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Integrative Physiology
Cysteine and Obesity
Amany K. Elshorbagy1,2, A. David Smith1, Viktor Kozich3 and Helga Refsum1,4
Obesity (2012) 20, 473–481. doi:10.1038/oby.2011.93
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, suggest-
ing that specific amino acids could
contribute to regulating weight gain.
Plasma concentrations of cysteine, but
not of other sulfur amino acids, corre-
late strongly with fat mass and BMI in
men and women. High plasma cysteine
is also linked to obesity-related dis-
orders such as cardiovascular disease
and metabolic syndrome. Several lines
of evidence suggest that increased
cysteine availability may promote obes-
ity. Evidence from interventions where
cysteine-containing, cysteine-produc-
ing, or anti-cysteine compounds are
administered or restricted supports a
causal role for cysteine in regulating
body weight. Genetic syndromes char-
acterized by high or low plasma cysteine
often exhibit corresponding changes in
body weight. Studies on cultured rat adi-
pocytes 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 attrac-
tive, since cysteine and its precursor,
methionine, are ingested in diet and at
least one licensed drug reduces cysteine
formation. This review summarizes cur-
rent knowledge about the relationship
between cysteine and body weight.
Cysteine is a conditionally essential pro-
teinogenic sulfur-containing amino acid.
Through its sulfhydryl group reactivity,
1
Department of Pharmacology, University of Oxford, Oxford, UK; 2Department of Physiology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt;
3
Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; 4Department of Nutrition,
Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. Correspondence: Amany K. Elshorbagy (amany.elshorbagy@pharm.ox.ac.uk)
Received 2 August 2010; accepted 14 March 2011; published online 5 May 2011. doi:10.1038/oby.2011.93
obesity | VOLUME 20 NUMBER 3 | march 2012
this amino acid can form disulfide link-
ages, which in turn control protein struc-
ture 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 intracel-
lular antioxidant glutathione (GSH) (3),
not only low plasma tCys, but also high
tCys, predicts adverse outcomes, includ-
ing cardiovascular disease (4). Here, we
review the evidence that high tCys may
also be causally related to obesity.
Cysteine: Sources and Fates
The cysteine pool is a function of dietary
intake, protein turnover, and endog-
enous 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 cystath-
ionine β-synthase (CBS), homocysteine
condenses with serine to form cystathio-
nine, 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).
Two major factors regulating CBS activ-
ity are methionine availability and cellu-
lar redox state. S-adenosylmethionine,
the methionine product mediating all
Reviews
transmethylation reactions, is an allos-
teric activator of CBS (5). This regula-
tory mechanism promotes disposal of
excess methionine through irreversible
conversion to cysteine (5), and inhibits
transsulfuration when methionine sup-
ply is limited. Flux through the trans-
sulfuration 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), local-
ized 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 coen-
zyme A (11). In conditions of sulfur
amino acid excess, cysteine can also be
oxidized to inorganic sulfur and pyru-
vate (11), which can be further used in
gluconeogenesis (12).
There is evidence that cysteine lev-
els 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).
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Integrative Physiology

SAM Since this was also a noninterventional

Methionine SAH study, two possibilities for interpreta-
Homocysteine tion of the findings were either that a
Serine high cysteine somehow promotes obes-
Protein CBS
ity or that obesity influences cysteine
Cystathionine
turnover, thereby raising plasma tCys.
α-Ketobutyrate
CGL Glutamate Results from our recent study of changes
H2S
in plasma sulfur amino acids in super-
γ -Glutamyl cysteine
Pantothenic Cysteine GGCS
obese patients undergoing bariatric sur-
acid
Glycine
gery suggest that body fat mass is not a
CDO
determinant of plasma tCys concentra-
Coenzyme A Cysteinesulfinate
tions (22). A third possibility is that one
GGT γ -Glutamyl cysteinyl-
or more confounding factor(s) simulta-
Cysteinyl-
glycine glycine (Glutathione) neously increases plasma cysteine and
Cysteamine Hypotaurine
Aminoacid predisposes to obesity, or that cysteine
Taurine Glutamyl is a marker associated with obesity or
a.a.
obesity-related morbidity.
Figure 1 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, The Cysteine-Fat Mass
mainly in the liver. Located at cell membranes, γ-glutamyltransferase (GGT) catalyzes breakdown of Relationship and Potential
glutathione to glutamate and cysteinylglycine, which ultimately releases cysteine, in the γ-glutamyl Confounders
cycle. Cysteine is also the precursor of coenzyme A, glutathione, and taurine. Dotted arrows indicate
GGT activity
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 One factor that fulfills the criteria of a
synthase; H2S, hydrogen sulfide; SAM, S-adenosyl methionine; SAH, S-adenosyl homocysteine. confounder in the tCys–fat mass asso-
ciation is GGT enzyme activity. GGT
Notably, cysteine dioxygenase shows tCys over time” (16). Two studies investi- is a recognized marker of obesity (7,23)
this powerful cysteine-responsiveness in gating tCys as a risk factor for cardiovas- which also catalyzes breakdown of
liver and adipose tissue (13), but not in cular disease recognized this tCys-BMI GSH in the γ-glutamyl cycle, eventu-
the kidney, lung, or brain (14), suggest- relationship (4,17). The tCys-BMI cor- ally releasing cysteine. Thus it is con-
ing a relation between cysteine homeos- relation was also reported in postmeno- ceivable that obese individuals, through
tasis and adipose tissue function. pausal women (18), metabolic syndrome an unknown mechanism (23), feature
This review summarizes available evi- patients (19), and healthy controls in a increased GGT activity which elevates
dence linking cysteine with body weight breast cancer study (20). These studies their tCys. However, in the COMAC
and obesity. First, epidemiologic studies did not specify whether tCys was related cohort of >1,500 men and women from
linking plasma tCys with BMI and body to fat mass or lean mass. nine European countries, plasma tCys
composition are presented. Subsequently In 2008, we investigated the relation was found to be associated with BMI
genetic syndromes and animal studies between tCys and body composition independent of plasma GGT activity
supporting a causal role for cysteine in measured by dual-energy X-ray absorp- (24). Subjects in the highest quartile of
weight regulation are reviewed. Finally tiometry, in >5,000 Norwegian subjects plasma tCys were 3.5 times as likely to
conflicting evidence is discussed and a from the Hordaland Homocysteine be obese, compared to those in the low-
putative mechanism for cysteine action Study (21). There was a positive linear est quartile, after adjusting for GGT.
is suggested based on in vitro findings. relationship between tCys and fat mass, These findings are limited by the ques-
but no association between tCys and lean tion of how far plasma GGT activity
Cysteine and Body Composition mass (21). The association of tCys with reflects tissue GGT activity, which is
in Epidemiologic Studies fat mass remained robust after adjust- localized to cellular plasma membranes.
Several large studies have reported a ment for age, gender, lean mass, and Nevertheless, in this study the statisti-
positive correlation between tCys and dietary intakes of protein, fat and total cal relationships of tCys and GGT with
BMI in humans, but the association energy, and plasma lipid concentrations. BMI followed different patterns. While
between tCys and BMI was not the main Depending on the model, tCys explained plasma GGT showed a strong associa-
focus of these studies. In 1999, BMI was 4–8% of the fat mass variability in men tion with odds of obesity that was weak-
shown to be a “determinant” of plasma and women (21). Subjects in the highest ened by adjustment for obesity-related
tCys in >16,000 men and women in the tCys quintile had 6–9 kg higher fat-mass factors (e.g., serum lipids), tCys was an
Hordaland Homocysteine Study (15). compared to those in the lowest quintile independent linear predictor of BMI
A longitudinal study of a subset of the (21). Furthermore, increase in plasma throughout the BMI range and was also
same cohort, subsequently reported that tCys over 6 years was associated with independently associated with odds of
“change in BMI predicted changes in higher fat-mass at follow-up (21). obesity (24).

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Integrative Physiology

6
Methionine tHcy Cystathionine
4

−2 Partial r = 0.10

Estimated difference in percent body fat, %

Partial r = −0.01 Partial r = 0.05
P < 0.001 P < 0.001
−4 P = 0.55
N = 5,179 N = 2,696
N = 2,696
−6

20 30 40 7 10 20 0.2 0.5 1 1.5

6
tCys Cysteinylglycine Triglycerides
4

−2 Partial r = 0.27 Partial r = 0.32

Partial r = 0.07 P < 0.001
−4 P < 0.001
P < 0.001 N = 5,191
N = 5,179
−6 N = 5,179

220 260 300 340 380 25 30 35 40 45 600 1,000 3,000

Figure 2 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).

Dietary cysteine intake as discussed below (see Dietary methio- percent by plasma sulfur amino acids
Diet would be a confounder in the tCys– nine restriction section). and triglyceride concentrations in the
fat mass association if subjects with Hordaland Homocysteine Study.
high tCys and high-fat mass consume Cysteine Vs. Other Amino Acids In summary, only plasma tCys, but
a diet that increases plasma tCys and is in Relation To Body Composition not methionine, tHcy, cystathionine,
simultaneously obesogenic, independ- Plasma sulfur amino acids and related taurine, tGSH, or cysteinylglycine, is a
ent of its effect on cysteine metabolism. sulfur compounds strong independent positive predictor of
In the Hordaland Homocysteine Study, We investigated whether structur- BMI, fat mass and obesity (21,24,31).
the tCys–fat mass relationship persisted ally and metabolically related sulfur
after adjustment for total protein, fat, amino acids showed a similar relation Whole blood-free cysteine
and energy intakes (21). Cysteine is to BMI as tCys. Plasma tHcy showed a concentrations
abundant in whey protein (25) as well as modest positive relation to fat mass in The distribution of several amino acids
some fruits and vegetables, including red the Hordaland Homocysteine Study, among the different blood compartments
pepper, asparagus, and strawberry (26), which became negative after adjusting is altered in obesity (33). To investigate
which are not recognized to be linked for tCys (21). Despite the association whether the association of tCys with obes-
with obesity. There is also some data of methionine intake with BMI (30), ity merely reflects a shift of cysteine from
suggesting that dietary cysteine intake is nonfasting plasma methionine was not red cells to the plasma in obese individuals,
not a major determinant of plasma tCys. related to fat mass (21), and fasting we examined the association of nonprotein
In a recent study, dietary cystine intake plasma methionine was unrelated to bound cysteine in whole blood with BMI.
was unrelated to plasma tCys in healthy BMI (31). Newgard et al. (32) similarly Similar to plasma tCys, free blood cysteine
women (20). A similar observation found no difference in plasma methio- was positively correlated with BMI (cohort
was made in cats fed different levels of nine between obese and lean subjects. described in ref. 34; Figure 3). This may
cysteine (27), and doubling cystine intake Plasma cystathionine correlated posi- indicate that it is the high plasma cysteine
in rats did not raise plasma cystine (28). tively with fat mass and BMI (21,31), availability in both cells and plasma, rather
Even parenteral cysteine administration but these correlations were weaker than than a shift in cysteine compartmentation
in neonates failed to raise plasma tCys those of tCys, and were attenuated by between blood cells and plasma, that is
(29). It remains possible that another adjustment for confounders such as associated with obesity.
dietary pattern, apart from high intake serum lipids. Plasma levels of taurine
of cysteine-rich foods, could simultane- and tGSH, two downstream products Nonsulfur amino acids
ously promote increase of plasma tCys of cysteine, were not significantly cor- Obesity is associated with elevation of
and of fat mass. One such possibility is related with BMI (31). Figure 2 shows circulating levels of several amino acids.
high intake of methionine-rich foods, the estimated differences in body fat Branched-chain amino acids, as well as

obesity | VOLUME 20 NUMBER 3 | march 2012 475

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Integrative Physiology

alanine, phenylalanine, and tyrosine, are branched-chain amino acid elevation in syndrome (40), resulting in markedly
consistently elevated in overweight and/ obesity to enhanced protein catabolism elevated plasma tCys (40), which may
or obese subjects (32,33,35). Several partly resulting from dietary overload be linked to the increased incidence of
mechanisms have been postulated to (32). She et al. demonstrated decreased obesity in this population.
explain plasma amino acid elevation branched-chain amino acid catabolic
in obesity. In an early study, Holm et enzymes in obese rodents (37), and that Homocystinuria due to CBS deficiency. The
al. found strong correlations between in humans, these amino acids decrease most common type of the inborn error
plasma amino acid concentrations and following gastric bypass surgery, with homocystinuria is caused by genetic
lean mass, and concluded that increased increase in their metabolizing enzymes defects in the CBS enzyme and is char-
lean mass in obesity contributes to the in adipose tissue samples (37). Thus acterized by marked elevation of plasma
elevated plasma amino acid concen- branched-chain amino acid elevation in and urinary tHcy coupled with decreased
trations (36). Newgard et al. ascribe obesity appears to be a consequence or cysteine synthesis, and a range of ocular,
adjunct, rather than cause, of obesity. In nervous, cardiovascular, and skeletal man-
3
contrast, several lines of evidence point ifestations (41,42). Notably, these patients
to a causal role for cysteine or a product often have low BMI (calculated from ref.
2
of cysteine, in promoting obesity. 43), decreased subcutaneous fat (44), and
1
body weight frequently below the 5th per-
Estimated difference in body mass index, kg/m2

0
The Evidence Linking Cysteine centile (45), and have been described by
−1 To Obesity Mudd et al. as being “tall and thin by the
−2 Partial r = 0.11 Inborn errors of cysteine metabolism time they reach late childhood” (41). The
P = 0.001
−3 If cysteine is a causal determinant of fat lean “marfanoid” phenotype has not been
mass, then an inborn error characterized reported in the form of homocystinuria
3 by increased cysteine synthesis should caused by homocysteine remethylation
2
be associated with obesity. Conversely, defects (42), in which cysteine synthesis is
inherited defects of cysteine formation essentially normal, thus potentially impli-
1
should be associated with a lean pheno- cating low cysteine availability in the thin
0
type. This is what is observed in the two phenotype of CBS deficiency.
−1
genetic syndromes, Down’s syndrome
−2 Partial r = 0.20 and the common variant of homo- Dietary cysteine supplementation
P < 0.001
−3 cystinuria (Figure 4). studies
50 70 90 110 Dietary supplementation with cysteine
Blood free cyste(i)ne, µmol/l Down’s syndrome. People with Down’s or a cysteine-rich protein has been
syndrome (Trisomy 21) are more fre- shown to increase weight gain in rats,
Figure 3 Whole blood-free cysteine and BMI.
Estimated differences in BMI according to
quently overweight and obese ­compared rabbits, and monkeys (14,46–49), as
concentration of nonprotein bound cysteine in to other populations with mental retar- well as in humans (50). Because mam-
whole blood in a cohort of 877 men and women dation (38). The cause of obesity in mals are unable to convert cysteine
(described in ref. 34), with adjustment for age Down’s syndrome is not clear, but has to methionine, the observed effects
and gender. Lower panel is additionally adjusted been proposed to be due to a low resting of cysteine on weight gain cannot be
for free glutathione in whole blood. Free cysteine
and glutathione measurements in whole blood
metabolic rate (39). Due to localization attri­buted to an increase in the essen-
were positively associated after adjustment for of the human CBS gene to chromosome tial amino acid methionine, although
age and gender (partial r = 0.54, P < 0.001). 21, this gene is over expressed in Down’s an adequate cysteine supply may spare
Homocystinuria
Down’s syndrome
J Clin Pathol 1964; 17: 427. Methionine

Homocysteine

Deficient CBS CBS Excess CBS

Cystathionine

Cysteine

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.

476 VOLUME 20 NUMBER 3 | march 2012 | www.obesityjournal.org


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 hypercholeste-
rolemia 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).
Dietary methionine restriction
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 desatu-
rase 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 associ-
ated 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 asso-
ciated with greater weight loss when
used for treatment of obesity (reviewed
in ref. 60). Furthermore, weight loss is
obesity | VOLUME 20 NUMBER 3 | march 2012
observed in humans on a methionine-
free diet for treatment of cancer, despite
energy and protein intakes being ade-
quate 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 pro-
motes weight gain and increases plasma
tCys by increasing methionine conver-
sion to cysteine.
Plasma tCys is decreased in methio-
nine-restricted rats (62), suggesting that
it may be the decreased cysteine avail-
ability 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 adi-
posity and hepatic stearoyl CoA desatu-
rase-1 expression, with corresponding
changes in plasma fatty acid and adipok-
ine profiles (63). The decrease in serum
methionine in methionine-restricted
rats was not restored by cysteine supple-
mentation (63). This suggests that it is
the reduced supply of cysteine that medi-
ates 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).
Anticysteine drugs
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 imi-
penem/cilastatin on body weight (68).
More consistent decrease in weight gain
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Integrative Physiology
is observed in rodents with administra-
tion of the cystathionase inhibitor, prop-
argylglycine, which prevents release of
cysteine from cystathionine (69).
Evidence Against the Cysteine-
Fat Mass Hypothesis
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).
Cysteine-rich proteins and fat mass
Data from cysteine-rich protein supple-
mentation 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 sub-
jects showed casein to be superior to
cysteine-rich whey protein in promoting
fat mass loss (71). Furthermore, immu-
nocal 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 adi-
posity when given before exercise train-
ing for 5 weeks, compared to whole milk
protein or glucose (72). The cysteine arm
of this study involved several factors (lac-
talbumin, 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 attrib-
uted 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 mediat-
ing these effects is not defined, and the
evidence for their effects on fat mass is
weak and conflicting.
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NAC and fat mass models (64) discussed above (see dietary
Hildebrandt et al. demonstrated that methionine restriction section), cysteine
NAC may reduce fat mass in a trial may also exert local insulin-like effects
including human subjects receiving in adipocytes. Insulin is the most potent
either NAC or placebo for 8 weeks (74). antilipolytic hormone known. It strongly
The NAC group (N = 11) featured a 3% inhibits hormone-sensitive lipase, the
decrease in fat mass compared to an 8% rate-limiting enzyme in catecholamine-
increase in the placebo group (74). The stimulated lipolysis, and stimulates adi-
lowered fat mass in the NAC group was pocyte triglyceride and glucose uptake
associated with decreased insulin sensi- (79). The functional roles of cysteine
tivity, and was therefore interpreted to and NAC in relation to insulin signal-
indicate that NAC decreased fat mass ing and insulin-mediated regulation of
by inhibiting insulin reactivity. Visceral lipid turnover have been investigated in
fat mass reduction was also observed in vitro. Findings from these studies may
rodents after 6–8 weeks of daily intra- elucidate a mechanism for the potential
peritoneal injection of NAC (75). obesogenic effect of cysteine, in contrast
Plasma tCys changes were not to NAC.
reported in the NAC-supplementation
studies. Although NAC is considered a Insulin signaling: Role of H2O2
synthetic cysteine analogue, effects of Insulin binds membrane receptors,
NAC supplementation on plasma tCys activating intracellular receptor subu-
are difficult to anticipate. Different stud- nits, with subsequent phosphorylation
ies have reported either no change (76), of “insulin receptor substrates,” which
an increase (77) or a lowering of plasma mediate insulin’s effects. Insulin action
cysteine levels following NAC admin- is terminated when the insulin recep-
istration (78). Below we postulate that tor substrates are dephosphorylated
NAC and cysteine may in fact exert and thus inactivated by protein tyro-
different effects on body composition sine phosphatase-1B (80). The catalytic
due to their contrasting redox proper- activity of protein tyrosine phosphatase-
ties in relation to insulin-regulated lipid 1B depends on the reduced state of its
turnover. cysteine thiol residue (80). Insulin sig-
naling initially elicits release of reac-
Nac Vs. Cysteine: the Potential tive oxygen species, particularly H2O2,
Importance of Insulin Signaling which facilitate insulin action by inhib-
In addition to its effects on stearoyl CoA iting protein tyrosine phosphatase-1B
desaturase-1 and metabolic rate in rodent (80). Treatment with factors that block
Cys-SH Cys-SH
Insulin
Cys-SS-Cys
+
H2O2 NAC
Cell
IR
membrane
PTP-1B
IRS IRS-P Lipid uptake
Lipolysis suppression
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.
H2O2 production (81), or catalyze H2O2
breakdown (80), blocks protein tyrosine
phosphatase-1B inhibition and insulin
receptor phosphorylation. H2O2 genera-
tion is thus vital to the insulin signaling
cascade in adipocytes. These findings
are consistent with pivotal early obser-
vations in adipocytes that insulinomi-
metic agents exert their lipogenic and
other insulin-like actions via H2O2 pro-
duction (82–84), and that H2O2 stimu-
lates lipid synthesis (85). It is therefore
noteworthy that cysteine and NAC have
contrasting effects on H2O2 in vitro
(Figure 5).
Insulin-like action of cysteine in vitro
linked to H2O2 production: Contrast
with NAC
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 (86–88).
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 obser-
vations that cysteine supplementation
ameliorated insulin resistance in dia-
betic rats (90).
In contrast, NAC is a free radi-
cal 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

478 VOLUME 20 NUMBER 3 | march 2012 | www.obesityjournal.org


Table 1 Questions for further study in the cysteine-fat mass relationship © 2011 The Obesity Society
Population-based studies
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Disclosure 18.
laboratories with different expertise will The authors declared no conflict of interest.
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