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W2022215953 abstract "Obesity is associated with elevation of circulating levels of several amino acids, but the mechanism of this elevation is unclear. The type of dietary protein influences the risk of obesity, suggesting that specific amino acids could contribute to regulating weight gain. Plasma concentrations of cysteine, but not of other sulfur amino acids, correlate strongly with fat mass and BMI in men and women. High plasma cysteine is also linked to obesity-related disorders such as cardiovascular disease and metabolic syndrome. Several lines of evidence suggest that increased cysteine availability may promote obesity. Evidence from interventions where cysteine-containing, cysteine-producing, or anti-cysteine compounds are administered or restricted supports a causal role for cysteine in regulating body weight. Genetic syndromes characterized by high or low plasma cysteine often exhibit corresponding changes in body weight. Studies on cultured rat adipocytes provide insight into the cellular mechanisms underlying the relation of cysteine with body fat. The prospect of weight control by modulating cysteine intake, synthesis or action is attractive, since cysteine and its precursor, methionine, are ingested in diet and at least one licensed drug reduces cysteine formation. This review summarizes current knowledge about the relationship between cysteine and body weight. Cysteine is a conditionally essential proteinogenic sulfur-containing amino acid. Through its sulfhydryl group reactivity, this amino acid can form disulfide linkages, which in turn control protein structure and stability (1). Nonprotein bound (free) cysteine in plasma often exists as homogeneous (cystine) or mixed (e.g., homocysteine-cysteine) disulfides. Plasma measurements of cysteine are often reported as total cysteine (tCys), which refers to all circulating forms including free, disulfide, and albumin-bound cysteine. Plasma tCys is largely oxidized, while cellular tCys is largely reduced (2). Although cysteine is the limiting precursor of the major intracellular antioxidant glutathione (GSH) (3), not only low plasma tCys, but also high tCys, predicts adverse outcomes, including cardiovascular disease (4). Here, we review the evidence that high tCys may also be causally related to obesity. The cysteine pool is a function of dietary intake, protein turnover, and endogenous synthesis (Figure 1) (2). Cysteine is synthesized by transsulfuration from homocysteine, a product of the essential sulfur amino acid, methionine (1). In the first reaction, catalyzed by cystathionine β-synthase (CBS), homocysteine condenses with serine to form cystathionine, which is cleaved by cystathionase, releasing cysteine. CBS thus catalyzes the first irreversible step that commits homocysteine to transsulfuration and cysteine synthesis (Figure 1) (5). Cysteine: metabolic pathways. Cysteine is a constituent of dietary proteins, a product of turnover of body protein pools, and is synthesized from methionine in the transsulfuration pathway, mainly in the liver. Located at cell membranes, γ-glutamyltransferase (GGT) catalyzes breakdown of glutathione to glutamate and cysteinylglycine, which ultimately releases cysteine, in the γ-glutamyl cycle. Cysteine is also the precursor of coenzyme A, glutathione, and taurine. Dotted arrows indicate pathways with omitted intermediates for purposes of clarity. a.a., amino acid; CBS, cystathionine β-synthase; CDO, cysteine dioxygenase; CGL, cystathionine γ-lyase; GGCS, γ-glutamylcysteine synthase; H2S, hydrogen sulfide; SAM, S-adenosyl methionine; SAH, S-adenosyl homocysteine. Two major factors regulating CBS activity are methionine availability and cellular redox state. S-adenosylmethionine, the methionine product mediating all transmethylation reactions, is an allosteric activator of CBS (5). This regulatory mechanism promotes disposal of excess methionine through irreversible conversion to cysteine (5), and inhibits transsulfuration when methionine supply is limited. Flux through the transsulfuration pathway in the liver is also favored under oxidative stress, which increases the supply cysteine for GSH synthesis (6). It is estimated that ∼50% of the cysteine utilized for hepatic GSH synthesis comes from transsulfuration (6). The enzyme γ-glutamyltransferase (GGT), localized to membranes of certain cell types, catalyzes extracellular GSH cleavage, ultimately releasing cysteine for uptake by cells (Figure 1) (7). The importance of GGT in plasma cysteine homeostasis is highlighted by mouse models (8,9), and one human case report (10), in which genetic GGT deficiency resulted in severe deficiency of plasma cysteine. Cysteine is also the precursor of coenzyme A (11). In conditions of sulfur amino acid excess, cysteine can also be oxidized to inorganic sulfur and pyruvate (11), which can be further used in gluconeogenesis (12). There is evidence that cysteine levels are regulated at the level of cysteine breakdown (13). Cysteine dioxygenase catalyses the first major step in cysteine catabolism and taurine production (Figure 1). Cysteine dioxygenase is markedly upregulated in response to high cysteine or protein availability, thus controlling the conservation or disposal of cysteine, depending on its supply (13). Notably, cysteine dioxygenase shows this powerful cysteine-responsiveness in liver and adipose tissue (13), but not in the kidney, lung, or brain (14), suggesting a relation between cysteine homeostasis and adipose tissue function. This review summarizes available evidence linking cysteine with body weight and obesity. First, epidemiologic studies linking plasma tCys with BMI and body composition are presented. Subsequently genetic syndromes and animal studies supporting a causal role for cysteine in weight regulation are reviewed. Finally conflicting evidence is discussed and a putative mechanism for cysteine action is suggested based on in vitro findings. Several large studies have reported a positive correlation between tCys and BMI in humans, but the association between tCys and BMI was not the main focus of these studies. In 1999, BMI was shown to be a “determinant” of plasma tCys in >16,000 men and women in the Hordaland Homocysteine Study (15). A longitudinal study of a subset of the same cohort, subsequently reported that “change in BMI predicted changes in tCys over time” (16). Two studies investigating tCys as a risk factor for cardiovascular disease recognized this tCys-BMI relationship (4,17). The tCys-BMI correlation was also reported in postmenopausal women (18), metabolic syndrome patients (19), and healthy controls in a breast cancer study (20). These studies did not specify whether tCys was related to fat mass or lean mass. In 2008, we investigated the relation between tCys and body composition measured by dual-energy X-ray absorptiometry, in >5,000 Norwegian subjects from the Hordaland Homocysteine Study (21). There was a positive linear relationship between tCys and fat mass, but no association between tCys and lean mass (21). The association of tCys with fat mass remained robust after adjustment for age, gender, lean mass, and dietary intakes of protein, fat and total energy, and plasma lipid concentrations. Depending on the model, tCys explained 4–8% of the fat mass variability in men and women (21). Subjects in the highest tCys quintile had 6–9 kg higher fat-mass compared to those in the lowest quintile (21). Furthermore, increase in plasma tCys over 6 years was associated with higher fat-mass at follow-up (21). Since this was also a noninterventional study, two possibilities for interpretation of the findings were either that a high cysteine somehow promotes obesity or that obesity influences cysteine turnover, thereby raising plasma tCys. Results from our recent study of changes in plasma sulfur amino acids in super-obese patients undergoing bariatric surgery suggest that body fat mass is not a determinant of plasma tCys concentrations (22). A third possibility is that one or more confounding factor(s) simultaneously increases plasma cysteine and predisposes to obesity, or that cysteine is a marker associated with obesity or obesity-related morbidity. One factor that fulfills the criteria of a confounder in the tCys–fat mass association is GGT enzyme activity. GGT is a recognized marker of obesity (7,23) which also catalyzes breakdown of GSH in the γ-glutamyl cycle, eventually releasing cysteine. Thus it is conceivable that obese individuals, through an unknown mechanism (23), feature increased GGT activity which elevates their tCys. However, in the COMAC cohort of >1,500 men and women from nine European countries, plasma tCys was found to be associated with BMI independent of plasma GGT activity (24). Subjects in the highest quartile of plasma tCys were 3.5 times as likely to be obese, compared to those in the lowest quartile, after adjusting for GGT. These findings are limited by the question of how far plasma GGT activity reflects tissue GGT activity, which is localized to cellular plasma membranes. Nevertheless, in this study the statistical relationships of tCys and GGT with BMI followed different patterns. While plasma GGT showed a strong association with odds of obesity that was weakened by adjustment for obesity-related factors (e.g., serum lipids), tCys was an independent linear predictor of BMI throughout the BMI range and was also independently associated with odds of obesity (24). Diet would be a confounder in the tCys–fat mass association if subjects with high tCys and high-fat mass consume a diet that increases plasma tCys and is simultaneously obesogenic, independent of its effect on cysteine metabolism. In the Hordaland Homocysteine Study, the tCys–fat mass relationship persisted after adjustment for total protein, fat, and energy intakes (21). Cysteine is abundant in whey protein (25) as well as some fruits and vegetables, including red pepper, asparagus, and strawberry (26), which are not recognized to be linked with obesity. There is also some data suggesting that dietary cysteine intake is not a major determinant of plasma tCys. In a recent study, dietary cystine intake was unrelated to plasma tCys in healthy women (20). A similar observation was made in cats fed different levels of cysteine (27), and doubling cystine intake in rats did not raise plasma cystine (28). Even parenteral cysteine administration in neonates failed to raise plasma tCys (29). It remains possible that another dietary pattern, apart from high intake of cysteine-rich foods, could simultaneously promote increase of plasma tCys and of fat mass. One such possibility is high intake of methionine-rich foods, as discussed below (see Dietary methionine restriction section). We investigated whether structurally and metabolically related sulfur amino acids showed a similar relation to BMI as tCys. Plasma tHcy showed a modest positive relation to fat mass in the Hordaland Homocysteine Study, which became negative after adjusting for tCys (21). Despite the association of methionine intake with BMI (30), nonfasting plasma methionine was not related to fat mass (21), and fasting plasma methionine was unrelated to BMI (31). Newgard et al. (32) similarly found no difference in plasma methionine between obese and lean subjects. Plasma cystathionine correlated positively with fat mass and BMI (21,31), but these correlations were weaker than those of tCys, and were attenuated by adjustment for confounders such as serum lipids. Plasma levels of taurine and tGSH, two downstream products of cysteine, were not significantly correlated with BMI (31). Figure 2 shows the estimated differences in body fat percent by plasma sulfur amino acids and triglyceride concentrations in the Hordaland Homocysteine Study. Plasma sulfur amino acids and body fat percent. Estimated differences in body fat % (dose–response curves and 95% confidence interval (CI)) according to plasma concentrations of individual sulfur amino acids (in µmol/l) and triglycerides (in mg/l) after adjustment for age-group and gender by Gaussian generalized additive regression models as described in ref. 21. P values and partial correlation coefficients are from corresponding linear regression analyses. tCys, total cysteine; tHcy, total homocysteine. Statistics for methionine, tHcy, cystathionine, and triglycerides are computed using log-transformed data. Data adapted from the Hordaland Homocysteine Study (21). In summary, only plasma tCys, but not methionine, tHcy, cystathionine, taurine, tGSH, or cysteinylglycine, is a strong independent positive predictor of BMI, fat mass and obesity (21,24,31). The distribution of several amino acids among the different blood compartments is altered in obesity (33). To investigate whether the association of tCys with obesity merely reflects a shift of cysteine from red cells to the plasma in obese individuals, we examined the association of nonprotein bound cysteine in whole blood with BMI. Similar to plasma tCys, free blood cysteine was positively correlated with BMI (cohort described in ref. 34; Figure 3). This may indicate that it is the high plasma cysteine availability in both cells and plasma, rather than a shift in cysteine compartmentation between blood cells and plasma, that is associated with obesity. Whole blood-free cysteine and BMI. Estimated differences in BMI according to concentration of nonprotein bound cysteine in whole blood in a cohort of 877 men and women (described in ref. 34), with adjustment for age and gender. Lower panel is additionally adjusted for free glutathione in whole blood. Free cysteine and glutathione measurements in whole blood were positively associated after adjustment for age and gender (partial r = 0.54, P < 0.001). Obesity is associated with elevation of circulating levels of several amino acids. Branched-chain amino acids, as well as alanine, phenylalanine, and tyrosine, are consistently elevated in overweight and/or obese subjects (32,33,35). Several mechanisms have been postulated to explain plasma amino acid elevation in obesity. In an early study, Holm et al. found strong correlations between plasma amino acid concentrations and lean mass, and concluded that increased lean mass in obesity contributes to the elevated plasma amino acid concentrations (36). Newgard et al. ascribe branched-chain amino acid elevation in obesity to enhanced protein catabolism partly resulting from dietary overload (32). She et al. demonstrated decreased branched-chain amino acid catabolic enzymes in obese rodents (37), and that in humans, these amino acids decrease following gastric bypass surgery, with increase in their metabolizing enzymes in adipose tissue samples (37). Thus branched-chain amino acid elevation in obesity appears to be a consequence or adjunct, rather than cause, of obesity. In contrast, several lines of evidence point to a causal role for cysteine or a product of cysteine, in promoting obesity. If cysteine is a causal determinant of fat mass, then an inborn error characterized by increased cysteine synthesis should be associated with obesity. Conversely, inherited defects of cysteine formation should be associated with a lean phenotype. This is what is observed in the two genetic syndromes, Down's syndrome and the common variant of homocystinuria (Figure 4). Genetic cysteine alterations and body weight. Opposite body weight phenotypes in inherited syndromes affecting cysteine synthesis: Left, homocystinuria due to cystathionine β-synthase (CBS) deficiency: decreased cysteine synthesis and a thin phenotype; right, Down's syndrome: increased cysteine synthesis and overweight/obesity. Down's syndrome. People with Down's syndrome (Trisomy 21) are more frequently overweight and obese compared to other populations with mental retardation (38). The cause of obesity in Down's syndrome is not clear, but has been proposed to be due to a low resting metabolic rate (39). Due to localization of the human CBS gene to chromosome 21, this gene is over expressed in Down's syndrome (40), resulting in markedly elevated plasma tCys (40), which may be linked to the increased incidence of obesity in this population. Homocystinuria due to CBS deficiency. The most common type of the inborn error homocystinuria is caused by genetic defects in the CBS enzyme and is characterized by marked elevation of plasma and urinary tHcy coupled with decreased cysteine synthesis, and a range of ocular, nervous, cardiovascular, and skeletal manifestations (41,42). Notably, these patients often have low BMI (calculated from ref. 43), decreased subcutaneous fat (44), and body weight frequently below the 5th percentile (45), and have been described by Mudd et al. as being “tall and thin by the time they reach late childhood” (41). The lean “marfanoid” phenotype has not been reported in the form of homocystinuria caused by homocysteine remethylation defects (42), in which cysteine synthesis is essentially normal, thus potentially implicating low cysteine availability in the thin phenotype of CBS deficiency. Dietary supplementation with cysteine or a cysteine-rich protein has been shown to increase weight gain in rats, rabbits, and monkeys (14,46,47,48,49), as well as in humans (50). Because mammals are unable to convert cysteine to methionine, the observed effects of cysteine on weight gain cannot be attributed to an increase in the essential amino acid methionine, although an adequate cysteine supply may spare methionine from transsulfuration (51). As early as 1960, authors concluded that “the equivalence of equimolar amounts of sulfur supplied as methionine, cystine, and cysteine in lowering hypercholesterolemia and promoting growth indicates that the effect was produced by cysteine or by some metabolite of cysteine” (46). In rats, adding cysteine to a low-protein diet restores body weight gain, despite the negligible change in dietary protein content (14,47). Cysteine-rich protein supplements also reversed weight loss in cancer patients (50), although there is no direct evidence that cysteine is the active agent responsible for increased weight gain. The increased weight gain in these studies does not appear to result from increased caloric consumption, since food intake was often decreased in the cysteine-supplemented group (47,49). This is in agreement with findings in the Hordaland Homocysteine Study that the correlation of tCys with fat mass appeared independent of energy intake (21). In rats, the methionine content of food tightly correlates with food conversion-efficiency (g weight gained per g food consumed) (52). Consistent with this finding, dietary methionine restriction in rodents results in decreased weight gain and/or fat mass coupled with increased metabolic rate (53,54). The hypermetabolic phenotype is linked to profound suppression of hepatic stearoyl CoA desaturase-1, a δ-9 fatty acid desaturase which is a key regulator of lipid and energy metabolism (55). This is a specific effect of lowered methionine content of diet, independent of caloric intake, as assessed by pair-feeding studies (53). In human diet, methionine is mainly derived from food of animal origin including meat and fish (56). In line with rodent findings, vegetarian diets which are low in methionine (56) are associated in large studies with lower 5-year weight gain (57), and lower obesity risk (58), and are also associated with lower tCys (59). Similarly, soy-based diets with low methionine content are often associated with greater weight loss when used for treatment of obesity (reviewed in ref. 60). Furthermore, weight loss is observed in humans on a methionine-free diet for treatment of cancer, despite energy and protein intakes being adequate or increased (61). In nearly 2,000 men, energy-adjusted methionine intake showed a dose-dependent relation with BMI (30). Thus it is plausible that high methionine intake simultaneously promotes weight gain and increases plasma tCys by increasing methionine conversion to cysteine. Plasma tCys is decreased in methionine-restricted rats (62), suggesting that it may be the decreased cysteine availability which mediates the effects of methionine restriction on body weight. To disentangle the effects of reduction of cysteine from that of methionine, we investigated whether supplementing methionine-restricted rats with cysteine would reverse their phenotype. Cysteine supplementation indeed blocked the effects of methionine restriction on adiposity and hepatic stearoyl CoA desaturase-1 expression, with corresponding changes in plasma fatty acid and adipokine profiles (63). The decrease in serum methionine in methionine-restricted rats was not restored by cysteine supplementation (63). This suggests that it is the reduced supply of cysteine that mediates the antiobesity effects of methionine restriction. Consistent with this view, we have also recently observed in a dietary mouse model that high cystine intake decreases metabolic rate (64). Several drugs that decrease cysteine synthesis, turnover or uptake by cells have a negative impact on body weight. Sulfasalazine, which blocks the cysteine transporter responsible for cysteine uptake by cells, produces weight loss as a side effect (65). Cilastatin, a dipeptidase inhibitor which prevents the release of cysteine from cysteinylglycine, resulting in decreased tCys (66), decreases weight gain in rats (67). However, cilastatin is normally administered as an adjuvant to the antibiotic imipenem, so the weight loss cannot be conclusively attributed to its tCys-lowering action, and studies in monkeys did not detect an effect of imipenem/cilastatin on body weight (68). More consistent decrease in weight gain is observed in rodents with administration of the cystathionase inhibitor, propargylglycine, which prevents release of cysteine from cystathionine (69). A body of literature also contradicts the hypothesis that cysteine could promote obesity. This mainly comprises a series of studies that collectively propose that cysteine favorably affects lean mass, and may under certain conditions decrease fat mass. The compounds used in these studies were either cysteine-rich whey protein isolates or the synthetic cysteine analogue, N-acetylcysteine (NAC). Data from cysteine-rich protein supplementation exists for both humans and rodents. One study found a 5% decrease in body fat% in nine subjects consuming oral immunocal, a cysteine-rich whey protein, compared to 5% increase in nine subjects receiving a casein placebo, as assessed by skin-fold thicknesses (70). In contrast, a comparable trial in 22 subjects showed casein to be superior to cysteine-rich whey protein in promoting fat mass loss (71). Furthermore, immunocal itself has been found to promote weight gain in cancer patients (50). A third study was conducted in rats (72). A cysteine-donor protein (α-lactalbumin-enriched whey protein) increased lean mass and decreased adiposity when given before exercise training for 5 weeks, compared to whole milk protein or glucose (72). The cysteine arm of this study involved several factors (lactalbumin, whey protein, and exercise). Thus despite the known high cysteine content of whey, it is not conclusive that body composition changes are a cysteine effect. The effects of whey protein on body composition have previously been attributed to its leucine content (73), which stimulates muscle protein synthesis. Thus while cysteine-rich protein supplements may have demonstrable benefits on body composition in some studies, the “active” constituent mediating these effects is not defined, and the evidence for their effects on fat mass is weak and conflicting. Hildebrandt et al. demonstrated that NAC may reduce fat mass in a trial including human subjects receiving either NAC or placebo for 8 weeks (74). The NAC group (N = 11) featured a 3% decrease in fat mass compared to an 8% increase in the placebo group (74). The lowered fat mass in the NAC group was associated with decreased insulin sensitivity, and was therefore interpreted to indicate that NAC decreased fat mass by inhibiting insulin reactivity. Visceral fat mass reduction was also observed in rodents after 6–8 weeks of daily intraperitoneal injection of NAC (75). Plasma tCys changes were not reported in the NAC-supplementation studies. Although NAC is considered a synthetic cysteine analogue, effects of NAC supplementation on plasma tCys are difficult to anticipate. Different studies have reported either no change (76), an increase (77) or a lowering of plasma cysteine levels following NAC administration (78). Below we postulate that NAC and cysteine may in fact exert different effects on body composition due to their contrasting redox properties in relation to insulin-regulated lipid turnover. In addition to its effects on stearoyl CoA desaturase-1 and metabolic rate in rodent models (64) discussed above (see dietary methionine restriction section), cysteine may also exert local insulin-like effects in adipocytes. Insulin is the most potent antilipolytic hormone known. It strongly inhibits hormone-sensitive lipase, the rate-limiting enzyme in catecholamine-stimulated lipolysis, and stimulates adipocyte triglyceride and glucose uptake (79). The functional roles of cysteine and NAC in relation to insulin signaling and insulin-mediated regulation of lipid turnover have been investigated in vitro. Findings from these studies may elucidate a mechanism for the potential obesogenic effect of cysteine, in contrast to NAC. Insulin binds membrane receptors, activating intracellular receptor subunits, with subsequent phosphorylation of “insulin receptor substrates,” which mediate insulin's effects. Insulin action is terminated when the insulin receptor substrates are dephosphorylated and thus inactivated by protein tyrosine phosphatase-1B (80). The catalytic activity of protein tyrosine phosphatase-1B depends on the reduced state of its cysteine thiol residue (80). Insulin signaling initially elicits release of reactive oxygen species, particularly H2O2, which facilitate insulin action by inhibiting protein tyrosine phosphatase-1B (80). Treatment with factors that block H2O2 production (81), or catalyze H2O2 breakdown (80), blocks protein tyrosine phosphatase-1B inhibition and insulin receptor phosphorylation. H2O2 generation is thus vital to the insulin signaling cascade in adipocytes. These findings are consistent with pivotal early observations in adipocytes that insulinomimetic agents exert their lipogenic and other insulin-like actions via H2O2 production (82,83,84), and that H2O2 stimulates lipid synthesis (85). It is therefore noteworthy that cysteine and NAC have contrasting effects on H2O2 in vitro (Figure 5). Cysteine and N-acetylcysteine in relation to insulin signaling. Schematic diagram for postulated effects of cysteine and N-acetylcysteine (NAC) on redox processes of the insulin signaling pathway. Insulin binds a membrane receptor (IR), activating an intracellular receptor subunit which phosphorylates insulin receptor substrates (IRS). Phosphorylated IRS (IRS-P) mediate intracellular effects of insulin including suppression of lipolysis. Protein tyrosine phosphatase-1B (PTP-1B), a natural inhibitor of IRS activation, is normally inhibited by H2O2, allowing the insulin signaling cascade to proceed. Cysteine (Cys-SH) auto-oxidation to cystine disulfide (Cys-SS-Cys) produces H2O2, whereas NAC is an H2O2 scavenger. Thus, given appropriate spatiotemporal considerations, cysteine and NAC can have opposite effects on insulin signaling. l-Cysteine was shown in early studies to exert insulin-like effects in adipocytes that are dependent upon its production of H2O2, concomitant with sulfhydryl oxidation to disulfide (86). A powerful Cu++-dependent antilipolytic action of cysteine, has been repeatedly observed in cultured rat adipocytes (86,87,88). This antilipolytic action was not caused by competitive binding to the insulin receptor, because it persisted when the insulin receptor was destroyed by mild trypsinization (89). Cysteine-stimulated glucose oxidation as well as fatty acid synthesis in addition to suppressing lipolysis (88). The insulin-like action of cysteine in vitro is paralleled by observations that cysteine supplementation ameliorated insulin resistance in diabetic rats (90). In contrast, NAC is a free radical scavenger, particularly effective in scavenging H2O2 (91). The ability of NAC to scavenge insulin-induced H2O2 and thus inhibit insulin signal transduction has been demonstrated in vitro (92,93), and is suggested by Hildebrandt et al. to explain the effect of NAC in decreasing fat mass at the expense of inducing insulin resistance in humans (74). The ultimate cellular functions of exogenous l-cyst(e)ine and NAC in vivo are therefore likely to be reciprocal due to contrasting redox characteristics of these agents, specifically their potential effects in relation to insulin-stimulated H2O2. Cysteine and NAC had opposite effects on H2O2- scavenging enzymes in mice fed a high-fat diet (94). In these mice, a pro-oxidant action of supplemental cysteine was observed, in contrast to antioxidant properties of NAC (95), prompting the conclusion that the noncysteine part of NAC is probably important for its antioxidant activity (95). This contrast may explain why NAC administration has been shown under some conditions to decrease fat mass (74,75), whereas l-cystine (14) and l-cysteine (47,49) supplementation increases weight gain in rats, and elevated tCys is associated with obesity in humans (21,24). The possible involvement of cysteine in human obesity suggests an important role for individual amino acids in weight regulation. Studies are under way to replicate the cysteine-obesity relationship in different age- and ethnic groups. An interesting question is whether the higher tCys in Indian Asians compared to European, as reported in one small study (96), is linked to the greater burden of adiposity in the former ethnic group (97). The findings described in this review open up other questions that will require much research before we can conclude that cysteine is a key player in the cause of obesity. Table 1 lists some examples. Some of these studies are already under way in our laboratory, but clearly laboratories with different expertise will potentially contribute to this field from different angles. The strongest evidence so far linking cysteine with obesity is from epidemiologic data. Population studies consistently show a positive association of plasma tCys and blood-free cysteine with BMI and/or fat mass, which is largely not shared by upstream or downstream sulfur amino acids. Furthermore, the association appears independent of lifestyle, dietary, and plasma confounders. Although some of these studies are longitudinal, they cannot establish causality. Recent animal studies implicate cysteine in regulating lipid and energy metabolism, but a clear obesogenic action of exogenous cysteine on top of a normal diet is yet to be demonstrated in animals and humans. Nevertheless, collective data from epidemiologic studies, genetic syndromes, animal experiments and in vitro findings suggest that increased cysteine availability may increase body fat, and provide sufficient evidence to stimulate systematic investigation of this potential novel obesity risk factor. We thank Elfrid Blomdal for literature support. The study was also supported by the Norwegian Research Council, the Charles Wolfson Charitable Trust, an Egyptian Government scholarship fund (to A.K.E.) and by grant NS10036-4 from the Ministry of Health of the Czech Republic (to V.K.). The authors declared no conflict of interest." @default.
W2022215953 created "2016-06-24" @default.
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W2022215953 date "2012-03-01" @default.
W2022215953 modified "2023-10-10" @default.
W2022215953 title "Cysteine and Obesity" @default.
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W2022215953 doi "https://doi.org/10.1038/oby.2011.93" @default.
W2022215953 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/21546934" @default.
W2022215953 hasPublicationYear "2012" @default.