Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis.
Diego Sáenz de UrturiXabier BuquéBegoña PorteiroCintia FolgueiraAlfonso MoraTeresa Cardoso DelgadoEndika Prieto-FernándezPaula OlaizolaBeatriz Gómez-SantosMaider Apodaka-BiguriFrancisco González-RomeroAne Nieva-ZuluagaMikel Ruiz de GaunaNaroa Goikoetxea-UsandizagaJuan Luis García-RodríguezVirginia Gutierrez de JuanIgor AurrekoetxeaValle Montalvo-RomeralEva M NovoaIdoia Martin-GuerreroMarta Varela-ReySanjay BhanotRichard G LeeJesus M BanalesWing-Kin SynGuadalupe SabioMaría Luz Martínez-ChantarRuben NogueirasPatricia AspichuetaPublished in: Nature communications (2022)
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.
Keyphrases
- insulin resistance
- adipose tissue
- weight gain
- weight loss
- high fat diet induced
- metabolic syndrome
- type diabetes
- high fat diet
- skeletal muscle
- polycystic ovary syndrome
- body mass index
- bariatric surgery
- birth weight
- body weight
- oxidative stress
- diabetic rats
- high glucose
- signaling pathway
- fatty acid
- liver injury
- mouse model
- obese patients