Cysteine and obesity

Elshorbagy, Amany K.; Kozich,; Smith, A.D.; Refsum, Helga

doi:10.1097/mco.0b013e32834d199f

Cited by 99 publications

(41 citation statements)

References 83 publications

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“…These pathways have been associated with obesity previously. For example, cysteine biosynthesis has been found to be positively associated with risk of obesity in Hispanic children [59], and total plasma cysteine has been independently associated with obesity and insulin resistance in the same population [60]. Furthermore, homocysteine degradation has been found to be positively associated with morbidly obese patients [61], and restriction of methionine intake has been shown to have a significant increase in fat oxidation [62].…”

Section: Discussionmentioning

confidence: 99%

Maternal BMI as a predictor of methylation of obesity-related genes in saliva samples from preschool-age Hispanic children at-risk for obesity

Oelsner

Guo

et al. 2017

BMC Genomics

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BackgroundThe study of epigenetic processes and mechanisms present a dynamic approach to assess complex individual variation in obesity susceptibility. However, few studies have examined epigenetic patterns in preschool-age children at-risk for obesity despite the relevance of this developmental stage to trajectories of weight gain. We hypothesized that salivary DNA methylation patterns of key obesogenic genes in Hispanic children would 1) correlate with maternal BMI and 2) allow for identification of pathways associated with children at-risk for obesity.ResultsGenome-wide DNA methylation was conducted on 92 saliva samples collected from Hispanic preschool children using the Infinium Illumina HumanMethylation 450 K BeadChip (Illumina, San Diego, CA, USA), which interrogates >484,000 CpG sites associated with ~24,000 genes. The analysis was limited to 936 genes that have been associated with obesity in a prior GWAS Study.Child DNA methylation at 17 CpG sites was found to be significantly associated with maternal BMI, with increased methylation at 12 CpG sites and decreased methylation at 5 CpG sites. Pathway analysis revealed methylation at these sites related to homocysteine and methionine degradation as well as cysteine biosynthesis and circadian rhythm. Furthermore, eight of the 17 CpG sites reside in genes (FSTL1, SORCS2, NRF1, DLC1, PPARGC1B, CHN2, NXPH1) that have prior known associations with obesity, diabetes, and the insulin pathway.ConclusionsOur study confirms that saliva is a practical human tissue to obtain in community settings and in pediatric populations. These salivary findings indicate potential epigenetic differences in Hispanic preschool children at risk for pediatric obesity. Identifying early biomarkers and understanding pathways that are epigenetically regulated during this critical stage of child development may present an opportunity for prevention or early intervention for addressing childhood obesity.Trial registrationThe clinical trial protocol is available at ClinicalTrials.gov (NCT01316653). Registered 3 March 2011

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Section: Discussionmentioning

confidence: 99%

Maternal BMI as a predictor of methylation of obesity-related genes in saliva samples from preschool-age Hispanic children at-risk for obesity

Oelsner

Guo

et al. 2017

BMC Genomics

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“…Cys can dramatically accelerate the oxidation of homocysteine [25], and high plasma levels of tCys, but not GSH have been linked to endothelial dysfunction [26]. High plasma tCys levels have been closely linked with obesity in both preclinical investigations and large population studies [27]. Further, increased plasma tCys has been associated with pathologic condition including CVD [28,29].…”

Section: Discussionmentioning

confidence: 99%

Effect of smoking reduction and cessation on the plasma levels of the oxidative stress biomarker glutathione – Post-hoc analysis of data from a smoking cessation trial

Mons

Muscat

Modesto

et al. 2016

Free Radical Biology and Medicine

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Cigarette smoke contains high concentrations of free radical components that induce oxidative stress. Smoking-induced oxidative stress is thought to contribute to chronic obstructive pulmonary disease, cardiovascular disease and lung cancer through degenerative processes in the lung and other tissues. It is uncertain however whether smoking cessation lowers the burden of oxidative stress. We used data from a randomized controlled cessation trial of 434 current smokers for a post-hoc examination of the effects of smoking cessation on blood plasma levels of total glutathione (tGSH), the most abundant endogenous antioxidant in cells, and total cysteine (tCys), an amino acid and constituent of glutathione. Smoking status was validated based on serum cotinine levels. Multivariate linear mixed models were fitted to examine the association of smoking cessation and change in cigarette consumption with tGSH and tCys. After 12 months follow-up, quitters (n=55) had significantly increased levels of tGSH compared to subjects who continued to smoke (P<0.01). No significant change in tGSH was found for subjects who continued to smoke but reduced their intensity of smoking. No significant effect of smoking cessation or reduction was observed on levels of tCys. These results suggest that smoking cessation but not smoking reduction reduces levels of oxidative stress.

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“…We first examined the effects of prolonged L-cysteine treatment on GSIS by MIN6 cells. The concentrations of L-cysteine in the media or assay buffers used in these experiments were determined with reference to previous reports (1,7,15). After incubating MIN6 cells in 25 mM glucose-containing medium (25G-M) that included 0, 1, or 2 mM L-cysteine for 24 h, the cells were preincubated with 3 mM glucose-containing Krebs-Ringer bicarbonate buffer (3G-KRBB) for 1 h and then used for GSIS assays for 30 min with 25 mM glucose-containing KRBB (25G-KRBB) in the presence or absence of L-cysteine (Fig.…”

Section: Resultsmentioning

confidence: 99%

l -cysteine reversibly inhibits glucose-induced biphasic insulin secretion and ATP production by inactivating PKM2

Nakatsu

Horiuchi

Kano

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Increase in the concentration of plasma L-cysteine is closely associated with defective insulin secretion from pancreatic β-cells, which results in type 2 diabetes (T2D). In this study, we investigated the effects of prolonged L-cysteine treatment on glucosestimulated insulin secretion (GSIS) from mouse insulinoma 6 (MIN6) cells and from mouse pancreatic islets, and found that the treatment reversibly inhibited glucose-induced ATP production and resulting GSIS without affecting proinsulin and insulin synthesis. Comprehensive metabolic analyses using capillary electrophoresis time-of-flight mass spectrometry showed that prolonged L-cysteine treatment decreased the levels of pyruvate and its downstream metabolites. In addition, methyl pyruvate, a membrane-permeable form of pyruvate, rescued L-cysteine-induced inhibition of GSIS. Based on these results, we found that both in vitro and in MIN6 cells, L-cysteine specifically inhibited the activity of pyruvate kinase muscle isoform 2 (PKM2), an isoform of pyruvate kinases that catalyze the conversion of phosphoenolpyruvate to pyruvate. L-cysteine also induced PKM2 subunit dissociation (tetramers to dimers/monomers) in cells, which resulted in impaired glucose-induced ATP production for GSIS. DASA-10 (NCGC00181061, a substituted N,N′-diarylsulfonamide), a specific activator for PKM2, restored the tetramer formation and the activity of PKM2, glucoseinduced ATP production, and biphasic insulin secretion in L-cysteinetreated cells. Collectively, our results demonstrate that impaired insulin secretion due to exposure to L-cysteine resulted from its direct binding and inactivation of PKM2 and suggest that PKM2 is a potential therapeutic target for T2D.A metabolite, L-cysteine, is found in blood plasma, and its concentration is closely associated with an increase in fat mass and the body-mass index. These values are used as an index of obesity (1, 2), which is a major risk factor for type 2 diabetes (T2D) (3). The relationship between L-cysteine and diabetes has attracted attention because there is increasing evidence for a positive correlation between increases in plasma L-cysteine concentrations and the development and progression of diabetes. For example, increased plasma L-cysteine concentrations were associated with T2D in African American women (4), renal insufficiency [reduced glomerular filtration rate (GFR)] in T2D patients (5), obstructive sleep apnea [a risk factor for diabetes (6, 7)], and insulin resistance among Europeans (8).Reduced insulin secretion from pancreatic β-cells is the major cause of T2D (9, 10). Many investigators have studied the molecular mechanisms of glucose-stimulated insulin secretion (GSIS), which have been elucidated in detail. Elevated extracellular glucose concentration results in the enhancement of ATP production, an increased ATP/ADP ratio, the closure of ATP-sensitive K channels (K ATP channels), and depolarization (11). The resulting activation of voltage-dependent Ca 2+ channels (VDCCs) induces an influx of calcium ions and elevated...

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Cysteine and obesity

Abstract: 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.

Cited by 99 publications

References 83 publications

Maternal BMI as a predictor of methylation of obesity-related genes in saliva samples from preschool-age Hispanic children at-risk for obesity

Maternal BMI as a predictor of methylation of obesity-related genes in saliva samples from preschool-age Hispanic children at-risk for obesity

Effect of smoking reduction and cessation on the plasma levels of the oxidative stress biomarker glutathione – Post-hoc analysis of data from a smoking cessation trial

l -cysteine reversibly inhibits glucose-induced biphasic insulin secretion and ATP production by inactivating PKM2

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