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

Hagar Elkafrawy,Radwa Mehanna,Ayman Barghash,Fredrik Jernerén,Fayrouz Ali,Iman Dessouky,Helga Refsum,Amany Elshorbagy,Cheryl Turner

doi:10.1007/s00726-021-03071-y

Hagar Elkafrawy, Radwa Mehanna + Show 7 more

Open Access

https://doi.org/10.1007/s00726-021-03071-y

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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.

Highlights

The past decade has seen increasing focus on the associations of specific amino acids with adiposity and cardiometabolic outcomes
Selected characteristics and plasma sulfur amino acid (SAA) and Scatterplots and unadjusted Spearman analysis showed strong positive correlations of cystine and mixed disulfides with fat mass (r ≥ 0.61, P < 0.001). total cysteine (tCys) and rCys were correlated with fat mass, whereas bCys was not (Fig. 1A–E)
After adjustment for age, gender and lean mass, the only cysteine species associated with fat mass were cystine and mixed disulfides (Fig. 1F)

Summary

Introduction

The past decade has seen increasing focus on the associations of specific amino acids with adiposity and cardiometabolic outcomes. High cystine intake in mice lowered energy expenditure, induced the adipogenic transcription factor peroxisome proliferator-activated receptor-γ (Pparg) in adipose tissue and increased weight gain and visceral fat (Elshorbagy et al 2012a). Restricted intake of the cysteine precursor methionine lowers tCys (Elshorbagy et al 2010), raises energy expenditure, lowers adiposity (Hasek et al 2010) and improves metabolic health in rodents (Yu et al 2018) and humans (Plaisance et al 2011). Cysteine supplementation reverses the anti-obesity (Elshorbagy et al 2011) and antioxidant effects of methionine restriction (Gomez et al 2015). This evidence links plasma total cysteine to obesity but the possible mechanisms have not been elucidated in humans

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