Mimetics of caloric restriction include agonists of lipid-activated nuclear receptors.
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 1alpha (PGC-1alpha). 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 alpha (PPARalpha), 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 PPARalpha. As determined by transcript profiling, 19% of all gene expression changes in wild-type mice were dependent on PPARalpha, including Cyp4a10 and Cyp4a14, involved in fatty acid omega-oxidation, acute phase response genes, and epidermal growth factor receptor but not increases in PGC-1alpha. CR protected the livers of wild-type mice from damage induced by thioacetamide, a liver toxicant and hepatocarcinogen. CR protection was lost in PPARalpha-null mice due to inadequate tissue repair. These results demonstrate that PPARalpha 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.
Corton
J Christopher
JC
ToxicoGenomics, Chapel Hill, North Carolina 27514, USA. ccorton@msn.com
Apte
Udayan
U
Anderson
Steven P
SP
Limaye
Pallavi
P
Yoon
Lawrence
L
Latendresse
John
J
Dunn
Corrie
C
Everitt
Jeffrey I
JI
Voss
Kenneth A
KA
Swanson
Cynthia
C
Kimbrough
Carie
C
Wong
Jean S
JS
Gill
Sarjeet S
SS
Chandraratna
Roshantha A S
RA
Kwak
Mi-Kyoung
MK
Kensler
Thomas W
TW
Stulnig
Thomas M
TM
Steffensen
Knut R
KR
Gustafsson
Jan-Ake
JA
Mehendale
Harihara M
HM
D000818:Animals; D031204:Caloric Restriction; D002318:Cardiovascular Diseases / Q000209:etiology; D002455:Cell Division; D004268:DNA-Binding Proteins; D005260:Female; D006706:Homeostasis; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D012307:Risk Factors; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors