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

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, i...

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Detalles Bibliográficos
Autores: Sáenz de Urturi, Diego, Buqué, Xabier, Porteiro, Begoña, Folgueira, Cintia, Mora, Alfonso, Delgado, Teresa C, Prieto-Fernández, Endika, Olaizola, Paula, Gómez-Santos, Beatriz, Apodaka-Biguri, Maider, González-Romero, Francisco, Nieva-Zuluaga, Ane, Ruiz de Gauna, Mikel, Goikoetxea-Usandizaga, Naroa, García-Rodríguez, Juan Luis, Gutierrez de Juan, Virginia, Aurrekoetxea, Igor, Montalvo-Romeral, Valle, Novoa, Eva M, Martín-Guerrero, Idoia, Varela-Rey, Marta, Bhanot, Sanjay, Lee, Richard, Banales, Jesus M, Syn, Wing-Kin, Sabio, Guadalupe, Martínez-Chantar, María L, Nogueiras, Rubén, Aspichueta, Patricia
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/15706
Acceso en línea:http://hdl.handle.net/20.500.12105/15706
Access Level:acceso abierto
Palabra clave:Adipose Tissue, Brown
Insulin Resistance
Methionine Adenosyltransferase
Obesity
Oligonucleotides, Antisense
Animals
Energy Metabolism
Liver
Mice
NF-E2-Related Factor 2
Descripción
Sumario: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.

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