Evidence from human, animal and cellular studies suggests that high plasma total
cysteine (tCys) is causally linked to human
obesity, but determinants of population tCys variability are unknown. We hypothesized that tCys elevation in
obesity may be mediated by an altered tCys response to intake of its precursor,
methionine. We investigated whether BMI influences the change in plasma tCys, total
homocysteine (tHcy) and total
cysteinylglycine (tCysGly) 6h following a 100 mg/kg oral
methionine load in 800 healthy subjects and 750
cardiovascular disease (CVD) cases.
Methionine loading decreased tCys from mean 275 (95% CI, 273, 277) μmol/L to 253 (251,255) μmol/L. The decline in tCys was less in
overweight (-8%) and obese (-6%) compared to normal weight (-9%) subjects, adjusting for age, gender and CVD (P-ANOVA = 0.006). Compared to normal weight subjects, individuals with
obesity had a 2.8-fold likelihood (95% CI, 1.52, 5.01) of experiencing a rise (rather than decline), in tCys postload, after multiple adjustments. tCysGly also decreased postload, and the decline was similarly smaller in
overweight (-18%) and obese (-15%) compared to normal weight (-21%) individuals (P-ANOVA <0.001). The tHcy response was modified by CVD status, with an increase in tHcy postload being BMI-dependent in controls (P-ANOVA<0.001) but not in CVD cases (P-interaction = 0.07). Although the
methionine dose used was supraphysiologic, these data suggest that an altered tCys response to ingested
methionine occurs in
obesity, whereby tCys might rise in response to dietary
methionine. This may contribute to explaining why human
obesity is consistently associated with elevated tCys.