The Origins, Evolution, and Future of Dietary Methionine Restriction

Abstract

The original description of dietary methionine restriction (MR) used semipurified diets to limit methionine intake to 20% of normal levels, and this reduction in dietary methionine increased longevity by ∼30% in rats. The MR diet also produces paradoxical increases in energy intake and expenditure and limits fat deposition while reducing tissue and circulating lipids and enhancing overall insulin sensitivity. In the years following the original 1993 report, a comprehensive effort has been made to understand the nutrient sensing and signaling systems linking reduced dietary methionine to the behavioral, physiological, biochemical, and transcriptional components of the response. Recent work has shown that transcriptional activation of hepatic fibroblast growth factor 21 (FGF21) is a key event linking the MR diet to many but not all components of its metabolic phenotype. These findings raise the interesting possibility of developing therapeutic, MR-based diets that produce the beneficial effects of FGF21 by nutritionally modulating its transcription and release.

Keywords: FGF21; essential amino acids; insulin sensitivity; lipid metabolism; nutrient sensing; obesity.

Figure 1

Time course of fold changes in food intake, water intake, body weight (BW), and adiposity of 6-week-old male C57BL/6J mice after introduction of dietary methionine restriction (MR). The changes in water intake are shown on the left axis, and changes in food intake, BW, and adiposity are shown on the right axis. The horizontal green line shows the water intake at zero time, while horizontal blue, red, and gray lines show the food intake, BW, and adiposity of the mice at zero time, respectively. Phase 1 is characterized by an early increase in food and water intake. Phase 2 is characterized by a gradual reduction in adiposity and BW. Phase 3 is characterized by stable increases in food and water intake and by stable decreases in adiposity and BW.

Figure 2

Bioinformatics analysis of hepatic gene expression in male C57BL/6J mice fed control or MR diets for 8 weeks. Canonical pathway analysis was conducted using Ingenuity Pathway Analysis of livers from six mice fed the control diet and six mice fed the MR diet. The algorithm identified the pathways most significantly up- or downregulated by the MR diet compared to the control diet. Canonical pathways with an activation z-score of ≥2 or ≤−2 were considered to be activated (red) or inhibited (blue), respectively. Heat maps were used to visualize the top 10 canonical pathways that were differentially affected by the MR diet. Abbreviations: eIF2, eukaryotic initiation factor 2; LXR, liver X receptor; MR, methionine restriction; NRF2, nuclear factor-erythroid 2–related factor 2; RXR, retinoid X receptor.

Figure 3

Model of proposed anatomical organization of the sensing and signaling mechanisms that produce the coordinated biochemical, transcriptional, physiological, and behavioral responses to dietary methionine restriction. The inset shows the details of the proposed mechanisms for sensing reduced methionine and GSH that lead to transactivation of hepatic FGF21 and remodeling of lipid metabolism in the liver. The model further proposes that FGF21 acts in the brain to increase SNS outflow to adipose tissue, leading to remodeling of BAT and WAT, activation of thermogenesis, and increased energy expenditure. The model proposes that FGF21 also acts directly in adipose tissue to enhance insulin sensitivity and increase glucose uptake and utilization. Abbreviations: ARE, antioxidant response element; ATF4, activating transcription factor 4; BAT, brown adipose tissue; CARE, C/EBP-ATF4 response element; DVC, dorsal vagal complex; eIF2, eukaryotic initiation factor 2; ER, endoplasmic reticulum; FGF21, fibroblast growth factor 21; GCN2, general control nonderepressible 2; GSH, glutathione; ISR, integrated stress response; IWAT, inguinal white adipose tissue; NRF2, nuclear factor-erythroid 2–related factor 2; PERK, PKR-like endoplasmic reticulum kinase; SNS, sympathetic nervous system; WAT, white adipose tissue.

Figure 4

Heat map showing the concentration-dependent effects of dietary methionine restriction on plasma fibroblast growth factor 21 (FGF21) and energy expenditure (EE) in male C57BL/6J mice after consuming their respective diets for 8 weeks. All diets were formulated without cysteine and were introduced to the mice at 6 weeks of age. Dietary methionine concentrations above 0.25% had no effect on FGF21 or EE relative to control mice (e.g., 0.86% methionine). Methionine concentrations between 0.12% and 0.25% increased FGF21 and EE without causing significant weight loss, while methionine concentrations below 0.12% caused rapid weight loss due to effective methionine deprivation.