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J. Biol. Chem., Vol. 279, Issue 44, 46204-46212, October 29, 2004

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Mimetics of Caloric Restriction Include Agonists of Lipid-activated Nuclear Receptors^*

From the ^aToxicoGenomics, Chapel Hill, North Carolina 27514, the ^dDepartment of Toxicology, College of Pharmacy, University of Louisiana, Monroe, Louisiana 71209, the ^fDepartment of Safety Assessment, GlaxoSmithKline, Research & Development, Research Triangle Park, North Carolina 27709, ^hPathology Associates International, National Center for Toxicological Research, Jefferson, Arkansas 72079, the ⁱCIIT Centers for Health Research, Research Triangle Park, North Carolina 27709, the ^kToxicology & Mycotoxin Research Unit, United States Department of Agriculture, Agricultural Research Service, Athens, Georgia 30604, the ^lEnvironmental Toxicology Graduate Program, Department of Cell Biology and Neuroscience, University of California, Riverside, California 92521, the ^mDepartments of Chemistry and Biology, Retinoid Research, Allergan Inc., Irvine, California 92612, the ⁿDepartment of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland 21205, and the ^oDepartments of BioSciences and Medical Nutrition, Novum, Karolinska Institute, S-141 86 Huddinge, Sweden

The obesity epidemic in industrialized countries is associated with increases in cardiovascular disease (CVD) and certain types of cancer. In animal models, caloric restriction (CR) suppresses these diseases as well as chemical-induced tissue damage. These beneficial effects of CR overlap with those altered by agonists of nuclear receptors (NR) under control of the fasting-responsive transcriptional co-activator, peroxisome proliferator-activated co-activator 1 (PGC-1). In a screen for compounds that mimic CR effects in the liver, we found statistically significant overlaps between the CR transcript profile in wild-type mice and the profiles altered by agonists of lipid-activated NR, including peroxisome proliferator-activated receptor (PPAR), liver X receptor, and their obligate heterodimer partner, retinoid X receptor. The overlapping genes included those involved in CVD (lipid metabolism and inflammation) and cancer (cell fate). Based on this overlap, we hypothesized that some effects of CR are mediated by PPAR. As determined by transcript profiling, 19% of all gene expression changes in wild-type mice were dependent on PPAR, including Cyp4a10 and Cyp4a14, involved in fatty acid -oxidation, acute phase response genes, and epidermal growth factor receptor but not increases in PGC-1. CR protected the livers of wild-type mice from damage induced by thioacetamide, a liver toxicant and hepatocarcinogen. CR protection was lost in PPAR-null mice due to inadequate tissue repair. These results demonstrate that PPAR mediates some of the effects of CR and indicate that a pharmacological approach to mimicking many of the beneficial effects of CR may be possible.

Received for publication, June 16, 2004 , and in revised form, July 29, 2004.

^* This work was supported by NIEHS, National Institutes of Health Grant ES-09870 and the Louisiana Board of Regents Support fund through the University of Louisiana Kitty DeGree Endowed Chair in pharmacy (Toxicology) (to H. H. M.), by a Marie Curie Fellowship of the European Community program Human Potential (contract number HPMF-CT-2000–00898) (to T. M. S.), and by the Swedish Science Council and KaroBio AB (to J.-Å. G.), The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Results, References, Figs. S1 and S2, and Tables S1–S3.

^c Both authors contributed equally to this work.

^e Present address: Dept. of Pathology, S433-BST, 200 Lotrop St., University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.

^g Present address: Bayer Corp., 85 T. W. Alexander Dr., Research Triangle Park, NC 27709.

^j Present address: GlaxoSmithKline, Research Triangle Park, NC 27709.

^p Present address: Dept. of Internal Medicine III, University of Vienna, and Center of Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria.

^b To whom correspondence may be addressed: ToxicoGenomics, 209 Silver Creek Tr., Chapel Hill, NC 27514. Tel.: 919-801-0887; Fax: 919-408-0365; E-mail: ccorton{at}msn.com. ^q To whom correspondence may be addressed: Dept. of Toxicology, 700 University Ave., Suger Hall 306A, University of Louisiana, Monroe, LA 71209. Tel.: 318-342-1691; Fax: 318-342-1686; E-mail: mehendale{at}ulm.edu.

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