Effects Of Dietary Methionine Restriction Research Articles

Effects of Dietary Methionine Restriction on Cognition in Mice

Dietary restriction of the essential amino acid, methionine, has been shown to induce unique metabolic protection. The peripheral benefits of methionine restriction (MR) are well established and include improvements in metabolic, energy, inflammatory, and lifespan parameters in preclinical models. These benefits all occur despite MR increasing energy intake, making MR an attractive dietary intervention for the prevention or reversal of many metabolic and chronic conditions. New and emerging evidence suggests that MR also benefits the brain and promotes cognitive health. Despite widespread interest in MR over the past few decades, many findings are limited in scope, and gaps remain in our understanding of its comprehensive effects on the brain and cognition. This review details the current literature investigating the impact of MR on cognition in various mouse models, highlights some of the key mechanisms responsible for its cognitive benefits, and identifies gaps that should be addressed in MR research moving forward. Overall findings indicate that in animal models, MR is associated with protection against obesity-, age-, and Alzheimer’s disease-induced impairments in learning and memory that depend on different brain regions, including the prefrontal cortex, amygdala, and hippocampus. These benefits are likely mediated by increases in fibroblast growth factor 21, alterations in methionine metabolism pathways, reductions in neuroinflammation and central oxidative stress, and potentially alterations in the gut microbiome, mitochondrial function, and synaptic plasticity.

Effects of dietary methionine restriction on age-related changes in perivascular and beiging adipose tissues in the mouse.

Perivascular adipose tissue (PVAT) regulates vascular health. Dietary methionine restriction (MetR) impacts age-related adiposity, and this study addresses its effects in PVAT. Male C57BL/6 mice at 8, 52, and 102 weeks of age were fed a standard (0.86%) or low-methionine (0.12%) diet for 52 weeks in 8-week-old and 52-week-old mice and for 15 weeks in 102-week-old mice. Mice with dietary MetR were resistant to weight gain and maintained a healthy blood profile. Aging increased lipid accumulation, and MetR reversed this phenotype. Notch signaling in inguinal white adipose tissue (iWAT) was decreased by MetR but increased in gonadal white adipose tissue. However, the Notch phenotype of brown adipose tissue (BAT) was not affected by MetR. Uncoupling protein 1 (UCP1) was increased in PVAT, iWAT, and BAT by MetR when initiated in young mice, but this effect was lost in middle-aged mice. Lipid in mouse PVAT peaked at 1year of age, consistent with peak body mass. MetR reduced body weight, normalized metabolic parameters, and decreased lipid in PVAT in all age cohorts. Mice fed a MetR diet from early maturity to 1 year of age displayed an increased thermogenic adipocyte phenotype in iWAT, PVAT, and BAT, all tissues with thermogenic capacity.

Sex-Specific Effects of Dietary Methionine Restriction on the Intestinal Microbiome

Dietary methionine restriction is associated with improved health outcomes and an increase in lifespan in animal models. We have previously shown that an increase in dietary methionine induces alteration in the intestinal microbiome. The composition of the intestinal microbiota is a determinant of health and we, therefore, hypothesized that dietary methionine restriction would also induce changes in the murine microbiome. After one month on a methionine-restricted diet, five-month-old male and female C57BL/6 mice had decreased levels of serum methionine, without changes in body weight. We identified a decrease in the hepatic methylation status of animals fed a methionine-restricted diet compared to controls. This decrease was not associated with changes in DNA or protein methylation in the liver. In males, we saw an increase in families Bacteroidaceae and Verrucoccaceae (mostly A. mucinophila) and a decrease in Rumminococcaceae in animals fed a methionine-restricted diet compared to controls. In females, Bacteroidales family S24-7 was increased two-fold, while families Bacteroidaceae, Verrucoccaceae, Rumminococcaceae, and Rikenellaceae were decreased compared to controls. In summary, feeding a methionine-restricted diet for one month was associated with significant and sex-specific changes in the intestinal microbiome.

Sexually Dimorphic Effects of Dietary Methionine Restriction are Dependent on Age when the Diet is Introduced.

Restricting dietary methionine to 0.17% in male mice increases energy expenditure, reduces fat deposition, and improves metabolic health. The goal of this work was to compare each of these responses in postweaning male and female mice and in physically mature male and female mice. Methionine-restricted(MR) diets were fed to age-matched cohorts of male and female mice for 8 to 10 weeks beginning at 8 weeks of age or beginning at 4 months of age. The physiological and transcriptional responses to MR were compared in the respective cohorts. Dietary MR produced sexually dimorphic changes in body composition in young growing animals, with males preserving lean at the expense of fat and females preserving fat at the expense of lean. The effects of MR on energy balance were comparable between sexes when the diet was initiated after attainment of physical maturity (4 months), and metabolic and endocrine responses were also comparable between males and females after 8 weeks on the MR diet. The sexually dimorphic effects of MR are limited to nutrient partitioning between lean and fat tissue deposition in young, growing mice. Introduction of the diet after physical maturity produced comparable effects on growth and metabolic responses in male and female mice.

The effects of dietary methionine restriction on the function and metabolic reprogramming in the liver and brain - implications for longevity.

Methionine is an essential sulphur-containing amino acid involved in protein synthesis, regulation of protein function and methylation reactions. Dietary methionine restriction (0.12-0.17% methionine in food) extends the life span of various animal species and delays the onset of aging-associated diseases and cancers. In the liver, methionine restriction attenuates steatosis and delays the development of non-alcoholic steatohepatitis due to antioxidative action and metabolic reprogramming. The limited intake of methionine stimulates the fatty acid oxidation in the liver and the export of lipoproteins as well as inhibits de novo lipogenesis. These effects are mediated by various signaling pathways and effector molecules, including sirtuins, growth hormone/insulin-like growth factor-1 axis, sterol regulatory element binding proteins, adenosine monophosphate-dependent kinase and general control nonderepressible 2 pathway. Additionally, methionine restriction stimulates the synthesis of fibroblast growth factor-21 in the liver, which increases the insulin sensitivity of peripheral tissues. In the brain, methionine restriction delays the onset of neurodegenerative diseases and increases the resistance to various forms of stress through antioxidative effects and alterations in lipid composition. This review aimed to summarize the morphological, functional and molecular changes in the liver and brain caused by the methionine restriction, with possible implications in the prolongation of maximal life span.

S-adenosylmethionine biosynthesis is a targetable metabolic vulnerability of cancer stem cells.

Many transformed cells and embryonic stem cells are dependent on the biosynthesis of the universal methyl-donor S-adenosylmethionine (SAM) from methionine by the enzyme MAT2A to maintain their epigenome. We hypothesized that cancer stem cells (CSCs) rely on SAM biosynthesis and that the combination of methionine depletion and MAT2A inhibition would eradicate CSCs. Human triple (ER/PR/HER2)-negative breast carcinoma (TNBC) cell lines were cultured as CSC-enriched mammospheres in control or methionine-free media. MAT2A was inhibited with siRNAs or cycloleucine. The effects of methionine restriction and/or MAT2A inhibition on the formation of mammospheres, the expression of CSC markers (CD44hi/C24low), MAT2A and CSC transcriptional regulators, apoptosis induction and histone modifications were determined. A murine model of metastatic TNBC was utilized to evaluate the effects of dietary methionine restriction, MAT2A inhibition and the combination. Methionine restriction inhibited mammosphere formation and reduced the CD44hi/C24low CSC population; these effects were partly rescued by SAM. Methionine depletion induced MAT2A expression (mRNA and protein) and sensitized CSCs to inhibition of MAT2A (siRNAs or cycloleucine). Cycloleucine enhanced the effects of methionine depletion on H3K4me3 demethylation and suppression of Sox9 expression. Dietary methionine restriction induced MAT2A expression in mammary tumors, and the combination of methionine restriction and cycloleucine was more effective than either alone at suppressing primary and lung metastatic tumor burden in a murine TNBC model. Our findings point to SAM biosynthesis as a unique metabolic vulnerability of CSCs that can be targeted by combining methionine depletion with MAT2A inhibition to eradicate drug-resistant CSCs.

Effects of dietary methionine restriction on postnatal growth, insulin sensitivity, and glucose metabolism in intrauterine growth retardation pigs at 49 and 105 d of age.

This study was conducted to investigate the effects of methionine restriction (MR) on growth performance, insulin sensitivity, and hepatic and muscle glucose metabolism in intrauterine growth retardation (IUGR) pigs at 49 and 105 d of age. At weaning (day 21), 30 female normal birth weight (NBW) piglets were fed control diets with adequate methionine (NBW-CON), whereas 60 female IUGR piglets were fed either the control diets (IUGR-CON) or MR diets which were 30% reduced in methionine (IUGR-MR) (n = 6 replicates (pens) with five piglets per replicate). At 49 and 105 d of age, one pig with a BW near to the mean of each replication was selected for biochemical analysis. Compared with NBW-CON pigs, IUGR-CON pigs exhibited lower relative daily gain (RDG) and homeostasis model assessment of insulin resistance (HOMA-IR) index at day 49 (P < 0.05), but higher RDG and HOMA-IR index at day 105 (P < 0.05). Hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase (G6Pase) activities were higher in IUGR-CON than NBW-CON pigs at both days 49 and 105 (P < 0.05), while hepatic glycogen synthase and glycogen phosphorylase activities were lower in IUGR-CON pigs at both two ages (P < 0.05). In addition, compared with NBW-CON pigs, IUGR-CON pigs (105-d old) had lower protein kinase B phosphorylation (PKB/Akt) in liver (P < 0.05), but not in muscle (P > 0.05). Compared with IUGR-CON pigs, IUGR-MR pigs had lower RDG at day 49, less blood glucose at day 105, and lower HOMA-IR index at both days 49 and 105 (P < 0.05). Additionally, compared with IUGR-CON pigs, MR decreased IUGR-MR pigs' hepatic G6Pase activities and increased their hepatic glycogen contents at day 105 (P < 0.05), as well as increased their hepatic and muscle PKB/Akt phosphorylation (P < 0.05). In conclusion, the ability of dietary MR to restrict IUGR pigs' growth and to reduce blood glucose appeared, respectively, in earlier and later period, but MR improved IUGR pigs' insulin sensitivity at both days 49 and 105.

Metabolic Regulation of Methionine Restriction in Diabetes.

Although the effects of dietary methionine restriction have been investigated in the physiology of aging and diseases related to oxidative stress, the relationship between methionine restriction (MR) and the development of metabolic disorders has not been explored extensively. This review summarizes studies of the possible involvement of dietary methionine restriction in improving insulin resistance, glucose homeostasis, oxidative stress, lipid metabolism, the pentose phosphate pathway (PPP), and inflammation, with an emphasis on the fibroblast growth factor 21 and protein phosphatase 2A signals and autophagy in diabetes. Diets deficient in methionine may be a useful nutritional strategy in patients with diabetes.

The Components of Age-Dependent Effects of Dietary Methionine Restriction on Energy Balance in Rats.

ObjectiveDietary methionine restriction (MR) improves biomarkers of metabolic health, in part through coordinated increases in energy intake and energy expenditure (EE). Some metabolic benefits of dietary MR are secondary to its effects on energy balance so this study’s purpose was to examine how age at initiation of MR influences its effects on energy balance and body composition.MethodsEnergy balance was examined in rats provided Control or MR diets for 9 months after weaning or in rats between 6 and 12 months of age.ResultsRats provided the Control diet for 9 months after weaning increased their body weight (BW) and fat mass by 5- and 8-fold, respectively, while BW and fat accumulation were reduced to 50% of Controls in the MR group. In adult rats fed the respective diets between 6 and 12 months of age, dietary MR increased energy intake by ~23% but the 15% increase in EE was sufficient to prevent increases in BW or fat mass.ConclusionsDietary MR produces comparable increases in EE in young, growing animals and in mature animals, but young animals continue to deposit new tissue because of the proportionately larger effect of MR on energy intake relative to maintenance requirements.

The role of suppression of hepatic SCD1 expression in the metabolic effects of dietary methionine restriction.

Dietary methionine restriction (MR) produces concurrent increases in energy intake and expenditure, but the proportionately larger increase in energy expenditure (EE) effectively limits weight gain and adipose tissue accretion over time. Increased hepatic fibroblast growth factor-21 (FGF21) is essential to MR-dependent increases in EE, but it is unknown whether the downregulation of hepatic stearoyl-coenzyme A desaturase-1 (SCD1) by MR could also be a contributing factor. Global deletion of SCD1 mimics cold exposure in mice housed at 23 °C by compromising the insular properties of the skin. The resulting cold stress increases EE, limits fat deposition, reduces hepatic lipids, and increases insulin sensitivity by activating thermoregulatory thermogenesis. To examine the efficacy of MR in the absence of SCD1 and without cold stress, the biological efficacy of MR in Scd1-/- mice housed near thermoneutrality (28 °C) was evaluated. Compared with wild-type mice on the control diet, Scd1-/- mice were leaner, had higher EE, lower hepatic and serum triglycerides, and lower serum leptin and insulin. Although dietary MR increased adipose tissue UCP1 expression, hepatic Fgf21 messenger RNA, 24 h EE, and reduced serum triglycerides in Scd1-/- mice, it failed to reduce adiposity or produce any further reduction in hepatic triglycerides, serum insulin, or serum leptin. These findings indicate that even when thermal stress is minimized, global deletion of SCD1 mimics and effectively masks many of the metabolic responses to dietary MR. However, the retention of several key effects of dietary MR in this model indicates that SCD1 is not a mediator of the biological effects of the diet.

FGF21 Mediates the Thermogenic and Insulin-Sensitizing Effects of Dietary Methionine Restriction but Not Its Effects on Hepatic Lipid Metabolism.

Dietary methionine restriction (MR) produces a rapid and persistent remodeling of white adipose tissue (WAT), an increase in energy expenditure (EE), and enhancement of insulin sensitivity. Recent work established that hepatic expression of FGF21 is robustly increased by MR. Fgf21-/- mice were used to test whether FGF21 is an essential mediator of the physiological effects of dietary MR. The MR-induced increase in energy intake and EE and activation of thermogenesis in WAT and brown adipose tissue were lost in Fgf21-/- mice. However, dietary MR produced a comparable reduction in body weight and adiposity in both genotypes because of a negative effect of MR on energy intake in Fgf21-/- mice. Despite the similar loss in weight, dietary MR produced a more significant increase in in vivo insulin sensitivity in wild-type than in Fgf21-/- mice, particularly in heart and inguinal WAT. In contrast, the ability of MR to regulate lipogenic and integrated stress response genes in liver was not compromised in Fgf21-/- mice. Collectively, these findings illustrate that FGF21 is a critical mediator of the effects of dietary MR on EE, remodeling of WAT, and increased insulin sensitivity but not of its effects on hepatic gene expression.

Effects of methionine restriction and endurance exercise on bones of ovariectomized rats: a study of histomorphometry, densitometry, and biomechanical properties.

To investigate the effects of dietary methionine restriction (MetR) and endurance exercise on bone quality under a condition of estrogen deficiency, female Sprague-Dawley rats (36-wk-old) were assigned to a sham surgery group or one of five ovariectomized groups subjected to interventions of no treatment (Ovx), endurance exercise (Exe), methionine restriction (MetR), methionine restriction plus endurance exercise (MetR + Exe), and estrogen treatment (Est). Rats in the exercise groups were subjected to a treadmill running regimen. MetR and control diets contained 0.172 and 0.86% methionine, respectively. After the 12-wk intervention, all animals were killed, and serum and bone tissues were collected for analyses. Compared with estrogen treatment, MetR diet and endurance exercise showed better or equivalent efficiency in reducing body weight gain caused by ovariectomy (P < 0.05). Whereas only the Est group showed evidence for reduced bone turnover compared with the Ovx group, MetR diet and/or endurance exercise demonstrated efficiencies in downregulating serum insulin, leptin, triglyceride, and thiobarbituric acid reactive substances (P < 0.05). Both the Exe and MetR groups showed higher femoral cortical and total volumetric bone mineral density (vBMD), but only the Exe and Est groups preserved cancellous bone volume and/or vBMD of distal femora (P < 0.05) compared with the Ovx group. After being normalized to body mass, femora of the MetR and MetR + Exe groups had relatively higher bending strength and dimension values followed by the Sham, Exe, and Est groups (P < 0.05). In conclusion, both MetR diet and endurance exercise improved cortical bone properties, but only endurance exercise preserved cancellous bone under estrogen deficiency.

Methionine restriction prevents the progression of hepatic steatosis in leptin-deficient obese mice

ObjectiveThis study investigated the effects of dietary methionine restriction (MR) on the progression of established hepatic steatosis in the leptin-deficient ob/ob mouse. Material/MethodsTen-week-old ob/ob mice were fed diets containing 0.86% (control-fed; CF) or 0.12% methionine (MR) for 14weeks. At 14weeks, liver and fat were excised and blood was collected for analysis. In another study, blood was collected to determine in vivo triglyceride (TG) and very-low-density lipoprotein (VLDL) secretion rates. Liver histology was conducted to determine the severity of steatosis. Hepatic TG, free fatty acid levels, and fatty acid oxidation (FAO) were also measured. Gene expression was analyzed by quantitative PCR. ResultsMR reversed the severity of steatosis in the ob/ob mouse. This was accompanied by reduced body weight despite similar weight-specific food intake. Compared with the CF group, hepatic TG levels were significantly reduced in response to MR, but adipose tissue weight was not decreased. MR reduced insulin and HOMA ratios but increased total and high-molecular-weight adiponectin levels. Scd1 gene expression was significantly downregulated, while Acadvl, Hadha, and Hadhb were upregulated in MR, corresponding with increased β-hydroxybutyrate levels and a trend toward increased FAO. The VLDL secretion rate was also significantly increased in the MR mice, as were the mRNA levels of ApoB and Mttp. The expression of inflammatory markers, such as Tnf-α and Ccr2, was also downregulated by MR. ConclusionsOur data indicate that MR reverses steatosis in the ob/ob mouse liver by promoting FAO, increasing the export of lipids, and reducing obesity-related inflammatory responses.

Effects of restricted methionine and energy intake on egg weight and shell quality : research note

An experiment involving two laying hen hybrids and four dietary treatments was conducted to study the effects of dietary methionine restriction (MR) (3,05 g/kg, MR 100MR did not significantly affect hen-day production (%) but reduced linearly (P