Abstract
The effects of methionine restriction (MR) in rodents are well established; it leads to decreased body and fat mass, improved glucose homeostasis and extended lifespan, despite increased energy intake. Leucine restriction (LR) replicates some, but not all, of these effects of MR. To determine any differences in metabolic effects between MR and LR, this study compared 8 weeks of MR (80% restriction), LR (80% restriction) and control diet in 10-month-old C57BL/6J male mice. Body composition, food intake and glucose homeostasis were measured throughout the study and biochemical analyses of white adipose tissue (WAT) and liver were performed. MR and LR decreased body and fat mass, increased food intake, elevated lipid cycling in WAT and improved whole-body glucose metabolism and hepatic insulin sensitivity in comparison to the control diet. MR produced more substantial effects than LR on body mass and glucose homeostasis and reduced hepatic lipogenic gene expression, which was absent with the LR diet. This could be a result of amino acid-specific pathways in the liver responsible for FGF21 stimulation (causing varied levels of FGF21 induction) and Akt activation. In summary, LR is effective at improving metabolic health; however, MR produces stronger effects, suggesting they activate distinct signalling pathways.
Highlights
Methionine restriction (MR) is a dietary technique, which consistently reduces body weight and adiposity levels and prevents high-fat diet (HFD) -induced obesity, despite increasing food consumption, in rodents[1,2,3]
general control nonderepressible 2 (GCN2) senses the presence of uncharged transfer RNA and responds by phosphorylating eukaryotic initiation factor 2α, causing reduced global protein synthesis but increased transcription of activating transcription factor 4 (ATF4)[25]
This study suggests that Leucine restriction (LR) produces many of the same metabolic effects as methionine restriction (MR), but there are some differences between the effects produced by the diets[38]
Summary
Methionine restriction (MR) is a dietary technique, which consistently reduces body weight and adiposity levels and prevents high-fat diet (HFD) -induced obesity, despite increasing food consumption, in rodents[1,2,3]. Lipid cycling is the process of glucose being used for de novo lipogenesis prior to lipids being oxidised and wastes more potential energy as heat (that could be used for ATP synthesis), versus directly oxidising glucose[9,10,11,12] This process of lipid cycling by dietary MR, together with its ability to increase UCP1 activity could explain the increased energy expenditure[1]. FGF21 treatment of HFD-fed mice improved glucose homeostasis and increased energy expenditure, leading to significant loss of body and fat mass[33]. FGF21 decreases lipid accumulation through lowering lipogenesis[33,34,35,36] and enhancing fatty acid oxidation[37]
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