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.

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ContextPlasma 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.ObjectiveTo 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.MethodsWe 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).ResultstCys, 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.ConclusiontCys 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.

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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.