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

Abstract

People with high plasma total cysteine (tCys) have higher fat mass and higher concentrations of the atherogenic apolipoprotein B (apoB). The disulfide form, cystine, enhanced human adipogenesis and correlated with total fat mass in a Middle-Eastern cohort. In 35 European adults with overweight (88.6% women) and with dual-X-ray absorptiometry measurements of regional fat, we investigated how cystine compared to other free disulfides in their association with total regional adiposity, plasma lipid and glucose biomarkers, and adipose tissue lipid enzyme mRNA (n = 19). Most total plasma homocysteine (tHcy) (78%) was protein-bound; 63% of total glutathione (tGSH) was reduced. tCys was 49% protein-bound, 30% mixed-disulfide, 15% cystine, and 6% reduced. Controlling for age and lean mass, cystine and total free cysteine were the fractions most strongly associated with android and total fat: 1% higher cystine predicted 1.97% higher android fat mass (95% CI 0.64, 3.31) and 1.25% (0.65, 2.98) higher total fat mass (both p = 0.005). A positive association between tCys and apoB (β: 0.64%; 95% CI 0.17, 1.12%, p = 0.009) was apparently driven by free cysteine and cystine; cystine was also inversely associated with the HDL-associated apolipoprotein A1 (β: −0.57%; 95% CI −0.96, −0.17%, p = 0.007). No independent positive associations with adiposity were noted for tGSH or tHcy fractions. Plasma cystine correlated with CPT1a mRNA (Spearman’s r = 0.68, p = 0.001). In conclusion, plasma cystine—but not homocysteine or glutathione disulfides—is associated with android adiposity and an atherogenic plasma apolipoprotein profile. The role of cystine in human adiposity and cardiometabolic risk deserves investigation. ClinicalTrials.gov identifiers: NCT02647970 and NCT03629392.

Cysteine‐lowering treatment with mesna against obesity: Proof of concept and results from a human phase I, dose‐finding study

“…Secondary trial endpoints included the effects of mesna on circulating tCys fractions, and on sulphur-related metabolites. Free cystine disulphide followed the same pattern of decline in postmesna administration as tCys, which is attractive in the light of studies showing that cystine is the main fraction associated with fat mass in humans 8,9 and enhances adipogenic differentiation and lipid accumulation in animal and human preadipocytes in vitro. 7,8 Free total cysteine (comprising the disulphide and reduced sulphydryl fractions) increased for up to 3 hours after mesna administration, and then decreased.…”

“…Longitudinal studies conducted for a duration of 6 years show that change in tCys is prospectively associated with corresponding changes in BMI 6 and fat mass, 4 after controlling for baseline tCys and BMI. Cystine, the disulphide form of cysteine, enhances adipogenesis and lipid accumulation in murine and human preadipocytes, 7,8 and is positively associated with fat mass in humans 8,9 . Transgenic and dietary animal studies also suggest that high cysteine availability promotes fat gain.…”

“…Cystine, the disulphide form of cysteine, enhances adipogenesis and lipid accumulation in murine and human preadipocytes, 7,8 and is positively associated with fat mass in humans. 8,9 Transgenic and dietary animal studies also suggest that high cysteine availability promotes fat gain. Mice fed a high cystine diet had lower energy expenditure and increased central adiposity and worsened glucose tolerance.…”

Dietary sulfur amino acid restriction in humans with overweight and obesity: Evidence of an altered plasma and urine sulfurome, and a novel metabolic signature that correlates with loss of fat mass and adipose tissue gene expression

“…Whether the effects of SAAR on body weight or WAT gene expression are directly linked to sulfurome changes in WAT remains to be investigated, since the WAT sulfurome could not be assayed in the present study. Despite the known elevation of plasma tCys [ 11 , 64 ], and its non-protein bound disulfide form, cystine in plasma and blood from people with obesity [ 9 , 65 , 66 ], a contrasting finding was observed in one study. Specifically, the concentrations of cystine and methionine were found to be 40 % lower in WAT from obese vs. lean individuals [ 67 ].…”

“…Such high intakes have been positively associated with diabetes risk [ 6 ] and related mortality [ 4 ], and cardiovascular disease risk scores [ 5 ]. Furthermore, observational studies have reported that high plasma total cysteine (tCys) was positively and strongly associated to obesity and fat mass [ [9] , [10] , [11] , [12] , [13] ], and impaired glucose metabolism [ 14 , 15 ], whereas high plasma Met was positively associated with liver fat [ 13 ]. Animal studies have demonstrated that dietary sulfur amino acid restriction (SAAR) can prolong life [ 16 ], improve body composition and insulin sensitivity [ 17 ], prevent fatty liver [ 18 ] and cognitive impairment [ 19 ], and influence tumor cell metabolism [ 20 ].…”