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.

A multiomics comparison of weight loss interventions shows the distinct effects of bariatric surgery and intermittent fasting on hepatic metabolism

“…However, increased levels of both methyl donors and methyl acceptors suggest altered regulation at the entry point of the transmethylation cycle itself. That this change may be causative in the metabolic effects seen after bariatric surgery is supported by a recent study showing that silencing of MAT1A prevents obesity and hepatic steatosis 29 . It should be noted that ratios of PC to PE were relatively unaffected following surgery, while GAA to creatine ratios were markedly lowered.…”

“…Although transcript levels of the various MATs were not different between the experimental groups, the alterations in redox metabolism may underlie what appears as a reduced entry of methionine into the transmethylation cycle. While oxidative stress is generally thought of as a deleterious phenomenon, the early stages of the development of liver steatosis are characterized by increased antioxidant capacity and GSH synthesis 57,58 , and several studies have pointed to a beneficial effect of reactive oxygen species (ROS) generation and glutathione depletion early in the development of NAFL 29,44,[59][60][61] or in the context of a methionine-and choline-deficient diet 61 . Indeed, so-called reductive stress is now appreciated to be in some cases as harmful as excess oxidative stress and a direct cause of ER stress 62 .…”

“…Homocysteine generated via the methionine cycle is also a precursor for synthesis of the antioxidant glutathione. Therefore, decreased entry of methionine into the methionine cycle is expected to result not only in depletion of SAM but also decreased production of glutathione, as indeed seen in some cases with methionine restricted diets 27,28 and, more directly, with knockout or silencing of MAT1A 29 . An excess of SAM is as injurious as its depletion, and may lead to the development of hepatic steatosis 30,31 .…”

“…An excess of SAM is as injurious as its depletion, and may lead to the development of hepatic steatosis 30,31 . Likewise, in different settings, knockout or silencing of the MAT1A gene has been seen to either result in increased susceptibility to hepatic steatosis 24 or protect from diet-induced NAFL 29 .…”

Normal and Pathological NRF2 Signalling in the Central Nervous System

“…Through upregulation of NRF2 levels, an FGF21 administration may also show positive effects by protecting against diabetes-induced blood-brain-barrier disruption [ 164 , 165 ]. Inversely, in periphery, NRF2 regulates hepatocyte FGF21 secretion [ 166 , 167 ]. Interestingly, activation of NRF2 in hepatocytes in obese mice represents a strategy to stimulate FGF21 release in the blood, which decreases lipogenesis in the liver, promotes lipolysis in the white adipose tissue, and stimulates thermogenesis in the brown adipose tissue, thus preventing obesity and associated hepatosteatosis [ 167 ].…”