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

Abstract

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 fastingresponsive 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.

Evaluation of Food-derived Functional Ingredients According to Activation of PPAR and Suppression of COX-2 Expression

“…Additionally, in a study using PPARα-knockout mice, resveratrol treatment (20 mg/kg body weight for 3 days) was shown to protect the brain from ischemic stroke through a PPARα-dependent mechanism in mice, indicating that resveratrol activates PPARs in vivo (Inoue et al, 2003). These findings have been corroborated by reports that PPARα mediates some of the effects of CR (Corton et al, 2004). Furthermore, we showed in a previous study that vaticanol C, a resveratrol tetramer, activates PPARα and PPARβ/ δ in vitro and in vivo, but has no effect on SIRT1 activation (Tsukamoto et al, 2010).…”

Time course investigation of PPARα- and Kupffer cell-dependent effects of WY-14,643 in mouse liver using microarray gene expression

“…While only 12 genes were found to be significantly changed it is notable that even some putative PPARα-target genes, such as cytochrome P450 4a14 (Cyp4a14), are regulated in PPARα-independent manner, which has been previously demonstrated (Corton et al, 2004). WY-14,643 treatment caused a decrease in integrin beta 1 binding protein (Itgb1bp1) expression and an increase in Irf2, which inhibits transcriptional activation of interferon, suggesting that a PPARα-independent mechanism of immunosuppression by peroxisome proliferators may be involved.…”

Caloric restriction and intermittent fasting: Two potential diets for successful brain aging

“…During CR/IF periods, when insulin levels are low, PGC-1α and PGC-1β gene expression is enhanced in rodents (Puigserver and Spiegelman, 2003;Herzig et al, 2001). PGC-1α was also induced in the livers of mice (Corton et al, 2004) and rats (Zhu et al, 2004) after longer term CR. PGC-1α and β can coordinately regulate genes involved in gluconeogenesis and fatty acid β-oxidation in a number of organs during fasting (Lin et al, 2002a(Lin et al, , 2004aKamei et al, 2003;Kressler et al, 2002).…”

“…It appears that functional PPARαs are crucial for the CR-mediated protection of the liver from damage induced by hepatotoxicants like thioacetamide. Specifically, it was demonstrated by Corton et al (2004) that PPARα knock-out mice, in contrast to wild-type mice, were not protected from thioacetamide by CR regimes. Lipid peroxide levels, associated with oxidative cell stress in the periphery and the central nervous system, are also significantly increased in aging.…”