The Origins, Evolution, and Future of Dietary Methionine Restriction.

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. Expected final online publication date for the Annual Review of Nutrition, Volume 42 is August 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

• Publication year

  2022

• Venue

  Annual review of nutrition

• Publication date

  2022-05-19

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1146/annurev-nutr-062320-111849PMID 35588443PMCID PMC9936953
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Hepatic Nfe2l2 Is Not an Essential Mediator of the Metabolic Phenotype Produced by Dietary Methionine Restriction

  2021cited by this paper
• Implementation of dietary methionine restriction using casein after selective, oxidative deletion of methionine

  2021cited by this paper
• The Role of Reduced Methionine in Mediating the Metabolic Responses to Protein Restriction Using Different Sources of Protein

  2021cited by this paper
• The acute transcriptional responses to dietary methionine restriction are triggered by inhibition of ternary complex formation and linked to Erk1/2, mTOR, and ATF4

  2021cited by this paper
• Physiologic Responses to Dietary Sulfur Amino Acid Restriction in Mice Are Influenced by Atf4 Status and Biological Sex

  2021cited by this paper
• Medical Foods for Inborn Errors of Metabolism: History, Current Status, and Critical Need

  2020cited by this paper
• FGF21 Signals to Glutamatergic Neurons in the Ventromedial Hypothalamus to Suppress Carbohydrate Intake.

  2020cited by this paper
• Dietary Methionine Restriction Signals to the Brain Through Fibroblast Growth Factor 21 to Regulate Energy Balance and Remodeling of Adipose Tissue

  2020cited by this paper
• Sexually Dimorphic Effects of Dietary Methionine Restriction are Dependent on Age when the Diet is Introduced

  2020cited by this paper
• The central fibroblast growth factor receptor/beta klotho system: Comprehensive mapping in Mus musculus and comparisons to nonhuman primate and human samples using an automated in situ hybridization platform

  2019cited by this paper
• Tanycytes Regulate Lipid Homeostasis by Sensing Free Fatty Acids and Signaling to Key Hypothalamic Neuronal Populations via FGF21 Secretion.

  2019cited by this paper
• Dietary Methionine Restriction Reduces Inflammation Independent of FGF21 Action

  2019cited by this paper
• Pegbelfermin (BMS‐986036), PEGylated FGF21, in Patients with Obesity and Type 2 Diabetes: Results from a Randomized Phase 2 Study

  2018cited by this paper
• The Hormone FGF21 Stimulates Water Drinking in Response to Ketogenic Diet and Alcohol.

  2018cited by this paper
• FGF21 increases water intake, urine output and blood pressure in rats

  2018cited by this paper
• THE COMPONENTS OF AGE-DEPENDENT EFFECTS OF DIETARY METHIONINE RESTRICTION ON ENERGY BALANCE IN RATS

  2018cited by this paper
• Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial.

  2018cited by this paper
• FGF21 Regulates Metabolism Through Adipose-Dependent and -Independent Mechanisms.

  2017cited by this paper
• CONCENTRATION-DEPENDENT LINKAGE OF DIETARY METHIONINE RESTRICTION TO THE COMPONENTS OF ITS METABOLIC PHENOTYPE

  2017cited by this paper
• Fibroblast growth factor 21, assisted by elevated glucose, activates paraventricular nucleus NUCB2/Nesfatin-1 neurons to produce satiety under fed states

  2017cited by this paper
• FGF21 Mediates the Thermogenic and Insulin-Sensitizing Effects of Dietary Methionine Restriction but Not Its Effects on Hepatic Lipid Metabolism

  2017cited by this paper
• An integrative analysis of tissue-specific transcriptomic and metabolomic responses to short-term dietary methionine restriction in mice

  2017cited by this paper
• Dietary Methionine Restriction Regulates Liver Protein Synthesis and Gene Expression Independently of Eukaryotic Initiation Factor 2 Phosphorylation in Mice.

  2017cited by this paper
• Direct comparison of methionine restriction with leucine restriction on the metabolic health of C57BL/6J mice

  2017cited by this paper
• mTORC1 Balances Cellular Amino Acid Supply with Demand for Protein Synthesis through Post-transcriptional Control of ATF4

  2017cited by this paper
• Defining the Nutritional and Metabolic Context of FGF21 Using the Geometric Framework.

  2016cited by this paper
• A Long-Acting FGF21 Molecule, PF-05231023, Decreases Body Weight and Improves Lipid Profile in Non-human Primates and Type 2 Diabetic Subjects.

  2016cited by this paper
• The regulation of FGF21 gene expression by metabolic factors and nutrients

  2016cited by this paper
• The integrated stress response

  2016cited by this paper
• FGF21 Lowers Plasma Triglycerides by Accelerating Lipoprotein Catabolism in White and Brown Adipose Tissues.

  2016cited by this paper
• Role of GCN2-Independent Signaling Through a Noncanonical PERK/NRF2 Pathway in the Physiological Responses to Dietary Methionine Restriction

  2016cited by this paper
• UCP1 is an essential mediator of the effects of methionine restriction on energy balance but not insulin sensitivity

  2015cited by this paper
• Metabolic responses to dietary leucine restriction involve remodeling of adipose tissue and enhanced hepatic insulin signaling.

  2015cited by this paper
• Compromised responses to dietary methionine restriction in adipose tissue but not liver of ob/ob mice

  2015cited by this paper
• Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21.

  2015cited by this paper
• Central Fibroblast Growth Factor 21 Browns White Fat via Sympathetic Action in Male Mice.

  2015cited by this paper
• Cellular and molecular remodeling of inguinal adipose tissue mitochondria by dietary methionine restriction.

  2015cited by this paper
• Protein and amino acid restriction, aging and disease: from yeast to humans.

  2014cited by this paper
• FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss.

  2014cited by this paper
• Transcriptional impact of dietary methionine restriction on systemic inflammation: Relevance to biomarkers of metabolic disease during aging

  2014cited by this paper
• The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice.

  2014cited by this paper
• Mechanisms of Increased In Vivo Insulin Sensitivity by Dietary Methionine Restriction in Mice

  2014cited by this paper
• Nrf2 induces fibroblast growth factor 21 in diabetic mice

  2014cited by this paper
• A systems biology analysis of the unique and overlapping transcriptional responses to caloric restriction and dietary methionine restriction in rats

  2014cited by this paper
• The Nrf2 regulatory network provides an interface between redox and intermediary metabolism.

  2014cited by this paper
• Effect of taurine and N-acetylcysteine on methionine restriction-mediated adiposity resistance.

  2013cited by this paper
• Stimulation of de Novo Pyrimidine Synthesis by Growth Signaling Through mTOR and S6K1

  2013cited by this paper
• Remodeling the Integration of Lipid Metabolism Between Liver and Adipose Tissue by Dietary Methionine Restriction in Rats

  2013cited by this paper
• FGF21 regulates metabolism and circadian behavior by acting on the nervous system

  2013cited by this paper
• The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes.

  2013cited by this paper
• Unfolded Protein Response Signaling and Metabolic Diseases*

  2013cited by this paper
• An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice.

  2013cited by this paper
• Remodeling of Lipid Metabolism by Dietary Restriction of Essential Amino Acids

  2013cited by this paper
• S6K1 in the Central Nervous System Regulates Energy Expenditure via MC4R/CRH Pathways in Response to Deprivation of an Essential Amino Acid

  2012cited by this paper
• βKlotho is required for fibroblast growth factor 21 effects on growth and metabolism.

  2012cited by this paper
• The Brain's Response to an Essential Amino Acid-Deficient Diet and the Circuitous Route to a Better Meal

  2012cited by this paper
• FGF21 Requires βklotho to Act In Vivo

  2012cited by this paper
• Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation.

  2012cited by this paper
• Genomic and Metabolic Responses to Methionine-Restricted and Methionine-Restricted, Cysteine-Supplemented Diets in Fischer 344 Rat Inguinal Adipose Tissue, Liver and Quadriceps Muscle

  2012cited by this paper
• Fundamentals of FGF19 & FGF21 Action In Vitro and In Vivo

  2012cited by this paper
• Detection of amino acid deprivation in the central nervous system

  2012cited by this paper
• Insulin resistance and aging: a cause or a protective response?

  2012cited by this paper
• Cysteine supplementation reverses methionine restriction effects on rat adiposity: significance of stearoyl-coenzyme A desaturase

  2011cited by this paper
• Phosphorylation of eIF2 Facilitates Ribosomal Bypass of an Inhibitory Upstream ORF to Enhance CHOP Translation*♦

  2011cited by this paper
• Leucine deprivation stimulates fat loss via increasing CRH expression in the hypothalamus and activating the sympathetic nervous system.

  2011cited by this paper
• Dietary methionine restriction increases fat oxidation in obese adults with metabolic syndrome.

  2011cited by this paper
• Evidence That Eukaryotic Translation Elongation Factor 1A (eEF1A) Binds the Gcn2 Protein C Terminus and Inhibits Gcn2 Activity*♦

  2011cited by this paper
• Dietary restriction and aging: a unifying perspective.

  2011cited by this paper
• Contribution of adipose tissue to health span and longevity.

  2010cited by this paper
• Dietary methionine restriction enhances metabolic flexibility and increases uncoupled respiration in both fed and fasted states.

  2010cited by this paper
• ATF4 regulates lipid metabolism and thermogenesis

  2010cited by this paper
• Methionine restriction effects on mitochondrial biogenesis and aerobic capacity in white adipose tissue, liver, and skeletal muscle of F344 rats.

  2010cited by this paper
• Role of beta-adrenergic receptors in the hyperphagic and hypermetabolic responses to dietary methionine restriction.

  2010cited by this paper
• ATF4-dependent transcription mediates signaling of amino acid limitation.

  2009cited by this paper
• Elevated ATF4 Expression, in the Absence of Other Signals, Is Sufficient for Transcriptional Induction via CCAAT Enhancer-binding Protein-activating Transcription Factor Response Elements*

  2009cited by this paper
• The transcription factor ATF4 regulates glucose metabolism in mice through its expression in osteoblasts.

  2009cited by this paper
• Specificity of amino acid regulated gene expression: analysis of genes subjected to either complete or single amino acid deprivation

  2009cited by this paper
• Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models--association with liver and adipose tissue effects.

  2009cited by this paper
• Role of visceral adipose tissue in aging.

  2009cited by this paper
• Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice

  2009cited by this paper
• Atf4 Regulates Obesity, Glucose Homeostasis, and Energy Expenditure

  2009cited by this paper
• Leucine Deprivation Decreases Fat Mass by Stimulation of Lipolysis in White Adipose Tissue and Upregulation of Uncoupling Protein 1 (UCP1) in Brown Adipose Tissue

  2009cited by this paper
• Amino acid imbalance explains extension of lifespan by dietary restriction in Drosophila

  2009cited by this paper
• Life-span extension in mice by preweaning food restriction and by methionine restriction in middle age.

  2009cited by this paper
• Amino acid limitation regulates the expression of genes involved in several specific biological processes through GCN2‐dependent and GCN2‐independent pathways

  2009cited by this paper
• Methionine restriction effects on 11β-HSD1 activity and lipogenic/lipolytic balance in F344 rat adipose tissue Published, JLR Papers in Press, October 1, 2007.

  2008cited by this paper
• Aging and survival: the genetics of life span extension by dietary restriction.

  2008cited by this paper
• C/EBP Homology Protein (CHOP) Interacts with Activating Transcription Factor 4 (ATF4) and Negatively Regulates the Stress-dependent Induction of the Asparagine Synthetase Gene*

  2008cited by this paper
• Fibroblast growth factor 21 corrects obesity in mice.

  2008cited by this paper
• The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21.

  2007cited by this paper
• The GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid.

  2007cited by this paper
• Activation of the ATF3 gene through a co-ordinated amino acid-sensing response programme that controls transcriptional regulation of responsive genes following amino acid limitation.

  2007cited by this paper
• Methionine restriction decreases visceral fat mass and preserves insulin action in aging male Fischer 344 rats independent of energy restriction

  2006cited by this paper
• Methionine‐deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF‐I and insulin levels, and increases hepatocyte MIF levels and stress resistance

  2005cited by this paper
• FGF-21 as a novel metabolic regulator.

  2005cited by this paper
• Calories Do Not Explain Extension of Life Span by Dietary Restriction in Drosophila

  2005cited by this paper
• Uncharged tRNA and Sensing of Amino Acid Deficiency in Mammalian Piriform Cortex

  2005cited by this paper
• The GCN2 kinase biases feeding behavior to maintain amino acid homeostasis in omnivores.

  2005cited by this paper
• PERK-dependent Activation of Nrf2 Contributes to Redox Homeostasis and Cell Survival following Endoplasmic Reticulum Stress*

  2004cited by this paper
• Amino Acid Deprivation Induces the Transcription Rate of the Human Asparagine Synthetase Gene through a Timed Program of Expression and Promoter Binding of Nutrient-responsive Basic Region/Leucine Zipper Transcription Factors as Well as Localized Histone Acetylation*

  2004cited by this paper

• Aging and Alzheimer’s: the critical role of mitochondrial dysfunction and synaptic alterations

  2026cites this paper
• Globulins from a New Brazilian Chickpea Cultivar GB Cappuccino: Insights into Compositional, Digestibility, and Bio-Functional Potential of Their Hydrolysates

  2026cites this paper
• Dietary methionine mitigates immune-mediated damage by enhancing renal clearance of cytokines.

  2026cites this paper
• Metabolic Modulation of Glioblastoma by Dietary Intervention: A Systematic Review

  2025cites this paper
• The impacts of different dietary restriction regimens on aging and longevity: from yeast to humans

  2025cites this paper
• Dietary methionine restriction restores wheat gluten-induced celiac-associated small intestine damage in association with affecting butyric acid production by intestinal flora.

  2025cites this paper
• The Amelioration of Methionine Restriction on the Celiac Toxic Effects of p31-43 Gliadin Peptide Is Disrupted by S-Adenosyl-Methionine.

  2025cites this paper
• Short-term methionine deprivation inhibits TCA cycle and regulates macrophage polarization through uncharged tRNA and PDHA1 phosphorylation.

  2025cites this paper
• Dietary methionine restriction ameliorates atherosclerosis by remodeling the gut microbiota in apolipoprotein E-knockout mice.

  2025cites this paper
• Contribution of dietary methionine to gut health and its related diseases: implications for precision nutrition

  2025cites this paper
• Dietary methionine deprivation enhances renal resilience against ischemia-reperfusion injury in mice through modulation of glucose oxidation

  2025cites this paper
• Methionine deficiency causes spermatogonial apoptosis via oxidative stress and DNA damage response pathway

  2025cites this paper
• Angiogenesis-independent VEGF signaling enhances exercise capacity by increasing fat oxidation in mice fed sulfur amino acid-restricted diets

  2025cites this paper
• Dietary sulfur amino acid restriction improves glucose homeostasis through hepatic de novo serine synthesis

  2025cites this paper
• Dietary sulfur amino acid restriction elicits a cold-like transcriptional response in inguinal but not epididymal white adipose tissue of male mice

  2025influential citation
• The Roles of White Adipose Tissue and Liver NADPH in Dietary Restriction-Induced Longevity

  2024cites this paper
• Vascular Dementia: From Pathobiology to Emerging Perspectives.

  2024cites this paper
• Adverse Cardiac Events of Hypercholesterolemia Are Enhanced by Sitagliptin Administration in Sprague Dawley Rats

  2024cites this paper
• Targeting methionine metabolism in cancer: opportunities and challenges.

  2024cites this paper
• Mice regulate dietary amino acid balance and energy intake by selecting between complementary protein sources.

  2024cites this paper
• Methionine Restriction Diets: Unravelling Biological Mechanisms and Enhancing Brain Health

  2024cites this paper
• Dietary sulfur amino acid restriction in humans with overweight and obesity: Evidence of an altered plasma and urine sulfurome, and a novel metabolic signature that correlates with loss of fat mass and adipose tissue gene expression

  2024cites this paper
• FGF21 as a mediator of adaptive changes in food intake and macronutrient preference in response to protein restriction.

  2024cites this paper
• Intermittent Fasting: Myths, Fakes and Truth on This Dietary Regimen Approach

  2024cites this paper
• Adverse cardiac events of hypercholesterolemia are enhanced by sitagliptin in sprague dawley rats

  2024cites this paper
• Sulfur Amino Acid Restriction Mitigates High-Fat Diet-Induced Molecular Alterations in Cardiac Remodeling Primarily via FGF21-Independent Mechanisms

  2024cites this paper
• Strength in diversity: Intra-cellular metabolite sharing enhances longevity.

  2023cites this paper
• Dietary sulfur amino acid restriction in humans with overweight and obesity: a translational randomized controlled trial

  2023cites this paper
• Effects of Dietary Methionine Restriction on Cognition in Mice

  2023cites this paper
• Changing ROS, NAD and AMP: A path to longevity via mitochondrial therapeutics.

  2023cites this paper
• Kinetic proteomics identifies targeted changes in liver metabolism and the ribo-interactome by dietary sulfur amino acid restriction

  2023cites this paper
• Mitochondrial ROS production, oxidative stress and aging within and between species: Evidences and recent advances on this aging effector.

  2023cites this paper
• Dietary methionine restriction alleviates oxidative stress and inflammatory responses in lipopolysaccharide-challenged broilers at early age

  2023cites this paper
• Dietary Methionine Restriction Alleviates Choline-Induced Tri-Methylamine-N-Oxide (TMAO) Elevation by Manipulating Gut Microbiota in Mice

  2023cites this paper
• Metabolic Homeostasis of Amino Acids and Diabetic Kidney Disease

  2022cites this paper
• The Association between Methionine Intake and Diabetes in Chinese Adults—Results from the China Health and Nutrition Survey

  2022cites this paper