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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Detalhes bibliográficos
Autores: Saenz-De-Urturi, D. (Diego)|||/items/9cae7551-eaae-49fd-a0f2-ee63e52246e5, Buque, X. (Xabier)|||/items/dac3924e-8d31-4515-9e76-f46cc41c0acc, Porteiro, B. (Begoña)|||/items/a0469e98-1bfb-4768-ada9-24573be6f1cb, Folgueira, C. (Cintia)|||/items/21c66d54-1c86-495d-bb41-d2c1e2d24733, Mora, A. (Alfonso)|||/items/342b4683-fb71-47aa-ab0e-f75217a6a135, Delgado, T.C. (Teresa C.)|||/items/3eca531a-fb4a-4068-bb67-7c9ca55c8fb0, Prieto-Fernández, E. (Endika)|||/items/de66a8cf-db02-4afb-85e0-3fda928f8afa, Olaizola, P. (Paula)|||/items/5426b4b4-4ac7-46f7-8304-17cb549c08a4, Gómez-Santos, B. (Beatriz)|||/items/426fd680-44c0-4bb1-8f75-aec188bd070b, Apodaka-Biguri, M. (Maider)|||/items/14dbc28a-065f-40f6-9706-a34517e83351, González-Romero, F. (Francisco)|||/items/27f57966-25e7-4089-9bb5-9cfcbc5747a2, Nieva-Zuluaga, A. (Ane)|||/items/5af56c2d-2f4c-4e29-8d04-4a95e9165960, Ruiz-de-Gauna, M. (Mikel)|||/items/b3fdb2fe-141e-4e66-b98f-339736cf9274, Goikoetxea-Usandizaga, N. (Naroa)|||/items/6dd502a3-6304-4050-aef5-ab4a408318bf, García-Rodríguez, J.L. (Juan L.)|||/items/7ecf881c-28bc-4787-a071-1655bbbe44eb, Gutiérrez-de-Juan, V. (Virginia)|||/items/6c2966d4-76df-45cb-b999-0f5b872aabd9, Aurrekoetxea, I. (Igor)|||/items/c109bf8d-7a3b-4b75-9cd6-05bc5e62331f, Montalvo-Romeral, V. (Valle)|||/items/490facb5-f891-46aa-92a4-dfb387d5ef1c, Novoa, E. (Eva)|||/items/766fd1b8-02a2-455c-9709-c565201be738, Martin-Guerrero, I. (Idoia)|||/items/75058248-45e7-4a0d-846a-c54070403a95, Varela-Rey, M. (Marta)|||/items/c142211c-bbe7-4b40-a3ad-8d17134ee686, Bhanot, S. (Sanjay)|||/items/c2343121-5b33-4d6b-97f9-592fe1d513fe, Lee, R. (Richard)|||/items/9273aea1-071b-47fc-a362-76204ac28f20, Banales, J.M. (Jesús M.)|||/items/0c1309ae-e4e4-4e85-b2f1-567a388889d5, Syn, W.K. (Wing-Kin)|||/items/a9c3edc6-25f2-4739-a458-d846ccfaa276, Sabio, G. (Guadalupe)|||/items/f04ae0a3-ab59-4e44-b814-5e413bd5584d, Martinez-Chantar, M.L. (María Luz)|||/items/df06120b-2a53-4074-a155-638f899b2ce5, Nogueiras, R. (Rubén)|||/items/d6d4c851-6ed5-47d3-9361-c80bbfae88e6, Aspichueta, P. (Patricia)|||/items/384763a9-5584-4c74-baec-92991a901d35
Tipo de documento: artigo
Data de publicação:2022
País:España
Recursos:Universidad de Navarra
Repositório:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglês
OAI Identifier:oai:dadun.unav.edu:10171/119270
Acesso em linha:https://hdl.handle.net/10171/119270
Access Level:Acceso aberto
Palavra-chave:Altered methionine metabolism
Methionine adenosyltransferase (MAT)
Obesity
Antisense oligonucleotides (ASO)
Descrição
Resumo: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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