Sunday, September 14, 2008

Methionine Restriction Limits Age-Related Adiposity

Originally published In Press as doi:10.1194/jlr.M700194-JLR200 on October 1, 2007

Journal of Lipid Research, Vol. 49, 12-23, January 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Methionine restriction effects on 11β-HSD1 activity and lipogenic/lipolytic balance in F344 rat adipose tissue

Carmen E. Perrone1, Dwight A. L. Mattocks, George Hristopoulos, Jason D. Plummer, Rozlyn A. Krajcik and Norman Orentreich

Orentreich Foundation for the Advancement of Science, Inc., Cold Spring-on-Hudson, NY 10516

Published, JLR Papers in Press, October 1, 2007.

1 To whom correspondence should be addressed. e-mail:

Methionine restriction (MR) limits age-related adiposity in Fischer 344 (F344) rats. To assess the mechanism of adiposity resistance, the effect of MR on adipose tissue (AT) 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) was examined. MR induced 11β-HSD1 activity in all ATs, correlating with increased tissue corticosterone. However, an inverse relationship between 11β-HSD1 activity and adipocyte size was observed. Because dietary restriction controls lipogenic and lipolytic rates, MR's effects on lipogenic and lipolytic enzymes were evaluated. MR increased adipose triglyceride lipase and acetyl-coenzyme A carboxylase (ACC) protein levels but induced ACC phosphorylation at serine residues that render the enzyme inactive, suggesting alterations of basal lipolysis and lipogenesis. In contrast, no changes in basal or phosphorylated hormone-sensitive lipase levels were observed. ACC-phosphorylated sites were specific for AMP-activated protein kinase (AMPK); therefore, AMPK activation was evaluated. Significant differences in AMPK{alpha} protein, phosphorylation, and activity levels were observed only in retroperitoneal fat from MR rats. No differences in protein kinase A phosphorylation and intracellular cAMP levels were detected. In vitro studies revealed increased lipid degradation and a trend toward increased lipid synthesis, suggesting the presence of a futile cycle. In conclusion, MR disrupts the lipogenic/lipolytic balance, contributing importantly to adiposity resistance in F344 rats.

Supplementary key words adiposity • glucocorticoid metabolism • signal transduction pathways • 11β-hydroxysteroid dehydrogenase-1

Abbreviations: ACC, acetyl-coenzyme A carboxylase; AMPK, AMP-activated protein kinase; AT, adipose tissue; ATGL, adipose triglyceride lipase; CF, control fed; F344, Fischer 344; 11β-HSD, 11β-hydroxysteroid dehydrogenase; HSL, hormone-sensitive lipase; IGF-1, insulin-like growth factor-1; MR, methionine restriction; PKA, protein kinase A; PPAR{gamma}, peroxisome proliferator-activated receptor {gamma}; SAMS peptide, substrate for AMPK-activated protein kinase; Ser, serine; SREBP-1c, sterol-regulatory element binding protein-1c; Thr172, threonine 172

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