Abstract
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.
Highlights
Emerging evidence from knockout studies points to the involvement of the sulfur amino acid (SAA) metabolic pathway in regulation of body weight and glucose homeostasis
In the present study we explored a) the associations of fasting plasma total cysteine (tCys) and related SAA with body fat% in the Viva La Familia cohort of Hispanic children and adolescents [23]; and b) the association of tCys with circulating non-esterified fatty acids (NEFA), inflammatory cytokines and insulin resistance
There was no meaningful interaction between tCys and gender in predicting body fat%, homeostasis model of insulin resistance (HOMA-IR) or inflammatory markers, so for these analyses, we present results pooled for girls and boys and adjusted for gender
Summary
Emerging evidence from knockout studies points to the involvement of the sulfur amino acid (SAA) metabolic pathway in regulation of body weight and glucose homeostasis. Knockout mice lacking betaine-homocysteine methyltransferase (BHMT), one of the enzymes that remethylate homocysteine to methionine, have increased energy expenditure and insulin sensitivity, and are resistant to diet-induced obesity [2]. A similar phenotype is observed in mice with a defect in glutathione synthesis due to deficiency of the glutamate-cysteine ligase modifier subunit [3,4], and in wild-type rats fed a methionine-restricted diet [5]. Common to all these models is decreased cysteine synthesis and/or plasma cysteine [1,3,5,6]. Profound hepatic suppression of stearoyl coenzyme A desaturase-1 (SCD1), a key lipid synthesizing enzyme and checkpoint in development of obesity [7], is seen in all models except for BHMT2/2 where it has not been tested
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