Apodaka-Biguri Maider M   González-Romero Francisco F   Nieva-Zuluaga Ane A   Ruiz de Gauna Mikel M   Goikoetxea-Usandizaga Naroa N   García-Rodríguez Juan Luis JL   Gutierrez de Juan Virginia V   Aurrekoetxea Igor I   Montalvo-Romeral Valle V   Novoa Eva M EM   Martín-Guerrero Idoia I   Varela-Rey Marta M   Bhanot Sanjay S   Lee Richard R   Banales Jesus M JM   Syn Wing-Kin WK   Sabio Guadalupe G   Martínez-Chantar María L ML   Nogueiras Rubén R   Aspichueta Patricia P  

Nature communications 20220301 1


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 rever  ...[more]

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