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Current Opinion in Clinical Nutrition & Metabolic Care:
doi: 10.1097/MCO.0b013e32834d199f
PROTEIN, AMINO ACID METABOLISM AND THERAPY: Edited by Olav Rooyackers and John Brosnan

Cysteine and obesity: consistency of the evidence across epidemiologic, animal and cellular studies

Elshorbagy, Amany K.a,b; Kozich, Viktorc; Smith, A. Davida; Refsum, Helgaa,d

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Author Information

aDepartment of Pharmacology, University of Oxford, Oxford, UK

bDepartment of Physiology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt

cInstitute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic

dDepartment of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway

Correspondence to Amany K. Elshorbagy, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK. Tel: +44 1865271877; e-mail: amany.elshorbagy@pharm.ox.ac.uk

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Abstract

Purpose of review: The concentrations of several plasma amino acids increase in obesity. Notably, plasma total concentrations of the sulphur amino acid cysteine (tCys) are linearly associated with fat mass in large population studies. Animal and cellular experiments support the concept that cysteine may be obesogenic. Here we review experimental and epidemiologic findings linking cysteine and related compounds with fat regulation and obesity.

Recent findings: tCys, and to a lesser extent cystathionine, are the only plasma sulphur amino acids consistently associated with human obesity, whereas glutathione is inversely associated with BMI. Supplementing cyste(i)ne in rodents decreases energy expenditure and promotes adiposity, whereas defects of cysteine-synthesizing enzymes decrease body weight. In adipocytes, cysteine inhibits lipolysis and promotes lipogenesis via H2O2 production. Unlike most plasma amino acids, tCys levels do not decrease with gastric bypass-induced weight loss, further supporting the concept that elevated cysteine may be a cause, not a consequence of obesity. Although cysteine products (glutathione, taurine and H2S) are altered in obesity, they do not appear to explain cysteine's effects on body weight.

Summary: Cellular, animal and epidemiologic data are consistent with the view that cysteine is obesogenic. Targeted research linking in-vitro and in-vivo findings is needed to elucidate mechanisms involved.

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INTRODUCTION

Methionine is the only essential sulphur amino acid (SAA). Upon activation to S-adenosylmethionine, methionine acts as a methyl donor, producing homocysteine, which can be remethylated to methionine. Alternatively, homocysteine is catabolized to cystathionine and subsequently cysteine by cystathionine beta-synthase (CBS) and cystathionase. CBS and cystathionase are under regulatory inhibition by insulin [1]. Cysteine can be used in formation of proteins, glutathione, or taurine (catalysed by cysteine dioxygenase). CBS and cystathionase also facilitate cysteine desulphurization, releasing hydrogen sulphide (H2S). Details of these processes, their regulation and biological significance were recently reviewed [2].

We recently highlighted the possibility that cysteine may be an unrecognized determinant of obesity [3]. Here we summarize cellular, animal and human data supporting this concept. For comparison, we also discuss in-vitro and in-vivo data linking related sulphur metabolites with fat regulation and body weight. For simplicity, methionine, cystathionine, homocysteine, cysteine and taurine, as well as the tripeptide glutathione will be referred to as ‘SAA’.

Cysteine is a thiol, which readily becomes oxidized, forming disulphide bonds with itself (cystine) or other thiols (mixed disulphide). Thus, plasma total cysteine (tCys) refers to all circulating forms including reduced cysteine (the thiol), cystine, and mixed disulphides. The latter include homocysteine-cysteine disulphide and albumin-bound cysteine. Nearly all nonprotein bound (free) cysteine in plasma is in oxidized (i.e. disulphide) state. Throughout this review, ‘cystine’ refers to the free disulphide, whereas ‘cysteine’ refers to the amino acid without specification of its form.

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SULPHUR AMINO ACIDS AND HYDROGEN SULPHIDE IN RELATION TO OBESITY

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Below we review experimental and epidemiologic evidence linking the SAA and H2S with fat turnover and obesity, with focus on cysteine.

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Methionine

Newgard et al.[4] reported plasma amino acid concentrations in obesity. The only SAA investigated was methionine, which was identical in lean and obese individuals. We similarly found that plasma methionine was not associated with BMI [5], or with fat mass [6▪▪]. However, methionine intake was positively associated with BMI [7].

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Homocysteine

There are conflicting reports on the associations of plasma total homocysteine (tHcy) with BMI. Variable correlations were found, including positive [8], negative [9] and no [10,11] associations. The discrepancy appears partly to relate to study design and statistical models employed. For example, we observed that a positive association of tHcy with BMI and fat mass changed to inverse when the model was adjusted for plasma tCys [6▪▪]. The conflicting results also suggest that association of tHcy with BMI is modest and subject to modification according to characteristics of the population under study. In weight loss trials, an increase of tHcy is frequently observed [12,13▪▪]. In high concentrations (100–500 μmol/l), homocysteine inhibits lipolysis in adipocytes [14].

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Cystathionine

Fasting plasma cystathionine is modestly higher in overweight vs. lean individuals, and higher still in obese individuals [5]. We observed that this association is approximately linear across the BMI range, is explained by fat mass, and persists after adjustment for tCys [5,6▪▪]. In contrast to tCys, the relationship of cystathionine with BMI is attenuated by adjusting for serum lipids and apolipoproteins [5].

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Cysteine

Several studies have reported a positive relationship of tCys with BMI, or elevation of tCys in overweight individuals [15–19]. Plasma cystine is also strongly associated with BMI (r = 0.49, P < 0.001, N = 47) [20▪]. However, cysteine is distinct from other amino acids that are elevated in plasma in obesity in several aspects, as discussed below. Experimental and epidemiologic evidence suggests that cysteine could be an unrecognized determinant of body weight.

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Total cysteine and fat mass

Plasma tCys is associated with BMI almost exclusively via fat mass, as measured by dual energy X-ray absorptiometry (DXA) in approximately 5000 individuals [6▪▪]. From low to high tCys levels, there was a difference in fat mass of approximately 11 kg, after adjustment for lean mass. Waist circumference and waist-hip ratio also increased with increasing tCys (difference in waist circumference of 9 cm in women and 7 cm in men from lowest to highest quintile), suggesting a relation with visceral fat. The association of tCys with fat mass (partial r = 0.25, P < 0.001) remained robust after controlling for physical activity, energy intake, protein and fat consumption, and plasma/serum concentrations of other SAA, lipids, and creatinine [6▪▪]. These findings were replicated in 1550 individuals, in whom tCys was associated with a 3.5-fold risk of obesity after multiple adjustments [15].

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Total cysteine and weight change

Changes in tCys and in BMI over 6 years were positively correlated [21]. Individuals whose plasma tCys increased from baseline to follow-up had a 2 kg higher fat mass at follow-up after controlling for baseline tCys and BMI [6▪▪]. Although it was not determined whether BMI/fat mass changes tracked tCys changes or vice versa, studies in obese patients undergoing gastric bypass show that tCys and cystine levels do not decrease despite major weight loss [13▪▪,22] (Fig. 1). A minor tCys reduction occurs after duodenal bypass surgery [13▪▪], likely due to malabsorption [23]. This suggests that fat mass is not a determinant of plasma tCys, in contrast to other amino acids that are elevated in obesity and drop after weight loss, including arginine [24], glutamate [4,13▪▪], leucine, isoleucine, valine and phenylalanine [4,22]. Table 1 summarizes changes in SAA and related compounds in obesity, and effect of weight loss following gastric bypass.

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Table 1
Table 1
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Genetic defects in cysteine-related enzymes and body weight

Mice defective in CBS or cystathionase, the enzymes involved in cysteine synthesis, are leaner than wild-type. Cystathionase knockout mice have slower weight gain and lower plasma cysteine, glutathione and H2S [43▪]. Of all organs, white adipose tissue mass is the most decreased (34% of wild-type). Supplementation with cysteine, but not with an H2S donor, restores plasma cysteine and weight gain, with the greatest increase reported in adipose tissue mass (53%). Food intake is not increased, suggesting an effect of cysteine on energy expenditure. Similarly in CBS knockout mice weight is reduced and is critically dependent on dietary cysteine content [44]. DXA analysis shows that the weight reduction is largely explained by lower fat mass (Kruger, personal communication). Spontaneously hypertensive rats with genetically reduced expression of folate transporter 1 (Folr1) have higher tCys concentrations, and exhibit adiposity and insulin resistance. In contrast, transgenic rats with increased expression of Folr1 show decreased cysteine levels and lower adiposity (Pravenec and Kožich, unpublished).

As recently reviewed [3], humans with genetic CBS deficiency have lower BMI, described as ‘tall and thin by the time they reach late childhood’. Down's syndrome (Trisomy 21) patients have an extra CBS allele, which is localized to chromosome 21. This results in high plasma tCys, and is associated with obesity. One genetic model with high tCys that conversely features lower body weight is the cysteine dioxygenase knockout mouse [45]. These mice have extremely low taurine levels and relatively modest cysteine elevation, with channelling of cysteine towards H2S formation. However, this model may be confounded by the severe taurine deficiency, which may reduce body mass as observed in the taurine-transporter knockout mouse [46].

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Dietary cysteine intake and body weight

Limiting dietary cysteine is normally compensated by endogenous synthesis if methionine intake is sufficient. Thus, a diet restricted in both cysteine and methionine is needed to observe effects of cysteine deficiency. Such diets include the methionine-restricted diet which is devoid of cysteine and contains 0.17% methionine (25% of control), and the methionine-choline-deficient diet (MCD), a high-sucrose, high-fat diet devoid of methionine and choline. In rodents, these diets induce hypermetabolism, with decreased weight gain and body fat%, and resistance to diet-induced obesity [47–50]. A hallmark of methionine-restricted diets is suppression of hepatic stearoyl-coenzyme A desaturase-1 (SCD1) [48,49], a condition that promotes hyper-metabolism by inducing a shift from lipogenesis towards β-oxidation via hepatic adenosine monophosphate-activated protein kinase [51].

We postulated that effects of methionine-restriction are caused by cysteine deficiency, since plasma tCys is decreased in methionine-restricted rats [52,53], and tCys, but not methionine, is associated with human obesity [5,6▪▪]. Upon supplementing methionine-restricted rats with cysteine, effects of methionine-restriction on weight gain, serum lipids, adipokines and fatty acid profile were abrogated [54▪]. Crucially, tissue-specific effects of methionine-restriction on SCD1 expression and SCD1 activity indices were partly or completely reversed by cysteine, concomitant with a phenotype suggestive of decreased energy expenditure [54▪]. In a study in mice, a high cystine diet decreased energy expenditure, enhanced visceral adiposity and reduced glucose tolerance (Fig. 2) [55▪], with increased expression genes for lipogenic and diabetogenic enzymes. Some studies report that supplementation of N-acetylcysteine decreases fat mass [56,57]. As previously discussed [3], we postulate that N-acetylcysteine may have opposite effects on fat mass to those of cysteine due to possible contrast in the redox properties of the two compounds in vivo.

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Cysteine increases lipogenesis and inhibits lipolysis in adipocytes via H2O2 production

In rat adipocytes, cysteine inhibits catecholamine-stimulated lipolysis (Fig. 3), in concentrations ranging from 10 μmol/l to 1 mmol/l [37]. The lower end of this range is physiologically relevant, since reduced cysteine in human plasma is typically around 10 μmol/l [58]. Furthermore, cysteine enhances oxidation of glucose and its utilization in de-novo lipogenesis [38,42].

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These cysteine effects are equipotent with insulin [37], the most powerful antilipolytic hormone known, and depend on Cu2+-dependent auto-oxidation of cysteine, with release of H2O2[38,42]. Subsequent work suggests that H2O2 inhibits hormone-sensitive lipase via disulphide modification within cAMP-dependent protein kinase A [59]. Cysteine auto-oxidation in human plasma releases H2O2[60], and extensive plasma cysteine oxidation occurs in humans following meals [61▪], which may thus favour lipid storage postprandially. Interestingly, cysteine oxidation in human plasma requires the copper-carrying protein ceruloplasmin [60], which is itself associated with future weight gain [40]. Furthermore, H2O2 production is increased in adipose tissue from obese mice [62], and plasma H2O2 in humans is positively associated with BMI [36,63].

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Possible mechanism of cysteine effects: H2O2 as a signalling molecule

H2O2 is formed in a number of processes, including cysteine oxidation in vivo. H2O2 is recognized as a key signalling molecule, acting via oxidative modification of cysteine switches in proteins [64–66]. Examples include protein tyrosine phosphatase-1B inhibition, an event integral to insulin signalling [67], and hormone-sensitive lipase inhibition [59]. We also postulate a potential metabolic effect of H2O2 via the mammalian target of rapamycin (mTOR). mTOR signalling integrates cell growth response to insulin and amino acids [68]. Activation of mTOR complex 1 (mTORC1) may play a role in adipose tissue expansion in response to nutrient excess (i.e. obesity) [69,70]. In adipocytes, mTORC1 activation inhibits hormone-sensitive lipase expression, suppresses lipolysis and promotes de-novo lipogenesis [71]. mTOR contains a disulphide-bonded loop that is subject to regulation by cytosolic redox potential [72]. Low-dose H2O2 and thiol-oxidizing agents (e.g. diamide) activate mTOR [73,74]. Thus, mTOR activation may be one signal linking endogenous thiol oxidation with fat storage.

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Glutathione

Glutathione peroxidases scavenge H2O2 concomitant with oxidation of reduced glutathione (GSH) to glutathione disulphide (GSSG) [66]. Glutathione peroxidase 3 expression is reduced in adipose tissue of obese animals [75]. Decreased GSH accelerates adipogenesis in 3T3-L1 cells, and promotes preadipocyte differentiation and lipid droplet formation [28▪]. Thus an oxidized thiol redox state appears to favour lipid accumulation in adipose tissue.

In line with in-vitro findings, plasma GSH is decreased in obesity [30], and the GSSG/GSH ratio is increased [29]. We observed a borderline inverse association of plasma total glutathione (tGSH) with BMI [5], and tGSH decreased with increasing waist circumference in metabolic syndrome patients [18]. Since intracellular glutathione is several orders of magnitude higher than plasma levels, it may be relevant to examine whole blood concentrations. We investigated the associations of blood-free (nonprotein-bound) glutathione (fGSH; which is largely intracellular and reduced) and blood-free cysteine (fCys; largely extracellular and oxidized) [76], with BMI in 877 individuals (cohort described in [77]). fCys was positively associated with BMI and fGSH [3]. However, within the higher fCys categories, high fGSH was associated with lower BMI. Thus, BMI was highest in individuals with greatest fCys and lowest fGSH (Fig. 4).

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Taurine

In contrast to cysteine, taurine inhibits insulin-stimulated H2O2 release and activates lipolysis in adipocytes [31], in line with earlier reports that taurine supplementation decreased weight gain and adiposity in mice [78]. However, in humans, taurine supplements failed to decrease BMI [79,80], despite modest weight reduction in one study [80]. Plasma taurine was not associated with BMI in a general population sample [5] and was unchanged in type 2 diabetes [27]. Yet in severely obese individuals, plasma taurine was clearly higher than in normal weight controls [13▪▪]. This may reflect enhanced oxidation of cysteine to taurine in obesity via cysteine dioxygenase, which is induced in adipose tissue by cysteine excess [81]. In rats, urine taurine is higher in obesity induced by a high fat diet [82]. Conflictingly, high urine taurine levels were strongly associated with low BMI in a large study [32]. However, urine taurine is a good marker of type of diet [83] including fish intake, which may independently influence BMI. Overall, the epidemiologic association of taurine with obesity needs to be reassessed using better markers of body taurine status, such as whole blood taurine, which is several folds higher than plasma levels and less subject to dietary fluctuations [84].

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Hydrogen sulphide

A potential role for H2S in metabolic regulation was recently reviewed [85,86]. When administered in sub-toxic doses H2S can induce a hypometabolic state in some mammals [87]. However, evidence suggests that endogenous H2S is not the mediator of cysteine-induced weight gain, since an H2S donor did not rescue weight gain in cystathionase knockout mice [43▪]. Plasma H2S concentrations are decreased in human obesity and correlate inversely with BMI and waist-hip ratio [34]. This may seem unusual in view of the tCys elevation in obesity, but an inverse correlation between plasma tCys and H2S has previously been reported [88]. Also in type 1 diabetic rodent models, plasma H2S is decreased [89,90] despite induction of its tissue synthesizing enzymes [89,90]. Thus plasma H2S does not appear to correlate with tCys or to reflect hepatic synthesis. It was recently shown that CBS and cystathionase enzymes circulate in plasma and produce H2S in human blood [91▪,92], which may contribute to plasma H2S.

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CONCLUSION

Cysteine is hitherto the only amino acid for which available cellular, animal and epidemiologic data all point to an obesogenic action. Although branched chain amino acids are consistently elevated in human obesity [4], effects of transgenic [93] and nutritional [4,94] manipulation of these amino acids in animals are in opposite direction to human findings. tCys is also distinct in that it does not markedly drop with major weight loss after bariatric surgery, suggesting that tCys elevation is not a consequence of increased body fat. Studies in rodents fed diets with low methionine/cysteine or excess cysteine suggest that cysteine may promote obesity by decreasing energy expenditure via an influence on SCD1. Cysteine also inhibits lipolysis and promotes lipogenesis in adipocytes via H2O2 production. In vitro, H2O2 stimulates enzymes and pathways that favour lipid storage, including hormone-sensitive lipase, PTP-1b, and mTORC1. In light of these observations, the positive association of plasma cystine, H2O2, ceruloplasmin and GSSG/GSH ratio with human obesity suggest that a shift of thiol redox state towards oxidation may favour fat storage, in addition to driving metabolic complications of obesity [62]. However, direct evidence linking elevated plasma tCys in humans with SCD1 function, energy expenditure or H2O2 signalling pathways has yet to be demonstrated.

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Acknowledgements

We wish to thank Elfrid Blomdal for literature support.

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Conflicts of interest

The study was supported by the Norwegian Research Council and the Charles Wolfson Charitable Trust, and by grants from the Ministry of Health of the Czech Republic (No. NS10036-4) and Ministry of Education of the Czech Republic (No. MSM0021620806).

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 94).

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References

1. Yusuf M, Kwong Huat BT, Hsu A, et al. Streptozotocin-induced diabetes in the rat is associated with enhanced tissue hydrogen sulfide biosynthesis. Biochem Biophys Res Commun 2005; 333:1146–1152.

2. Stipanuk MH, Ueki I. Dealing with methionine/homocysteine sulfur: cysteine metabolism to taurine and inorganic sulfur. J Inherit Metab Dis 2011; 34:17–32.

3. Elshorbagy AK, Smith AD, Kozich V, Refsum H. Cysteine and obesity. Obesity (Silver Spring) 2011. doi: oby201193 **[pii] 201110.201038/oby.202011.201193.

4. Newgard CB, An J, Bain JR, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 2009; 9:311–326.

5. Elshorbagy AK, Valdivia-Garcia M, Graham IM, et al. The association of fasting plasma sulfur-containing compounds with BMI, serum lipids and apolipoproteins. Nutr Metab Cardiovasc Dis 2011 (in press). doi: 10.1016/j.numecd.2011.01.008.

Elshorbagy AK, Nurk E, Gjesdal CG, et al. Homocysteine, cysteine, and body composition in the Hordaland Homocysteine Study: does cysteine link amino acid and lipid metabolism? Am J Clin Nutr 2008; 88:738–746.

The first study demonstrating that the tCys-BMI association is mediated by fat mass. Shows a quantitatively large difference in fat mass (11 kg) from low to high tCys levels in more than 5000 subjects.

7. Virtanen JK, Voutilainen S, Rissanen TH, et al. High dietary methionine intake increases the risk of acute coronary events in middle-aged men. Nutr Metab Cardiovasc Dis 2006; 16:113–120.

8. Jacques PF, Bostom AG, Wilson PW, et al. Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr 2001; 73:613–621.

9. Ganji V, Kafai MR. Demographic, health, lifestyle, and blood vitamin determinants of serum total homocysteine concentrations in the third National Health and Nutrition Examination Survey, 1988–1994. Am J Clin Nutr 2003; 77:826–833.

10. Brasileiro RS, Escrivao MA, Taddei JA, et al. Plasma total homocysteine in Brazilian overweight and nonoverweight adolescents: a case-control study. Nutr Hosp 2005; 20:313–319.

11. Uysal O, Arikan E, Cakir B. Plasma total homocysteine level and its association with carotid intima-media thickness in obesity. J Endocrinol Invest 2005; 28:928–934.

12. Dixon JB, Dixon ME, O’Brien PE. Elevated homocysteine levels with weight loss after Lap-Band surgery: higher folate and vitamin B12 levels required to maintain homocysteine level. International Journal of Obesity and Related Metabolic Disorders 2001; 25:219–227.

Aasheim ET, Elshorbagy A, Diep LM, et al. Effect of bariatric surgery on sulfur amino acids and glutamate. Br J Nutr 2011. doi: 10.1017/S0007114511000201.

Describes 1-year changes in plasma sulphur amino acids and glutamate, as well as the related enzyme gamma glutamyl-transferrase in 60 patients undergoing bariatric surgery. The drop in glutamate, methionine and cystathionine as well as in gamma glutamyl-transferase activity contrasts with the relative stability of cysteine with weight loss.

14. Wang Z, Pini M, Yao T, et al. Homocysteine suppresses lipolysis in adipocytes by activating the AMPK pathway. Am J Physiol Endocrinol Metab 2011; 301:E703–E712.

15. Elshorbagy AK, Refsum H, Smith AD, Graham IM. The association of plasma cysteine and gamma-glutamyltransferase with BMI and obesity. Obesity (Silver Spring) 2009; 17:1435–1440.

16. van den Brandhof WE, Haks K, Schouten EG, Verhoef P. The relation between plasma cysteine, plasma homocysteine and coronary atherosclerosis. Atherosclerosis 2001; 157:403–409.

17. Baines M, Kredan MB, Davison A, et al. The association between cysteine, bone turnover, and low bone mass. Calcif Tissue Int 2007; 81:450–454.

18. Giral P, Jacob N, Dourmap C, et al. Elevated gamma-glutamyltransferase activity and perturbed thiol profile are associated with features of metabolic syndrome. Arterioscler Thromb Vasc Biol 2008; 28:587–593.

19. Lin J, Lee IM, Song Y, et al. Plasma homocysteine and cysteine and risk of breast cancer in women. Cancer Res 2010; 70:2397–2405.

Dhawan SS, Eshtehardi P, McDaniel MC, et al. The role of plasma aminothiols in the prediction of coronary microvascular dysfunction and plaque vulnerability. Atherosclerosis 2011 (in press). DOI: 10.1016/j.atherosclerosis.2011.05.020.

Shows a strong association (r = 0.49) of plasma cystine disulphide with BMI.

21. El-Khairy L, Vollset SE, Refsum H, Ueland PM. Predictors of change in plasma total cysteine: longitudinal findings from the Hordaland homocysteine study. Clin Chem 2003; 49:113–120.

22. Mutch DM, Fuhrmann JC, Rein D, et al. Metabolite profiling identifies candidate markers reflecting the clinical adaptations associated with Roux-en-Y gastric bypass surgery. PLoS One 2009; 4:e7905.

23. Kendrick ML, Dakin GF. Surgical approaches to obesity. Mayo Clinic Proc 2006; 81:S18–S24.

24. Sledzinski T, Sledzinski M, Smolenski RT, Swierczynski J. Increased serum nitric oxide concentration after bariatric surgery: a potential mechanism for cardiovascular benefit. Obes Surg 2010; 20:204–210.

25. Aasheim ET, Bjorkman S, Sovik TT, et al. Vitamin status after bariatric surgery: a randomized study of gastric bypass and duodenal switch. Am J Clin Nutr 2009; 90:15–22.

26. Li Y, Jiang C, Xu G, et al. Homocysteine upregulates resistin production from adipocytes in vivo and in vitro. Diabetes 2008; 57:817–827.

27. Fiehn O, Garvey WT, Newman JW, et al. Plasma metabolomic profiles reflective of glucose homeostasis in nondiabetic and type 2 diabetic obese African-American women. PLoS One 2010; 5:e15234.

Vigilanza P, Aquilano K, Baldelli S, et al. Modulation of intracellular glutathione affects adipogenesis in 3T3-L1 cells. J Cell Physiol 2011; 226:2016–2024.

Demonstrates that an oxidized glutathione redox state is associated with greater preadipocyte differentiation and lipid accumulation.

29. Kaur S, Zilmer K, Kairane C, et al. Clear differences in adiponectin level and glutathione redox status revealed in obese and normal-weight patients with psoriasis. Br J Dermatol 2008; 159:1364–1367.

30. Di Renzo L, Galvano F, Orlandi C, et al. Oxidative stress in normal-weight obese syndrome. Obesity (Silver Spring) 2010; 18:2125–2130.

31. Pina-Zentella G, de la Rosa-Cuevas G, Vazquez-Meza H, et al. Taurine in adipocytes prevents insulin-mediated H(2)o (2) generation and activates Pka and lipolysis. Amino Acids 2011 (in press). DOI: 10.1007/s00726-011-0919-x.

32. Yamori Y, Liu L, Mizushima S, et al. Male cardiovascular mortality and dietary markers in 25 population samples of 16 countries. J Hypertens 2006; 24:1499–1505.

33. Yamori Y, Taguchi T, Mori H, Mori M. Low cardiovascular risks in the middle aged males and females excreting greater 24-h urinary taurine and magnesium in 41 WHO-CARDIAC study populations in the world. J Biomed Sci 2010; 17 (Suppl 1):S21.

34. Whiteman M, Gooding KM, Whatmore JL, et al. Adiposity is a major determinant of plasma levels of the novel vasodilator hydrogen sulphide. Diabetologia 2010; 53:1722–1726.

35. Feng X, Chen Y, Zhao J, et al. Hydrogen sulfide from adipose tissue is a novel insulin resistance regulator. Biochem Biophys Res Commun 2009; 380:153–159.

36. Lacy F, Kailasam MT, O’Connor DT, et al. Plasma hydrogen peroxide production in human essential hypertension: role of heredity, gender, and ethnicity. Hypertension 2000; 36:878–884.

37. Olefsky JM. Comparison of the effects of insulin and insulin-like agents on different aspects of adipocyte metabolism. Horm Metab Res 1979; 11:209–213.

38. Czech MP, Lawrence JC Jr, Lynn WS. Evidence for electron transfer reactions involved in the Cu2+-dependent thiol activation of fat cell glucose utilization. J Biol Chem 1974; 249:1001–1006.

39. Kaysen GA, Kotanko P, Zhu F, et al. Relationship between adiposity and cardiovascular risk factors in prevalent hemodialysis patients. J Ren Nutr 2009; 19:357–364.

40. Engstrom G, Hedblad B, Stavenow L, et al. Inflammation-sensitive plasma proteins are associated with future weight gain. Diabetes 2003; 52:2097–2101.

41. Balsa JA, Botella-Carretero JI, Gomez-Martin JM, et al. Copper and zinc serum levels after derivative bariatric surgery: differences between Roux-en-Y gastric bypass and biliopancreatic diversion. Obes Surg 2011; 21:744–750.

42. Czech MP, Fain JN. Cu++-dependent thiol stimulation of glucose metabolism in white fat cells. J Biol Chem 1972; 247:6218–6223.

Mani S, Yang G, Wang R. A critical life-supporting role for cystathionine gamma-lyase in the absence of dietary cysteine supply. Free Radic Biol Med 2011; 50:1280–1287.

Shows decreased body weight, maximally affecting adipose tissue mass, and decreased plasma cysteine in cystathionase-deficient mice. Both conditions are reversed by supplementation of cysteine, but not of a hydrogen sulphide donor.

44. Akahoshi N, Kobayashi C, Ishizaki Y, et al. Genetic background conversion ameliorates semi-lethality and permits behavioral analyses in cystathionine {beta}-synthase-deficient mice, an animal model for hyperhomocysteinemia. Hum Mol Genet 2008; 17:1994–2005.

45. Ueki I, Roman HB, Valli A, et al. Knockout of the cysteine dioxygenase gene results in severe impairment in taurine synthesis and increased catabolism of cysteine to hydrogen sulfide. Am J Physiol Endocrinol Metab 2011.

46. Warskulat U, Heller-Stilb B, Oermann E, et al. Phenotype of the taurine transporter knockout mouse. Methods Enzymol 2007; 428:439–458.

47. Malloy VL, Krajcik RA, Bailey SJ, et al. Methionine restriction decreases visceral fat mass and preserves insulin action in aging male Fischer 344 rats independent of energy restriction. Aging Cell 2006; 5:305–314.

48. Rizki G, Arnaboldi L, Gabrielli B, et al. Mice fed a lipogenic methionine-choline-deficient diet develop hypermetabolism coincident with hepatic suppression of SCD-1. J Lipid Res 2006; 47:2280–2290.

49. Perrone CE, Mattocks DAL, Jarvis-Morar M, et al. Methionine restriction effects on mitochondrial biogenesis and aerobic capacity in white adipose tissue, liver and skeletal muscle of F344 rats. Metab Clin Exp 2010; 59:1000–1011.

50. Hasek BE, Stewart LK, Henagan TM, et al. Dietary methionine restriction enhances metabolic flexibility and increases uncoupled respiration in both fed and fasted states. Am J Physiol Regul Integr Comp Physiol 2010; 299:R728–R739.

51. Dobrzyn P, Dobrzyn A, Miyazaki M, et al. Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver. Proc Natl Acad Sci U S A 2004; 101:6409–6414.

52. Elshorbagy AK, Valdivia-Garcia M, Refsum H, et al. Sulfur amino acids in methionine-restricted rats: hyperhomocysteinemia. Nutrition 2010; 26:1201–1204.

53. Richie JP Jr, Komninou D, Leutzinger Y, et al. Tissue glutathione and cysteine levels in methionine-restricted rats. Nutrition 2004; 20:800–805.

Elshorbagy AK, Valdivia-Garcia M, Mattocks DA, et al. Cysteine supplementation reverses methionine restriction effects on rat adiposity: significance of stearoyl-coenzyme A desaturase. J Lipid Res 2011; 52:104–112.

Demonstrates that methionine restriction effects on rat weight gain, fatty acid profile and SCD1 are at least partly mediated by cysteine reduction.

Elshorbagy AK, Church C, Valdivia-Garcia M, et al. Dietary cystine level affects metabolic rate and glycaemic control in adult mice. J Nutr Biochem 2011. doi: S0955-2863(0911)00038-00036 [pii] 00010.01016/j.jnutbio.02010.00012.00009.

Reports a direct effect of excess dietary cystine in suppressing metabolic rate.

56. Kim JR, Ryu HH, Chung HJ, et al. Association of antiobesity activity of N-acetylcysteine with metallothionein-II down-regulation. Exp Mol Med 2006; 38:162–172.

57. Hildebrandt W, Hamann A, Krakowski-Roosen H, et al. Effect of thiol antioxidant on body fat and insulin reactivity. J Mol Med 2004; 82:336–344.

58. Mannery YO, Ziegler TR, Park Y, Jones DP. Oxidation of plasma cysteine/cystine and GSH/GSSG redox potentials by acetaminophen and sulfur amino acid insufficiency in humans. J Pharmacol Exp Therapeut 2010; 333:939–947.

59. de Pina MZ, Vazquez-Meza H, Pardo JP, et al. Signaling the signal, cyclic AMP-dependent protein kinase inhibition by insulin-formed H2O2 and reactivation by thioredoxin. J Biol Chem 2008; 283:12373–12386.

60. Sengupta S, Wehbe C, Majors AK, et al. Relative roles of albumin and ceruloplasmin in the formation of homocystine, homocysteine-cysteine-mixed disulfide, and cystine in circulation. J Biol Chem 2001; 276:46896–46904.

Park Y, Ziegler TR, Gletsu-Miller N, et al. Postprandial cysteine/cystine redox potential in human plasma varies with meal content of sulfur amino acids. J Nutr 2010; 140:760–765.

Provides evidence for occurrence of oxidation of plasma cysteine to cystine in humans postprandially.

62. Furukawa S, Fujita T, Shimabukuro M, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Investig 2004; 114:1752–1761.

63. Ostrow V, Wu S, Aguilar A, et al. Association between oxidative stress and masked hypertension in a multiethnic population of obese children and adolescents. J Pediatr 2011; 158:628–633.e621.

64. Go YM, Jones DP. Cysteine/cystine redox signaling in cardiovascular disease. Free Radic Biol Med 2011; 50:495–509.

65. Paulsen CE, Carroll KS. Orchestrating redox signaling networks through regulatory cysteine switches. ACS Chem Biol 2010; 5:47–62.

66. Forman HJ, Maiorino M, Ursini F. Signaling functions of reactive oxygen species. Biochemistry 2010; 49:835–842.

67. Mahadev K, Zilbering A, Zhu L, Goldstein BJ. Insulin-stimulated hydrogen peroxide reversibly inhibits protein-tyrosine phosphatase 1b in vivo and enhances the early insulin action cascade. J Biol Chem 2001; 276:21938–21942.

68. Howell JJ, Manning BD. mTOR couples cellular nutrient sensing to organismal metabolic homeostasis. Trends Endocrinol Metab 2011; 22:94–102.

69. Laplante M, Sabatini DM. An emerging role of mTOR in lipid biosynthesis. Curr Biol 2009; 19:R1046–R1052.

70. Polak P, Cybulski N, Feige JN, et al. Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration. Cell Metab 2008; 8:399–410.

71. Chakrabarti P, English T, Shi J, et al. Mammalian target of rapamycin complex 1 suppresses lipolysis, stimulates lipogenesis, and promotes fat storage. Diabetes 2010; 59:775–781.

72. Dames SA, Mulet JM, Rathgeb-Szabo K, et al. The solution structure of the FATC domain of the protein kinase target of rapamycin suggests a role for redox-dependent structural and cellular stability. J Biol Chem 2005; 280:20558–20564.

73. Li M, Zhao L, Liu J, et al. Multimechanisms are involved in reactive oxygen species regulation of mTORC1 signaling. Cell Signal 2010; 22:1469–1476.

74. Sarbassov DD, Sabatini DM. Redox regulation of the nutrient-sensitive raptor-mTOR pathway and complex. J Biol Chem 2005; 280:39505–39509.

75. Lee YS, Kim AY, Choi JW, et al. Dysregulation of adipose glutathione peroxidase 3 in obesity contributes to local and systemic oxidative stress. Molec Endocrinol 2008; 22:2176–2189.

76. Go YM, Jones DP. Redox compartmentalization in eukaryotic cells. Biochim Biophys Acta 2008; 1780:1273–1290.

77. Janosikova B, Pavlikova M, Kocmanova D, et al. Genetic variants of homocysteine metabolizing enzymes and the risk of coronary artery disease. Mol Genet Metab 2003; 79:167–175.

78. Tsuboyama-Kasaoka N, Shozawa C, Sano K, et al. Taurine (2-aminoethanesulfonic acid) deficiency creates a vicious circle promoting obesity. Endocrinology 2006; 147:3276–3284.

79. Brons C, Spohr C, Storgaard H, et al. Effect of taurine treatment on insulin secretion and action, and on serum lipid levels in overweight men with a genetic predisposition for type II diabetes mellitus. Eur J Clin Nutr 2004; 58:1239–1247.

80. Zhang M, Bi LF, Fang JH, et al. Beneficial effects of taurine on serum lipids in overweight or obese nondiabetic subjects. Amino Acids 2004; 26:267–271.

81. Ueki I, Stipanuk MH. 3T3-L1 adipocytes and rat adipose tissue have a high capacity for taurine synthesis by the cysteine dioxygenase/cysteinesulfinate decarboxylase and cysteamine dioxygenase pathways. J Nutr 2009; 139:207–214.

82. Kim SH, Yang SO, Kim HS, et al. 1H-nuclear magnetic resonance spectroscopy-based metabolic assessment in a rat model of obesity induced by a high-fat diet. Anal Bioanal Chem 2009; 395:1117–1124.

83. Yamori Y, Murakami S, Ikeda K, Nara Y. Fish and lifestyle-related disease prevention: experimental and epidemiological evidence for antiatherogenic potential of taurine. Clin Exp Pharmacol Physiol 2004; 31 (Suppl 2):S20–S23.

84. Rakotoambinina B, Marks L, Badran AM, et al. Taurine kinetics assessed using [1,2–13C2]taurine in healthy adult humans. Am J Physiol Endocrinol Metab 2004; 287:E255–E262.

85. Desai KM, Chang T, Untereiner A, Wu L. Hydrogen sulfide and the metabolic syndrome. Expert Rev Clin Pharm 2011; 4:63–73.

86. Zhu X-Ya, Gu Hb, Ni Xa. Hydrogen sulfide in the endocrine and reproductive systems. Expert Rev Clin Pharm 2011; 4:75–82.

87. Haouzi P, Notet V, Chenuel B, et al. H2S induced hypometabolism in mice is missing in sedated sheep. Respir Physiol Neurobiol 2008; 160:109–115.

88. Perna AF, Luciano MG, Ingrosso D, et al. Hydrogen sulphide-generating pathways in haemodialysis patients: a study on relevant metabolites and transcriptional regulation of genes encoding for key enzymes. Nephrol Dial Transplant 2009; 24:3756–3763.

89. Brancaleone V, Roviezzo F, Vellecco V, et al. Biosynthesis of H2S is impaired in nonobese diabetic (NOD) mice. Br J Pharmacol 2008; 155:673–680.

90. Jain SK, Bull R, Rains JL, et al. Low levels of hydrogen sulfide in the blood of diabetes patients and streptozotocin-treated rats causes vascular inflammation? Antioxid Redox Signal 2010; 12:1333–1337.

Bearden SE, Beard RS Jr, Pfau JC. Extracellular transsulfuration generates hydrogen sulfide from homocysteine and protects endothelium from redox stress. Am J Physiol Heart Circ Physiol 2010; 299:H1568–H1576.

Shows that CBS and cystathionase are active in human blood so might contribute to plasma hydrogen sulfide and cysteine levels.

92. Krijt J, Kopecka J, Hnizda A, et al. Determination of cystathionine beta-synthase activity in human plasma by LC-MS/MS: potential use in diagnosis of CBS deficiency. J Inherited Metab Dis 2011; 34:49–55.

93. She P, Reid TM, Bronson SK, et al. Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle. Cell Metab 2007; 6:181–194.

94. Zhang Y, Guo K, LeBlanc RE, et al. Increasing dietary leucine intake reduces diet-induced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms. Diabetes 2007; 56:1647–1654.

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Keywords:

glutathione; H2O2; lipolysis; metabolic rate; redox state

© 2012 Lippincott Williams & Wilkins, Inc.

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