Summary S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) link one-carbon metabolism to methylation status. However it is unknown whether regulation of SAM and SAH by nutrient availability can be directly sensed to alter the kinetics of key histone methylation marks. We provide evidence that the status of methionine metabolism is sufficient to determine levels of histone methylation by modulating SAM and SAH. This dynamic interaction led to rapid changes in H3K4me3, altered gene transcription, provided feedback regulation to one-carbon metabolism and could be fully recovered upon restoration of methionine. Modulation of methionine in diet led to changes in metabolism and histone methylation in liver. In humans, methionine variability in fasting serum was commensurate with concentrations needed for these dynamics and could be partly explained by diet. Together these findings demonstrate that flux through methionine metabolism and the sensing of methionine availability may allow for direct communication to the chromatin state in cells.

Stearoyl-CoA desaturase-1 (SCD1) is a key enzyme in fatty acid and energy metabolism, but little is known about its nutritional regulation. Dietary methionine restriction in rats decreases hepatic Scd1 mRNA and protein, increases energy expenditure, and decreases fat-pad mass/body-weight% (FM/BW%). In humans, plasma concentrations of the methionine product, cysteine, are associated with obesity. To determine which consequences of methionine-restriction are mediated by decreased cysteine availability, we monitored obesity-related variables in 4 dietary groups for 12 weeks: control-fed (CF), methionine-restricted (MR), MR supplemented with 0.5% l-cysteine (MR+Cys) and CF+Cys rats. MR lowered weight gain and FM/BW% despite higher food intake/weight than CF, and lowered serum cysteine. Hepatic Scd1 expression was decreased, with decreased serum SCD1 activity indices (calculated from serum fatty acid profile), decreased serum insulin, leptin and triglycerides, and higher adiponectin. Cysteine supplementation (MR+Cys) essentially reversed all these phenotypes and raised serum cysteine but not methionine to CF levels. Adding extra cysteine to control diet (CF+Cys) increased serum taurine but did not affect serum cysteine, lipids, proteins, or total weight gain. FM/BW% and serum leptin were modestly decreased. Our results indicate that anti-obesity effects of MR are caused by low cysteine and that dietary sulfur amino acid composition contributes to SCD1 regulation.

Background/Aims: Methionine restriction (MR) is a dietary intervention that increases lifespan, reduces adiposity and improves insulin sensitivity. These effects are reversed by supplementation of the MR diet with cysteine (MRC). Genomic and metabolomic studies were conducted to identify potential mechanisms by which MR induces favorable metabolic effects, and that are reversed by cysteine supplementation. Methods: Gene expression was examined by microarray analysis and TaqMan quantitative PCR. Levels of selected proteins were measured by Western blot and metabolic intermediates were analyzed by mass spectrometry. Results: MR increased lipid metabolism in inguinal adipose tissue and quadriceps muscle while it decreased lipid synthesis in liver. In inguinal adipose tissue, MR not only caused the transcriptional upregulation of genes associated with fatty acid synthesis but also of Lpin1, Pc, Pck1 and Pdk1, genes that are associated with glyceroneogenesis. MR also upregulated lipolysis-associated genes in inguinal fat and led to increased oxidation in this tissue, as suggested by higher levels of methionine sulfoxide and 13-HODE + 9-HODE compared to control-fed (CF) rats. Moreover, MR caused a trend toward the downregulation of inflammation-associated genes in inguinal adipose tissue. MRC reversed most gene and metabolite changes induced by MR in inguinal adipose tissue, but drove the expression of Elovl6, Lpin1, Pc, and Pdk1 below CF levels. In liver, MR decreased levels of a number of long-chain fatty acids, glycerol and glycerol-3-phosphate corresponding with the gene expression data. Although MR increased the expression of genes associated with carbohydrate metabolism, levels of glycolytic intermediates were below CF levels. MR, however, stimulated gluconeogenesis and ketogenesis in liver tissue. As previously reported, sulfur amino acids derived from methionine were decreased in liver by MR, but homocysteine levels were elevated. Increased liver homocysteine levels by MR were associated with decreased cystathionine β-synthase (CBS) protein levels and lowered vitamin B6 and 5-methyltetrahydrofolate (5MeTHF) content. Finally, MR upregulated fibroblast growth factor 21 (FGF21) gene and protein levels in both liver and adipose tissues. MRC reversed some of MR’s effects in liver and upregulated the transcription of genes associated with inflammation and carcinogenesis such as Cxcl16, Cdh17, Mmp12, Mybl1, and Cav1 among others. In quadriceps muscle, MR upregulated lipid metabolism-associated genes and increased 3-hydroxybutyrate levels suggesting increased fatty acid oxidation as well as stimulation of gluconeogenesis and glycogenolysis in this tissue. Conclusion: Increased lipid metabolism in inguinal adipose tissue and quadriceps muscle, decreased triglyceride synthesis in liver and the downregulation of inflammation-associated genes are among the factors that could favor the lean phenotype and increased insulin sensitivity observed in MR rats.

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