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Abstract: Objectives: Methionine-restricted (MR) rats, which are lean and insulin sensitive, have low serum total cysteine (tCys) and taurine and decreased hepatic expression and activity indices of stearoyl-coenzyme A desaturase-1 (SCD1). These effects are partly or completely reversed by cysteine supplementation. We investigated whether reversal of MR phenotypes can be achieved by other sulfur compounds, namely taurine or N-acetylcysteine (NAC). Methods: MR and control-fed (CF) rats were supplemented with taurine (0.5%) or NAC (0.5%) for 12weeks. Adiposity, serum sulfur amino acids (SAA), Scd1 gene expression in liver and white adipose tissue, and SCD1 activity indices (calculated from serum fatty acid profile) were monitored. Results: Taurine supplementation of MR rats did not restore weight gain or hepatic Scd1 expression or indices to CF levels, but further decreased adiposity. Taurine supplementation of CF rats did not affect adiposity, but lowered triglyceridemia. NAC supplementation in MR rats raised tCys and partly or completely reversed MR effects on weight, fat %, Scd1 expression in liver and white adipose tissue, and estimated SCD1 activity. In CF rats, NAC decreased body fat % and lowered SCD1-18 activity index (P<0.001). Serum triglycerides and leptin were over 40% lower in CF+NAC relative to CF rats (P≤0.003 for both). In all groups, change in tCys correlated with change in SCD1-16 index (partial r=0.60, P<0.001) independent of other SAA. Conclusion: The results rule out taurine as a mediator of increased adiposity produced by cysteine in MR, and show that NAC, similar to L-cysteine, blocks anti-obesity effects of MR. Our data show that dietary SAA can influence adiposity in part through mechanisms that converge on SCD1 function. This may have implications for understanding and preventing human obesity. [Copyright &y& Elsevier]

Context: Plasma total cysteine (tCys) independently relates to fat mass in adults. Dietary cyst(e)ine promotes adiposity and decreases glucose tolerance in some rodent models, but alleviates insulin resistance in others. Objective: To investigate whether the association of tCys with body fat extends to children at particular risk of obesity, and whether tCys is associated with insulin resistance and obesity-associated inflammation. Methods: We explored the cross-sectional relations of fasting plasma tCys and related metabolites with body composition measured by dual-energy X-ray absorptiometry in 984 Hispanic children and adolescents aged 4-19 years from the Viva La Familia Study. Linear and logistic regression and dose-response curves were used to evaluate relations of tCys with obesity, insulin resistance and inflammatory markers including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and C-reactive protein (CRP). Results: tCys, methionine and total homocysteine (tHcy) increased with age. Upper tCys quartile was independently associated with a 5-fold increased risk of obesity (95% CI 3.5-8.0, P<0.001), and 2-fold risk of insulin resistance (95% CI: 1.6-5.0, P<0.001; adjusted for body fat%). Within the overweight/obese subgroup, but not in normal-weight children, tCys accounted for 9% of the variability in body fat% (partial r = 0.30, P<0.001; adjusted for age and gender). tCys correlated positively with serum non-esterified fatty acids and leptin, partly independent of body fat, but was not associated with serum IL-6, TNF-α or MCP-1. A positive correlation with CRP disappeared after adjustment for BMI. Conclusion: tCys is independently associated with obesity and insulin resistance in Hispanic children and adolescents, highlighting a previously underappreciated link between the sulfur amino acid metabolic pathway and obesity and cardiometabolic risk. [ABSTRACT FROM AUTHOR]

Plasma total cysteine (tCys) concentrations are associated with BMI. To study the relationship between tCys and BMI, we monitored the changes in serum concentrations of tCys and metabolically related compounds in sixty obese patients (BMI 50–60 kg/m2) from before to 1 year after either gastric bypass surgery (mean 30 % weight loss) or duodenal switch surgery (mean 41 % weight loss). A total of fifty-eight healthy persons (BMI 17–31 kg/m2) served as controls. Before surgery, obese patients had modestly (approximately 17 %) higher mean serum tCys, and markedly (>2-fold) higher glutamate concentrations, than controls (P ≤ 0·001 for both). Serial examinations after surgery revealed that gastric bypass patients had no change in tCys concentrations (P = 0·22), while duodenal switch patients showed a modest (approximately 12 %) but significant decrease in tCys (P < 0·001). Total homocysteine concentrations increased in duodenal switch patients but not in gastric bypass patients. Independent of surgery type, serum concentrations of methionine and cystathionine decreased (P < 0·05 for both), while serum glutathione and taurine remained stable. Glutamate concentrations declined, as did γ-glutamyltransferase activity (P < 0·001 for both). These results show that despite 30 % weight loss, and decreases in methionine, cystathionine and glutamate, there was no significant change in serum tCys in patients after gastric bypass surgery. The decrease in tCys in patients undergoing duodenal switch could be related to malabsorption. The present findings do not suggest that BMI is a causal determinant of plasma tCys. [ABSTRACT FROM PUBLISHER]

Objective: Dietary methionine restriction in Fischer-344 rats favorably influences visceral fat mass, insulin sensitivity, metabolic parameters, and longevity. However, little is known about the effects of methionine restriction on serum methionine and its downstream sulfur amino acids. We investigated the serum sulfur amino acid profile of male Fischer-344 rats fed a methionine-restricted diet for 3 mo. Methods and results: Using tandem mass spectrometry, we observed marked reduction in serum concentrations of methionine, cystathionine, cysteine, and taurine in methionine-restricted rats compared with control (P <0.001) and a 2.5-fold elevation of homocysteine (P <0.001). Conclusion: This suggests that homocysteine trans-sulfuration may be inhibited by methionine restriction, and that some of the effects of methionine restriction may be mediated by changes in sulfur amino acids downstream of methionine. [Copyright &y& Elsevier]

Abstract: Plasma total cysteine (tCys) is strongly and independently associated with obesity in large human cohorts, but whether the association is causal is unknown. Dietary cyst(e)ine increases weight gain in some rodent models. We investigated the body composition, metabolic rate and metabolic phenotype of mature C3H/HeH mice assigned to low-cystine (LC) or high-cystine (HC) diets for 12 weeks. Compared to LC mice, HC mice gained more weight (P=.004 for 12-week weight gain %), with increased fat mass and lean mass, and lowered O2 consumption and CO2 production by calorimetry. The HC mice had 30% increase in intestinal fat/body weight % (P=.003) and ∼twofold elevated hepatic triglycerides (P=.046), with increased expression of hepatic lipogenic factors, peroxisome proliferator-activated receptor-γ and sterol regulatory element binding protein-1. Gene expression of both basal and catecholamine-stimulated lipolytic enzymes, adipose triglyceride lipase and hormone-sensitive lipase was inhibited in HC mice adipose tissue. The HC mice also had elevated fasting glucose (7.0 vs. 4.5 mmol/L, P<.001) and a greater area under the curve (P<.001) in intraperitoneal glucose tolerance tests, with enhanced expression of the negative regulator of insulin signaling, protein tyrosine phosphatase-1B, in liver and adipose tissue. Overall, high cystine intake promotes adiposity and an adverse metabolic phenotype in mice, indicating that the positive association of plasma tCys with obesity in humans may be causal. [Copyright &y& Elsevier]