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

Abstract

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.

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

“…Human observations support this hypothesis. Plasma tCys has been consistently associated with BMI and body fat mass [3][4][5][6][7][8][9]. Only a few studies examined its relationship with central adiposity, reporting positive correlations with WC [4], trunk fat-to-total fat ratio [5], and central fat mass [7], but inconsistent associations with VAT [7,14].…”

“…Mounting evidence suggests that SAAs are related to obesity. Plasma tCys has been consistently and positively associated with body mass index (BMI) and whole-body fat mass [3][4][5][6][7][8][9] in human observational studies. For the other SAAs, some [4][5][6][7][10][11][12], but not all [4-8, 13, 14], observational studies report positive correlations for methionine, tHcy and cystathionine with BMI or other measures of overall adiposity.…”

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

“…The present study aims to replicate and extend our recent findings of the association between cystine and total fat mass (Elkafrawy et al 2021) by exploring, a-the association of plasma tCys fractions with distinct body fat depots that vary in their association with cardiometabolic risk; and b-if other plasma-free disulfide fractions (of homocysteine and/or GSH) are associated with fat mass in healthy adults. For the thiol fractions consistently associated with body fat depots, we explored associations with plasma markers of lipid and glucose metabolism and adipose tissue mRNA expression of genes involved in lipid metabolism in vivo.…”

Potential Mechanisms for How Long-Term Physical Activity May Reduce Insulin Resistance

“…Most research so far has focused on SAA and obesity, which is particularly relevant for plasma total cysteine (tCys) (reviewed in [ 150 ]). Plasma tCys has been shown to be strongly and positively associated with fat mass and adiposity in several studies [ 150 , 151 , 152 ]. Following gastric bypass surgery, plasma tCys concentration remains unchanged [ 153 ] and predicts weight regain [ 154 ].…”

“…Following gastric bypass surgery, plasma tCys concentration remains unchanged [ 153 ] and predicts weight regain [ 154 ]. In addition, in vitro studies suggest that administration of cysteine or the cysteine-cysteine disulfide induces adipose tissue differentiation [ 152 , 155 ]. Other SAAs, such as S-adenosylmethionine and methionine are strongly related to increased fat mass [ 156 ] and liver fat [ 157 ], respectively.…”