Dietary sulfur amino acid restriction in humans with overweight and obesity: a translational randomized controlled trial.

BACKGROUND: Dietary sulfur amino acid restriction (SAAR) improves metabolic health in animals. In this study, we investigated the effect of dietary SAAR on body weight, body composition, resting metabolic rate, gene expression profiles in white adipose tissue (WAT), and an extensive blood biomarker profile in humans with overweight or obesity. METHODS: N = 59 participants with overweight or obesity (73% women) were randomized stratified by sex to an 8-week plant-based dietary intervention low (~ 2 g/day, SAAR) or high (~ 5.6 g/day, control group) in sulfur amino acids. The diets were provided in full to the participants, and both investigators and participants were blinded to the intervention. Outcome analyses were performed using linear mixed model regression adjusted for baseline values of the outcome and sex. RESULTS: SAAR led to a ~ 20% greater weight loss compared to controls (ß 95% CI - 1.14 (- 2.04, - 0.25) kg, p = 0.013). Despite greater weight loss, resting metabolic rate remained similar between groups. Furthermore, SAAR decreased serum leptin, and increased ketone bodies compared to controls. In WAT, 20 genes were upregulated whereas 24 genes were downregulated (FDR < 5%) in the SAAR group compared to controls. Generally applicable gene set enrichment analyses revealed that processes associated with ribosomes were upregulated, whereas processes related to structural components were downregulated. CONCLUSION: Our study shows that SAAR leads to greater weight loss, decreased leptin and increased ketone bodies compared to controls. Further research on SAAR is needed to investigate the therapeutic potential for metabolic conditions in humans. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04701346, registered Jan 8th 2021, https://www. CLINICALTRIALS: gov/study/NCT04701346.

Acute effects of oral mesna administration on the full amino acid profile and 3-methylhistidine: secondary results from the CYLOB dose-finding study.

Plasma total cysteine (tCys) is strongly associated with fat mass in humans. Mesna lowers plasma tCys in a dose-dependent manner, but it is not known whether it interferes with metabolism of other amino acids or protein. In this Phase-1 study, we show that a single dose of mesna administered at 400, 800, 1200 or 1600 mg to 6-7 individuals per dose only slightly affects amino acid profiles, with increases in plasma valine across dose levels. There were no effects of mesna on 3-methylhistidine, a marker of protein breakdown.

The Associations of Habitual Intake of Sulfur Amino Acids, Proteins and Diet Quality with Plasma Sulfur Amino Acid Concentrations: The Maastricht Study.

BACKGROUND: Plasma sulfur amino acids (SAAs), i.e., methionine, total cysteine (tCys), total homocysteine (tHcy), cystathionine, total glutathione (tGSH), and taurine, are potential risk factors for obesity and cardiometabolic disorders. However, except for plasma tHcy, little is known about how dietary intake modifies plasma SAA concentrations. OBJECTIVE: To investigate whether the intake of SAAs and proteins or diet quality is associated with plasma SAAs. METHODS: Data from a cross-sectional subset of The Maastricht Study (n = 1145, 50.5% men, 61 interquartile range: [55, 66] y, 22.5% with prediabetes and 34.3% with type 2 diabetes) were investigated. Dietary intake was assessed using a validated food frequency questionnaire. The intake of SAAs (total, methionine, and cysteine) and proteins (total, animal, and plant) was estimated from the Dutch and Danish food composition tables. Diet quality was assessed using the Dutch Healthy Diet Index, the Mediterranean Diet Score, and the Dietary Approaches to Stop Hypertension score. Fasting plasma SAAs were measured by liquid chromatography (LC) tandem mass spectrometry (MS) (LC/MS-MS). Associations were investigated with multiple linear regressions with tertiles of dietary intake measures (main exposures) and z-standardized plasma SAAs (outcomes). RESULTS: Intake of total SAAs and total proteins was positively associated with plasma tCys and cystathionine. Associations were stronger in women and in those with normal body weight. Higher intake of cysteine and plant proteins was associated with lower plasma tHcy and higher cystathionine. Higher methionine intake was associated with lower plasma tGSH, whereas cysteine intake was positively associated with tGSH. Higher intake of methionine and animal proteins was associated with higher plasma taurine. Better diet quality was consistently related to lower plasma tHcy concentrations, but it was not associated with the other SAAs. CONCLUSION: Targeted dietary modifications might be effective in modifying plasma concentrations of tCys, tHcy, and cystathionine, which have been associated with obesity and cardiometabolic disorders.

The association of fasting plasma thiol fractions with body fat compartments, biomarker profile, and adipose tissue gene expression.

People with high plasma total cysteine (tCys) have higher fat mass and higher concentrations of the atherogenic apolipoprotein B (apoB). The disulfide form, cystine, enhanced human adipogenesis and correlated with total fat mass in a Middle-Eastern cohort. In 35 European adults with overweight (88.6% women) and with dual-X-ray absorptiometry measurements of regional fat, we investigated how cystine compared to other free disulfides in their association with total regional adiposity, plasma lipid and glucose biomarkers, and adipose tissue lipid enzyme mRNA (n = 19). Most total plasma homocysteine (tHcy) (78%) was protein-bound; 63% of total glutathione (tGSH) was reduced. tCys was 49% protein-bound, 30% mixed-disulfide, 15% cystine, and 6% reduced. Controlling for age and lean mass, cystine and total free cysteine were the fractions most strongly associated with android and total fat: 1% higher cystine predicted 1.97% higher android fat mass (95% CI 0.64, 3.31) and 1.25% (0.65, 2.98) higher total fat mass (both p = 0.005). A positive association between tCys and apoB (ß: 0.64%; 95% CI 0.17, 1.12%, p = 0.009) was apparently driven by free cysteine and cystine; cystine was also inversely associated with the HDL-associated apolipoprotein A1 (ß: -0.57%; 95% CI -0.96, -0.17%, p = 0.007). No independent positive associations with adiposity were noted for tGSH or tHcy fractions. Plasma cystine correlated with CPT1a mRNA (Spearman's r = 0.68, p = 0.001). In conclusion, plasma cystine-but not homocysteine or glutathione disulfides-is associated with android adiposity and an atherogenic plasma apolipoprotein profile. The role of cystine in human adiposity and cardiometabolic risk deserves investigation. ClinicalTrials.gov identifiers: NCT02647970 and NCT03629392.

Cysteine-lowering treatment with mesna against obesity: Proof of concept and results from a human phase I, dose-finding study.

AIM: To investigate whether mesna-sodium-2-mercaptoethane sulfonate) can reduce diet-induced fat gain in mice, and to assess the safety of single ascending mesna doses in humans to find the dose associated with lowering of plasma tCys by at least 30%. METHODS: C3H/HeH mice were shifted to a high-fat diet ± mesna in drinking water; body composition was measured at weeks 0, 2 and 4. In an open, phase I, single ascending dose study, oral mesna (400, 800, 1200, 1600 mg) was administered to 17 men with overweight or obesity. Mesna and tCys concentrations were measured repeatedly for a duration of 48 hours postdosing in plasma, as well as in 24-hour urine. RESULTS: Compared with controls, mesna-treated mice had lower tCys and lower estimated mean fat mass gain from baseline (week 2: 4.54 ± 0.40 vs. 6.52 ± 0.36 g; week 4: 6.95 ± 0.35 vs. 8.19 ± 0.34 g; Poverall = .002), but similar lean mass gain. In men with overweight, mesna doses of 400-1600 mg showed dose linearity and were well tolerated. Mesna doses of 800 mg or higher decreased plasma tCys by 30% or more at nadir (4h post-dosing). With increasing mesna dose, tCys AUC0-12h decreased (Ptrend < .001), and urine tCys excretion increased (Ptrend = .004). CONCLUSIONS: Mesna reduces diet-induced fat gain in mice. In men with overweight, single oral doses of mesna (800-1600 mg) were well tolerated and lowered plasma tCys efficiently. The effect of sustained tCys-lowering by repeated mesna administration on weight loss in humans deserves investigation.

Associations between plasma sulfur amino acids and specific fat depots in two independent cohorts: CODAM and The Maastricht Study.

PURPOSE: Sulfur amino acids (SAAs) have been associated with obesity and obesity-related metabolic diseases. We investigated whether plasma SAAs (methionine, total cysteine (tCys), total homocysteine, cystathionine and total glutathione) are related to specific fat depots. METHODS: We examined cross-sectional subsets from the CODAM cohort (n = 470, 61.3% men, median [IQR]: 67 [61, 71] years) and The Maastricht Study (DMS; n = 371, 53.4% men, 63 [55, 68] years), enriched with (pre)diabetic individuals. SAAs were measured in fasting EDTA plasma with LC-MS/MS. Outcomes comprised BMI, skinfolds, waist circumference (WC), dual-energy X-ray absorptiometry (DXA, DMS), body composition, abdominal subcutaneous and visceral adipose tissues (CODAM: ultrasound, DMS: MRI) and liver fat (estimated, in CODAM, or MRI-derived, in DMS, liver fat percentage and fatty liver disease). Associations were examined with linear or logistic regressions adjusted for relevant confounders with z-standardized primary exposures and outcomes. RESULTS: Methionine was associated with all measures of liver fat, e.g., fatty liver disease [CODAM: OR = 1.49 (95% CI 1.19, 1.88); DMS: OR = 1.51 (1.09, 2.14)], but not with other fat depots. tCys was associated with overall obesity, e.g., BMI [CODAM: ß = 0.19 (0.09, 0.28); DMS: ß = 0.24 (0.14, 0.34)]; peripheral adiposity, e.g., biceps and triceps skinfolds [CODAM: ß = 0.15 (0.08, 0.23); DMS: ß = 0.20 (0.12, 0.29)]; and central adiposity, e.g., WC [CODAM: ß = 0.16 (0.08, 0.25); DMS: ß = 0.17 (0.08, 0.27)]. Associations of tCys with VAT and liver fat were inconsistent. Other SAAs were not associated with body fat. CONCLUSION: Plasma concentrations of methionine and tCys showed distinct associations with different fat depots, with similar strengths in the two cohorts.

The association of serum sulfur amino acids and related metabolites with incident diabetes: a prospective cohort study.

AIM: Plasma total cysteine (tCys) is associated with fat mass and insulin resistance, whereas taurine is inversely related to diabetes risk. We investigated the association of serum sulfur amino acids (SAAs) and related amino acids (AAs) with incident diabetes. METHODS: Serum AAs were measured at baseline in 2997 subjects aged ≥ 65 years. Diabetes was recorded at baseline and after 4 years. Logistic regression evaluated the association of SAAs [methionine, total homocysteine (tHcy), cystathionine, tCys, and taurine] and related metabolites [serine, total glutathione (tGSH), glutamine, and glutamic acid] with diabetes risk. RESULTS: Among 2564 subjects without diabetes at baseline, 4.6% developed diabetes. Each SD increment in serum tCys was associated with a 68% higher risk (95% CI 1.27, 2.23) of diabetes [OR for upper vs. lower quartile 2.87 (1.39, 5.91)], after full adjustments (age, sex, other AAs, adiposity, eGFR, physical activity, blood pressure, diet and medication); equivalent ORs for cystathionine were 1.33 (1.08, 1.64) and 1.68 (0.85, 3.29). Subjects who were simultaneously in the upper tertiles of both cystathionine and tCys had a fivefold risk [OR = 5.04 (1.55, 16.32)] of diabetes compared with those in the lowest tertiles. Higher serine was independently associated with a lower risk of developing diabetes [fully adjusted OR per SD = 0.68 (0.54, 0.86)]. Glutamic acid and glutamine showed positive and negative associations, respectively, with incident diabetes in age- and sex-adjusted analysis, but only the glutamic acid association was independent of other confounders [fully adjusted OR per SD = 1.95 (1.19, 3.21); for upper quartile = 7.94 (3.04, 20.75)]. tGSH was inversely related to diabetes after adjusting for age and sex, but not other confounders. No consistent associations were observed for methionine, tHcy or taurine. CONCLUSION: Specific SAAs and related metabolites show strong and independent associations with incident diabetes. This suggests that perturbations in the SAA metabolic pathway may be an early marker for diabetes risk.

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.

Extracellular cystine influences human preadipocyte differentiation and correlates with fat mass in healthy adults.

Plasma cysteine is associated with human obesity, but it is unknown whether this is mediated by reduced, disulfide (cystine and mixed-disulfides) or protein-bound (bCys) fractions. We investigated which cysteine fractions are associated with adiposity in vivo and if a relevant fraction influences human adipogenesis in vitro. In the current study, plasma cysteine fractions were correlated with body fat mass in 35 adults. Strong positive correlations with fat mass were observed for cystine and mixed disulfides (r ≥ 0.61, P < 0.001), but not the quantitatively major form, bCys. Primary human preadipocytes were differentiated in media containing cystine concentrations varying from 10-50 µM, a range similar to that in plasma. Increasing extracellular cystine (10-50 µM) enhanced mRNA expression of PPARG2 (to sixfold), PPARG1, PLIN1, SCD1 and CDO1 (P = 0.042- < 0.001). Adipocyte lipid accumulation and lipid-droplet size showed dose-dependent increases from lowest to highest cystine concentrations (P < 0.001), and the malonedialdehyde/total antioxidant capacity increased, suggesting increased oxidative stress. In conclusion, increased cystine concentrations, within the physiological range, are positively associated with both fat mass in healthy adults and human adipogenic differentiation in vitro. The potential role of cystine as a modifiable factor regulating human adipocyte turnover and metabolism deserves further study.

Food Overconsumption in Healthy Adults Triggers Early and Sustained Increases in Serum Branched-Chain Amino Acids and Changes in Cysteine Linked to Fat Gain.

Background: Plasma concentrations of branched-chain amino acids (BCAAs) and the sulfur-containing amino acid cysteine are associated with obesity and insulin resistance. BCAAs predict future diabetes. Objective: We investigated amino acid changes during food overconsumption. Methods: Forty healthy men and women with a body mass index (mean ± SEM) of 25.6 ± 0.6 were overfed by 1250 kcal/d for 28 d, increasing consumption of all macronutrients. Insulin sensitivity and body composition were assessed at baseline (day 0) and day 28. Fasting serum amino acids were measured at days 0, 3, and 28. Linear mixed-effects models evaluated the effect of time in the total group and separately in those with low and high body fat gain (below compared with at or above median fat gain, 1.95 kg). At days 0 and 28, insulin-induced suppression of serum amino acids during a hyperinsulinemic-euglycemic clamp test and, in a subset (n = 20), adipose tissue mRNA expression of selected amino acid metabolizing enzymes were assessed. Results: Weight increased by 2.8 kg. High fat gainers gained 2.6 kg fat mass compared with 1.1 kg in low fat gainers. Valine and isoleucine increased at day 3 (+17% and +22%, respectively; P ≤ 0.002) and remained elevated at day 28, despite a decline in valine (P = 0.019) from day 3 values. Methionine, cystathionine, and taurine were unaffected. Serum total cysteine (tCys) transiently increased at day 3 (+11%; P = 0.022) only in high fat gainers (P-interaction = 0.043), in whom the cysteine catabolic enzyme cysteine dioxygenase (CDO1) was induced (+26%; P = 0.025) in adipose tissue (P-interaction = 0.045). Overconsumption did not alter adipose tissue mRNA expression of the BCAA-metabolizing enzymes branched-chain keto acid dehydrogenase E1α polypeptide (BCKDHA) or branched-chain amino transferase 1 (BCAT1). In the total population at day 0, insulin infusion decreased all serum amino acids (-11% to -47%; P < 0.01), except for homocysteine and tCys, which were unchanged, and glutathione, which was increased by 54%. At day 28, insulin increased tCys (+8%), and the insulin-induced suppression of taurine and phenylalanine observed at day 0, but not that of BCAAs, was significantly impaired. Conclusions: These findings highlight the role of nutrient oversupply in increasing fasting BCAA concentrations in healthy adults. The link between cysteine availability, CDO1 expression, and fat gain deserves investigation. This trial was registered at www.clinicaltrials.gov as NCT00562393.

Circulating Polyunsaturated Fatty Acids as Biomarkers for Dietary Intake across Subgroups: The CODAM and Hoorn Studies.

AIMS: To evaluate whether participant characteristics and way of expressing circulating fatty acids (FA) influence the strengths of associations between self-reported intake and circulating levels of linoleic acid (LA), alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). METHODS: Cross-sectional analyses were performed in pooled data from the CODAM (n = 469) and Hoorn (n = 702) studies. Circulating FA were measured by gas liquid chromatography and expressed as proportions (% of total FA) and concentrations (µg/mL). Dietary intakes were calculated from a validated food frequency questionnaire. Effects of participant characteristics on associations between dietary and circulating FA were calculated using interaction analyses. RESULTS: Standardized regression coefficients between dietary FA and proportions of circulating FA (% of total FA) were LA ß = 0.28, ALA ß = 0.13, EPA ß = 0.34, and DHA ß = 0.45. Body mass index (BMI), waist circumference, and presence of CVD influenced associations for LA; gender influenced LA, EPA, and DHA; alcohol intake influenced LA and DHA; and glucose tolerance status influenced ALA (p values interaction <0.05). Coefficients for circulating FA as concentrations were LA ß = 0.19, ALA ß = 0.10, EPA ß = 0.31, and DHA ß = 0.41. CONCLUSIONS: This study suggests that characteristics such as BMI, alcohol intake, and expressing circulating FA as proportions or concentrations, influence associations between dietary and circulating FA.

Protective effect of melatonin versus montelukast in cisplatin-induced seminiferous tubule damage in rats.

We compared the protective effects of melatonin and montelukast against cisplatin-induced testicular damage. Adult male rats were assigned to one of four groups: a control group, a cisplatin (Cis) group treated with a single intraperitoneal injection of 7 mg/kg cisplatin, a cisplatin + melatonin group (Cis-Mel) and a cisplatin + montelukast group (Cis-Mon) each treated with the same dose of cisplatin together with either oral melatonin (20 mg/kg) or oral montelukast (10 mg/kg) in 2 ml water from day 1 to day 10 starting on the day of the cisplatin injection. Cisplatin-induced oxidative stress, with a significant increase in testicular malonedialdehyde (MDA), decreased testicular glutathione (GSH), histological testicular damage and body weight loss. Additionally, increased abnormal sperm forms and decreased count and motility were noted. Melatonin and montelukast both rescued GSH concentrations, increased sperm count and motility and decreased abnormal forms. Montelukast resulted in better rescue of weight loss, while greater improvement in sperm count and testicular pathology, and a trend for decreased MDA were noted with melatonin. These findings suggest that melatonin and montelukast protect against different aspects of cisplatin-induced toxicity. Future studies should assess whether both drugs may have additive benefit when used in combination.

Amino acid changes during transition to a vegan diet supplemented with fish in healthy humans.

PURPOSE: To explore whether changes in dietary protein sources can lower plasma branched-chain amino acids (BCAAs), aromatic amino acids and sulfur amino acids (SAAs) that are often elevated in the obese, insulin-resistant state and in type 2 diabetes. METHODS: Thirty-six subjects (mean age 31 ± 2 years) underwent a voluntary abstinence from meat, poultry, eggs, and dairy products for 6 weeks, while enriching the diet with fish, in fulfillment of a religious fast. Subjects were assessed 1 week before the fast (V1), 1 week after initiation of the fast (V2) and in the last week of the fast (V3). Thirty-four subjects completed all three visits. RESULTS: Fasting plasma BCAAs decreased at V2 and remained low at V3 (P < 0.001 for all). Valine showed the greatest decline, by 20 and 19 % at V2 and V3, respectively. Phenylalanine and tryptophan, but not tyrosine, also decreased at V2 and V3. The two proteinogenic SAAs, methionine and cysteine, remained stable, but the cysteine product, taurine, decreased from 92 ± 7 µmol/L to 66 ± 6 (V2; P = 0.003) and 65 ± 6 µmol/L (V3; P = 0.003). A progressive decline in plasma glutamic acid, coupled with an increase in glutamine, was observed. Plasma total and LDL cholesterol decreased at V2 and V3 (P < 0.001 for all). CONCLUSION: Changing dietary protein sources to plant- and fish-based sources in an ad libitum setting lowers the plasma BCAAs that have been linked to diabetes risk. These findings point to habitual diet as a potentially modifiable determinant of fasting plasma BCAA concentrations.

Circulating linoleic acid and alpha-linolenic acid and glucose metabolism: the Hoorn Study.

PURPOSE: Data on the relation between linoleic acid (LA) and alpha-linolenic acid (ALA) and type 2 diabetes mellitus (T2DM) risk are scarce and inconsistent. The aim of this study was to investigate the association of serum LA and ALA with fasting and 2 h post-load plasma glucose and glycated hemoglobin (HbA1c). METHOD: This study included 667 participants from third examination (2000) of the population-based Hoorn study in which individuals with glucose intolerance were overrepresented. Fatty acid profiles in serum total lipids were measured at baseline, in 2000. Diabetes risk markers were measured at baseline and follow-up in 2008. Linear regression models were used in cross-sectional and prospective analyses. RESULTS: In cross-sectional analyses (n = 667), serum LA was inversely associated with plasma glucose, both in fasting conditions (B = -0.024 [-0.045, -0.002]) and 2 h after glucose tolerance test (B = -0.099 [-0.158, -0.039]), but not with HbA1c (B = 0.000 [-0.014, 0.013]), after adjustment for relevant factors. In prospective analyses (n = 257), serum LA was not associated with fasting (B = 0.003 [-0.019, 0.025]) or post-load glucose (B = -0.026 [-0.100, 0.049]). Furthermore, no significant associations were found between serum ALA and glucose metabolism in cross-sectional or prospective analyses. CONCLUSIONS: In this study, serum LA was inversely associated with fasting and post-load glucose in cross-sectional, but not in prospective analyses. Further studies are needed to elucidate the exact role of serum LA and ALA levels and dietary polyunsaturated fatty acids in glucose metabolism.

Body composition in gene knockouts of sulfur amino acid-metabolizing enzymes.

Plasma concentrations of several amino acids are elevated in human obesity and insulin resistance, but there is no conclusive evidence on whether the amino acid alterations are causal. Dietary restriction of the essential SAA methionine (MR) in rats produces a hypermetabolic phenotype, with an integrated set of transcriptional changes in lipid enzymes in liver and adipose tissue. MR also induces an array of changes in methionine metabolites, including elevated plasma homocysteine and decreased cystathionine, cysteine, glutathione, and taurine. Several knockouts of enzymes acting downstream of methionine recapitulate the phenotypic results of MR, suggesting that the MR phenotype may be driven by changes distal to methionine. Here we review the changes in SAA and body composition in seven relevant knockout mouse models. All seven models feature decreased body weight, which in five of these have been further explored and shown to result from predominantly decreased fat mass. Common to several models is increased energy expenditure, enhanced insulin sensitivity, and protection against dietary obesity, as occurs in MR. A decrease in plasma total cysteine concentrations is also seen in most models. The lean phenotype could often be reversed by dietary supplementation of cysteine or choline, but not taurine, betaine or a H2S donor. Importantly, the plasma concentrations of both cysteine and choline are positively associated with fat mass in large populations studies, while taurine, betaine, and H2S are not. Collectively, the emerging data from dietary and knockout models are in harmony with human epidemiologic data, suggesting that the availability of key nutrients in the SAA pathway regulates fat storage pathways.

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.

BACKGROUND: In animals, dietary sulfur amino acid restriction (SAAR) improves metabolic health, possibly mediated by altering sulfur amino acid metabolism and enhanced anti-obesogenic processes in adipose tissue. AIM: To assess the effects of SAAR over time on the plasma and urine SAA-related metabolites (sulfurome) in humans with overweight and obesity, and explore whether such changes were associated with body weight, body fat and adipose tissue gene expression. METHODS: Fifty-nine subjects were randomly allocated to SAAR (∼2 g SAA, n = 31) or a control diet (∼5.6 g SAA, n = 28) consisting of plant-based whole-foods and supplemented with capsules to titrate contents of SAA. Sulfurome metabolites in plasma and urine at baseline, 4 and 8 weeks were measured using HPLC and LC-MS/MS. mRNA-sequencing of subcutaneous white adipose tissue (scWAT) was performed to assess changes in gene expression. Data were analyzed with mixed model regression. Principal component analyses (PCA) were performed on the sulfurome data to identify potential signatures characterizing the response to SAAR. RESULTS: SAAR led to marked decrease of the main urinary excretion product sulfate (p < 0.001) and plasma and/or 24-h urine concentrations of cystathionine, sulfite, thiosulfate, H2S, hypotaurine and taurine. PCA revealed a distinct metabolic signature related to decreased transsulfuration and H2S catabolism that predicted greater weight loss and android fat mass loss in SAAR vs. controls (all pinteraction < 0.05). This signature correlated positively with scWAT expression of genes in the tricarboxylic acid cycle, electron transport and ß-oxidation (FDR = 0.02). CONCLUSION: SAAR leads to distinct alterations of the plasma and urine sulfurome in humans, and predicted increased loss of weight and android fat mass, and adipose tissue lipolytic gene expression in scWAT. Our data suggest that SAA are linked to obesogenic processes and that SAAR may be useful for obesity and related disorders. TRIAL IDENTIFIER: https://clinicaltrials.gov/study/NCT04701346.

Evaluation of the body adiposity index in a Caucasian population: the Hordaland health study.

In this study, we compared the relationships of body mass index (BMI) and body adiposity index (BAI) with body fat percentage (BF%) in a Caucasian, European population. BF% was measured by dual-energy x-ray absorptiometry in a population-based cross-sectional study of 5,193 middle-aged (47-49 years) and elderly (71-74 years) men and women from the Hordaland Health Study in western Norway from 1997 to 1999. In the total population, the correlation between BAI and BF% was stronger (r = 0.78) than the correlation between BMI and BF% (r = 0.56) with similar results in the middle-aged and elderly groups. However, in men and women separately, BMI was a better correlate of BF% (for men, r = 0.76; for women, r = 0.81) than was BAI (for men, r = 0.57; for women, r = 0.72). BMI was also a better correlate of BF% than was BAI assessed by partial correlations adjusted for sex (for BMI-BF%, r = 0.79; for BAI-BF%, r = 0.67). Bland-Altman plots and BF%-stratified analyses showed that BAI tended to overestimate BF% in lean subjects and to underestimate it in those with higher proportions of body fat, but that it predicted BF% well for those whose BMI was in a normal range. At the individual level and in population studies adjusted for sex, BMI outperforms BAI as a predictor of BF%.

S-adenosylmethionine is associated with fat mass and truncal adiposity in older adults.

S-adenosylmethionine (SAM) is synthesized from methionine, which is abundant in animal-derived protein, in an energy-consuming reaction. SAM and S-adenosylhomocysteine (SAH) correlate with body mass index (BMI). Plasma total concentration of the SAM-associated product cysteine (tCys) correlates with fat mass in humans and cysteine promotes adiposity in animals. In a cross-sectional study of 610 participants, we investigated whether SAM and SAH are associated with BMI via lean mass or fat mass and dietary protein sources as determinants of SAM and tCys concentrations. Plasma SAM was not associated with lean mass, but mean adjusted fat mass increased from 24 kg (95% CI: 22.6, 25.1) to 30 kg (95% CI: 28.7, 31.3) across SAM quartiles (P < 0.001) and trunk fat:total fat ratio increased from 0.48 to 0.52 (P < 0.001). Erythrocyte SAM was also positively associated with fat mass and trunk fat:total fat ratio. The association of SAM with fat mass was not weakened by adjustment for serum tCys, lipids, creatinine, or dietary or lifestyle confounders. Concentrations of the SAM precursor, methionine, and the SAM product, SAH, were not independently associated with adiposity. Intake of animal-derived protein was not related to serum methionine but was positively associated with plasma SAM (partial r = 0.11) and serum tCys (partial r = 0.13; P < 0.05 for both after adjustment for age, gender, and total energy intake). In conclusion, plasma SAM, but not methionine, is independently associated with fat mass and truncal adiposity, suggesting increased conversion of methionine to SAM in obese individuals. Prospective studies are needed to investigate the interactions among dietary energy and animal protein content, SAM concentrations, and change in body weight and cardiometabolic risk.

Many Paths to Alzheimer's Disease: A Unifying Hypothesis Integrating Biological, Chemical, and Physical Risk Factors.

Sporadic Alzheimer's disease (AD) is a complex, multifactorial disease. We should therefore expect to find many factors involved in its causation. The known neuropathology seen at autopsy in patients dying with AD is not consistently seen in all patients with AD and is sometimes seen in patients without dementia. This suggests that patients follow different paths to AD, with different people having slightly different combinations of predisposing physical, chemical and biologic risk factors, and varying neuropathology. This review summarizes what is known of the biologic and chemical predisposing factors and features in AD. We postulate that, underlying the neuropathology of AD is a progressive failure of neurons, with advancing age or other morbidity, to rid themselves of entropy, i.e., the disordered state resulting from brain metabolism. Understanding the diverse causes of AD may allow the development of new therapies targeted at blocking the paths that lead to dementia in each subset of patients.