Sulfur amino acid restriction, energy metabolism and obesity: a study protocol of an 8-week randomized controlled dietary intervention with whole foods and amino acid supplements.

BACKGROUND: Dietary sulfur amino acid (SAA) restriction is an established animal model for increasing lifespan and improving metabolic health. Data from human studies are limited. In the study outlined in this protocol, we will evaluate if dietary SAA restriction can reduce body weight and improve resting energy expenditure (REE) and parameters related to metabolic health. METHOD/DESIGN: Men and women (calculated sample size = 60), aged 18-45 years, with body mass index of 27-35 kg/m2 will be included in a double-blind 8-week dietary intervention study. The participants will be randomized in a 1:1 manner to a diet with either low or high SAA. Both groups will receive an equal base diet consisting of low-SAA plant-based whole foods and an amino acid supplement free of SAA. Contrasting SAA contents will be achieved using capsules with or without methionine and cysteine (SAAhigh, total diet SAA ~ 50-60 mg/kg body weight/day; SAAlow, total diet SAA ~ 15-25 mg/kg body weight/day). The primary outcome is body weight change. Data and material collection will also include body composition (dual X-ray absorptiometry), resting energy expenditure (whole-room indirect calorimetry) and samples of blood, urine, feces and adipose tissue at baseline, at 4 weeks and at study completion. Measures will be taken to promote and monitor diet adherence. Data will be analyzed using linear mixed model regression to account for the repeated measures design and within-subject correlation. DISCUSSION: The strength of this study is the randomized double-blind design. A limitation is the restrictive nature of the diet which may lead to poor compliance. If this study reveals a beneficial effect of the SAAlow diet on body composition and metabolic health, it opens up for new strategies for prevention and treatment of overweight, obesity and its associated disorders. Trial registration ClinicalTrials.gov: NCT04701346, Registration date: January 8th, 2021.

Effects of short-term methionine and cysteine restriction and enrichment with polyunsaturated fatty acids on oral glucose tolerance, plasma amino acids, fatty acids, lactate and pyruvate: results from a pilot study.

OBJECTIVE: In this 7-day pilot study we randomized healthy, normal-weight men and women to either a dietary intervention with methionine and cysteine restriction enriched in PUFA (Met/Cyslow + PUFA, n = 7) or with high contents of methionine, cysteine and SFA (Met/Cyshigh + SFA, n = 7). The objective was to describe the short-term responses in oral glucose tolerance, amino acid profile, total fatty acid profile, pyruvate and lactate following a Met/Cyslow + PUFA diet vs. Met/Cyshigh + SFA. RESULTS: The diet groups consisted of five women and two men, aged 20-38 years. After the 7-d intervention median pre- and post-oral glucose tolerance test (OGTT) glucose concentrations were 5 mmol/L and 4 mmol/L respectively in the Met/Cyslow + PUFA group. In the Met/Cyshigh + SFA group, median pre- and post-OGTT glucose concentrations were 4.8 mmol/L and 4.65 mmol/L after the 7-d intervention. The responses in the amino acid profiles were similar in both groups during the intervention with the exception of serine. Fatty acids decreased from baseline to day 7 in both groups. Plasma lactate and pyruvate were similar for both groups with an increase to day 3 before approaching baseline values at day 7. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02647970, registration date: January 6th 2016.

Plasma Sulfur Amino Acids and Risk of Cerebrovascular Diseases: A Nested Case-Control Study in the EPIC-Norfolk Cohort.

BACKGROUND AND PURPOSE: B-vitamin supplements lower circulating concentrations of homocysteine and may reduce stroke incidence. Homocysteine concentrations are associated with the incidence of stroke but other sulfur-containing compounds in the related metabolic pathway have not yet been investigated for an association with incident cerebrovascular diseases. METHODS: Nested within the EPIC (European Prospective Investigation Into Cancer and Nutrition)-Norfolk cohort, we established a case-control study with 480 incident cases of cerebrovascular diseases and 480 controls matched by age, sex, and year of baseline examination (1993-1997). Using baseline plasma samples, we assayed sulfur-containing compounds including methionine, homocysteine, cystathionine, cysteine, glutathione, and taurine with liquid chromatography-tandem mass spectrometry. We examined the association of concentrations of each of the compounds and the ratio of methionine to homocysteine (representing activity of one-carbon metabolism) with risk of incident cerebrovascular diseases, adjusted for potential confounders. RESULTS: Plasma methionine and the methionine/homocysteine ratio were inversely associated with risk of cerebrovascular diseases, with odds ratios per 1 SD of 0.83 (95% CI, 0.72-0.96) and 0.82 (95% CI, 0.71-0.95), respectively. The association of methionine remained significant after adjustment for homocysteine. None of the other examined compounds was significantly associated with incident cerebrovascular diseases. CONCLUSIONS: These findings suggest that greater availability of methionine, an essential amino acid, may play a role in the prevention of cerebrovascular diseases and explain the previously recognized link between elevated homocysteine and stroke. Further research is needed to determine causation and the potential of circulating methionine as a target in cerebrovascular disease prevention.

Exhaustive Exercise and Post-exercise Protein Plus Carbohydrate Supplementation Affect Plasma and Urine Concentrations of Sulfur Amino Acids, the Ratio of Methionine to Homocysteine and Glutathione in Elite Male Cyclists.

Plasma and tissue sulfur amino acid (SAA) availability are crucial for intracellular methylation reactions and cellular antioxidant defense, which are important processes during exercise and in recovery. In this randomized, controlled crossover trial among eight elite male cyclists, we explored the effect of exhaustive exercise and post-exercise supplementation with carbohydrates and protein (CHO+PROT) vs. carbohydrates (CHO) on plasma and urine SAAs, a potential new marker of methylation capacity (methionine/total homocysteine ratio [Met/tHcy]) and related metabolites. The purpose of the study was to further explore the role of SAAs in exercise and recovery. Athletes cycled to exhaustion and consumed supplements immediately after and in 30 min intervals for 120 min post-exercise. After ~18 h recovery, performance was tested in a time trial in which the CHO+PROT group cycled 8.5% faster compared to the CHO group (41:53 ± 1:51 vs. 45:26 ± 1:32 min, p < 0.05). Plasma methionine decreased by ~23% during exhaustive exercise. Two h post-exercise, further decline in methionine had occured by ~55% in the CHO group vs. ~33% in the CHO+PROT group (pgroup × time < 0.001). The Met/tHcy ratio decreased by ~33% during exhaustive exercise, and by ~54% in the CHO group vs. ~27% in the CHO+PROT group (pgroup × time < 0.001) post-exercise. Plasma cystathionine increased by ~72% in the CHO group and ~282% in the CHO+PROT group post-exercise (pgroup × time < 0.001). Plasma total cysteine, taurine and total glutathione increased by 12% (p = 0.03), 85% (p < 0.001) and 17% (p = 0.02), respectively during exhaustive exercise. Using publicly available transcriptomic data, we report upregulated transcript levels of skeletal muscle SLC7A5 (log2 fold-change: 0.45, FDR:1.8e-07) and MAT2A (log2 fold-change: 0.38, FDR: 3.4e-0.7) after acute exercise. Our results show that exercise acutely lowers plasma methionine and the Met/tHcy ratio. This response was attenuated in the CHO+PROT compared to the CHO group in the early recovery phase potentially affecting methylation capacity and contributing to improved recovery.

Associations between plasma polyunsaturated fatty acids, plasma stearoyl-CoA desaturase indices and body fat.

OBJECTIVE: Stearoyl-CoA desaturase (SCD)-1 deficient mice are resistant to obesity and plasma SCD indices are related to obesity in humans. Both n-3 and n-6 polyunsaturated fatty acids (PUFA) regulate expression of the SCD enzymes. Whether higher plasma PUFA were associated with lower SCD indices in humans was examined. DESIGN AND METHODS: Population-based study of 2,021 elderly subjects from the Hordaland Health Study. Using multivariate linear regression, the cross-sectional associations among plasma PUFA, estimated SCD indices (from fatty acid profiles in plasma total lipids), and fat mass measured by dual-energy X-ray absorptiometry were explored. Two plasma SCD indices were used: SCD-16 (16:1n-7/16:0) and SCD-18 (18:1n-9/18:0). RESULTS: Plasma total, n-6 and n-3 PUFA were inversely associated with both SCD indices (P < 0.001 for all). Among the individual PUFA, 18:2n-6 showed the strongest association with SCD-16 (partial r = -0.59, P < 0.001) followed by 20:5n-3 (partial r = -0.13; P < 0.001). Plasma total, n-6 and n-3 PUFA were inversely associated with body fat (P < 0.001 for all); the associations were markedly attenuated following adjustment for SCD-16. CONCLUSIONS: The epidemiological data are in line with animal studies and suggest that PUFA may decrease SCD1 activity in humans, with possible reduction in body fat.