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.
Highlights
Altered methionine metabolism is associated with weight gain in obesity
The results showed that administration of both methionine adenosyltransferase 1a (Mat1a) antisense oligonucleotides (ASO) or Mat1a ASO2 did not induce changes in liver or renal damage markers in high-fat diet (HFD)-fed mice (Table 1 and Supplementary Table 1)
The results showed that feeding a HFD did not alter liver levels of MATI/III (Fig. 1a), or induce the transcription of Mat1a in brown adipose tissue (BAT) or white adipose tissue (WAT), in which protein levels were absent (Supplementary Fig. 1c)
Summary
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. Our results showed that targeting Mat1a in HFD-fed mice did not induce changes in FAO when compared with controls, as demonstrated by levels of [14C]Palmitate oxidation and serum ketone bodies concentration (Fig. 3b).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
