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Vol. 5, No. 3, 2012
Issue release date: November 2012
Section title: Original Paper
J Nutrigenet Nutrigenomics 2012;5:132–157
(DOI:10.1159/000339347)

Genomic and Metabolic Responses to Methionine-Restricted and Methionine-Restricted, Cysteine-Supplemented Diets in Fischer 344 Rat Inguinal Adipose Tissue, Liver and Quadriceps Muscle

Perrone C.E. · Mattocks D.A.L. · Plummer J.D. · Chittur S.V. · Mohney R. · Vignola K. · Orentreich D.S. · Orentreich N.
aOrentreich Foundation for the Advancement of Science, Inc., Cold Spring-on-Hudson, N.Y., bCenter for Functional Genomics, State University of New York at Albany, Rensselaer, N.Y., and cMetabolon Inc., Durham, N.C., USA

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Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 1/24/2012
Accepted: 5/4/2012
Published online: 10/9/2012

Number of Print Pages: 26
Number of Figures: 3
Number of Tables: 5

ISSN: 1661-6499 (Print)
eISSN: 1661-6758 (Online)

For additional information: http://www.karger.com/JNN

Abstract

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.


  

Author Contacts

Carmen E. Perrone, PhD
Cell Biology Laboratory
855 Route 301
Cold Spring-on-Hudson, NY 10516 (USA)
Tel. +1 845 265 4200, ext. 235, E-Mail perrone@orentreich.org

  

Article Information

Received: January 24, 2012
Accepted: May 4, 2012
Published online: October 9, 2012
Number of Print Pages : 26
Number of Figures : 3, Number of Tables : 5, Number of References : 63
Additional supplementary material is available online - Number of Parts : 13

  

Publication Details

Journal of Nutrigenetics and Nutrigenomics

Vol. 5, No. 3, Year 2012 (Cover Date: November 2012)

Journal Editor: Kang J.X. (Boston, Mass.)
ISSN: 1661-6499 (Print), eISSN: 1661-6758 (Online)

For additional information: http://www.karger.com/JNN


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 1/24/2012
Accepted: 5/4/2012
Published online: 10/9/2012

Number of Print Pages: 26
Number of Figures: 3
Number of Tables: 5

ISSN: 1661-6499 (Print)
eISSN: 1661-6758 (Online)

For additional information: http://www.karger.com/JNN


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