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, 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.