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Elshorbagy A.K.,University of Oxford | Valdivia-Garcia M.,University of Oxford | Mattocks D.A.L.,Alexandria University | Plummer J.D.,Alexandria University | And 4 more authors.
Journal of Lipid Research | Year: 2011

Stearoyl-CoA desaturase-1 (SCD1) is a key enzyme in fatty acid and energy metabolism, but little is known about its nutritional regulation. Dietary methionine restriction in rats decreases hepatic Scd1 mRNA and protein, increases energy expenditure, and decreases fat-pad mass/body-weight% (FM/BW%). In humans, plasma concentrations of the methionine product, cysteine, are associated with obesity. To determine which consequences of methioninerestriction are mediated by decreased cysteine availability, we monitored obesity-related variables in 4 dietary groups for 12weeks: control-fed (CF), methionine-restricted (MR), MR supplemented with 0.5% L -cysteine (MR+Cys) and CF+Cys rats. MR lowered weight gain and FM/BW% despite higher food intake/weight than CF, and lowered serum cysteine. Hepatic Scd1 expression was decreased, with decreased serum SCD1 activity indices (calculated from serum fatty acid profile), decreased serum insulin, leptin and triglycerides, and higher adiponectin. Cysteine supplementation (MR+Cys) essentially reversed all these phenotypes and raised serum cysteine but not methionine to CF levels. Adding extra cysteine to control diet (CF+Cys) increased serum taurine but did not affect serum cysteine, lipids, proteins, or total weight gain. FM/BW% and serum leptin were modestly decreased. Our results indicate that antiobesity effects of MR are caused by low cysteine and that dietary sulfur amino acid composition contributes to SCD1 regulation. -Elshorbagy, A. K., M. Valdivia-Garcia, D. A. L. Mattocks, J. D. Plummer, A. D. Smith, C. A. Drevon, H. Refsum, and C. E. Perrone. Cysteine supplementation reverses methionine restriction effects on rat adiposity: significance of stearoyl-coenzyme A desaturase. © by the American Society for Biochemistry and Molecular Biology, Inc.

Sinha R.,Pennsylvania State University | Cooper T.K.,Pennsylvania State University | Rogers C.J.,Pennsylvania State University | Sinha I.,Pennsylvania State University | And 4 more authors.
Prostate | Year: 2014

BACKGROUND Prostate cancer (PCa) is a major aging-related disease for which little progress has been made in developing preventive strategies. Over the past several years, methionine restriction (MR), the feeding of a diet low in methionine (Met), has been identified as an intervention which significantly extends lifespan and reduces the onset of chronic diseases, including cancer, in laboratory animals. We, therefore, hypothesized that MR may be an effective strategy for inhibiting PCa. METHODS Control (0.86% Met) or MR (0.12% Met) diets were fed to 5-week old TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, a well-characterized model for PCa. The mice were sacrificed at 16 weeks of age and prostate and other tissues were harvested for histological and biochemical analyses. RESULTS As previously reported, MR was associated with a decrease in body weight which was not associated with lowered food intake. MR led to significant reductions in the development of Prostatic Intraepithelial Neoplasia (PIN) lesions, specifically in the anterior and dorsal lobes of the prostate where the incidence of high-grade PIN was reduced by ∼50% (P < 0.02). The reduction in PIN severity was associated with 46-64% reductions in cell proliferation rates (P < 0.02) and plasma IGF-1 levels (P < 0.0001), which might, in part, explain the effects on carcinogenesis. Additionally, no adverse consequences of MR on immune function were observed in the TRAMP mice. CONCLUSIONS Overall, these findings indicate that MR is associated with a reduction in prostate cancer development in the TRAMP model and supports the continued development of MR as a potential PCa prevention strategy. © 2014 Wiley Periodicals, Inc.

Nichenametla S.N.,South Dakota State University | Nichenametla S.N.,Orentreich Foundation for the Advancement of Science Inc. | Weidauer L.A.,South Dakota State University | Wey H.E.,South Dakota State University | And 3 more authors.
Molecular Nutrition and Food Research | Year: 2014

A metabolic health crisis is evident as cardiovascular diseases (CVD) remain the leading cause of mortality in the United States. Effects of resistant starch type 4 (RS4), a prebiotic fiber, in comprehensive management of metabolic syndrome (MetS) remain unknown. This study examined the effects of a blinded exchange of RS4-enriched flour (30% v/v) with regular/control flour (CF) diet on multiple MetS comorbidities. In a double blind (participants-investigators), placebo-controlled, cluster cross-over intervention (n = 86, age≥18, 2-12 week interventions, 2-week washout) in the United States, individuals were classified as having MetS (With-MetS) or not (No-MetS) following International Diabetes Federation (IDF)-criteria. RS4 consumption compared with CF resulted in 7.2% (p = 0.002) lower mean total cholesterol, 5.5% (p = 0.04) lower non-HDL, and a 12.8% (p < 0.001) lower HDL cholesterol in the With-MetS group. No-MetS individuals had a 2.6% (p = 0.02) smaller waist circumference and 1.5% (p = 0.03) lower percent body fat following RS4 intervention compared to CF. A small but significant 1% increase in fat-free mass was observed in all participants combined (p = 0.02). No significant effect of RS4 was observed for glycemic variables and blood pressures. RS4 consumption improved dyslipidemia and body composition. Incorporation of RS4 in routine diets could offer an effective strategy for public cardio-metabolic health promotion. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Perrone C.E.,Orentreich Foundation for the Advancement of Science Inc.
Journal of Nutrigenetics and Nutrigenomics | Year: 2012

Background/Aims: Methionine restriction (MR) is a dietary intervention that increases lifespan, reduces adiposity and improves insulin sensitivity. These effects are reversed by supplementation of the MR diet with cysteine (MRC). Genomic and metabolomic studies were conducted to identify potential mechanisms by which MR induces favorable metabolic effects, and that are reversed by cysteine supplementation. Methods: Gene expression was examined by microarray analysis and TaqMan quantitative PCR. Levels of selected proteins were measured by Western blot and metabolic intermediates were analyzed by mass spectrometry. Results: MR increased lipid metabolism in inguinal adipose tissue and quadriceps muscle while it decreased lipid synthesis in liver. In inguinal adipose tissue, MR not only caused the transcriptional upregulation of genes associated with fatty acid synthesis but also of Lpin1, Pc, Pck1 and Pdk1, genes that are associated with glyceroneogenesis. MR also upregulated lipolysis-associated genes in inguinal fat and led to increased oxidation in this tissue, as suggested by higher levels of methionine sulfoxide and 13-HODE + 9-HODE compared to control-fed (CF) rats. Moreover, MR caused a trend toward the downregulation of inflammation-associated genes in inguinal adipose tissue. MRC reversed most gene and metabolite changes induced by MR in inguinal adipose tissue, but drove the expression of Elovl6, Lpin1, Pc, and Pdk1 below CF levels. In liver, MR decreased levels of a number of long-chain fatty acids, glycerol and glycerol-3-phosphate corresponding with the gene expression data. Although MR increased the expression of genes associated with carbohydrate metabolism, levels of glycolytic intermediates were below CF levels. MR, however, stimulated gluconeogenesis and ketogenesis in liver tissue. As previously reported, sulfur amino acids derived from methionine were decreased in liver by MR, but homocysteine levels were elevated. Increased liver homocysteine levels by MR were associated with decreased cystathionine β-synthase (CBS) protein levels and lowered vitamin B6 and 5-methyltetrahydrofolate (5MeTHF) content. Finally, MR upregulated fibroblast growth factor 21 (FGF21) gene and protein levels in both liver and adipose tissues. MRC reversed some of MR's effects in liver and upregulated the transcription of genes associated with inflammation and carcinogenesis such as Cxcl16, Cdh17, Mmp12, Mybl1, and Cav1 among others. In quadriceps muscle, MR upregulated lipid metabolism-associated genes and increased 3-hydroxybutyrate levels suggesting increased fatty acid oxidation as well as stimulation of gluconeogenesis and glycogenolysis in this tissue. Conclusion: Increased lipid metabolism in inguinal adipose tissue and quadriceps muscle, decreased triglyceride synthesis in liver and the downregulation of inflammation-associated genes are among the factors that could favor the lean phenotype and increased insulin sensitivity observed in MR rats. Copyright © 2012 S. Karger AG, Basel.

Elshorbagy A.K.,University of Oxford | Valdivia-Garcia M.,University of Oxford | Refsum H.,University of Oxford | Refsum H.,University of Oslo | And 3 more authors.
Nutrition | Year: 2010

Objective: Dietary methionine restriction in Fischer-344 rats favorably influences visceral fat mass, insulin sensitivity, metabolic parameters, and longevity. However, little is known about the effects of methionine restriction on serum methionine and its downstream sulfur amino acids. We investigated the serum sulfur amino acid profile of male Fischer-344 rats fed a methionine-restricted diet for 3 mo. Methods and results: Using tandem mass spectrometry, we observed marked reduction in serum concentrations of methionine, cystathionine, cysteine, and taurine in methionine-restricted rats compared with control (P< 0.001) and a 2.5-fold elevation of homocysteine (P< 0.001). Conclusion: This suggests that homocysteine trans-sulfuration may be inhibited by methionine restriction, and that some of the effects of methionine restriction may be mediated by changes in sulfur amino acids downstream of methionine. © 2010.

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