[Show abstract][Hide abstract] ABSTRACT: Targeting of the nuclear prostaglandin receptor peroxisome proliferator-activated receptor delta (PPARdelta) by homologous recombination results in placental defects and frequent (>90%) midgestation lethality. Surviving PPARdelta(-/-) mice exhibit a striking reduction in adiposity relative to wild-type levels. This effect is not reproduced in mice harboring an adipose tissue-specific deletion of PPARdelta, and thus likely reflects peripheral PPARdelta functions in systemic lipid metabolism. Finally, we observe that PPARdelta is dispensable for polyp formation in the intestine and colon of APC(min) mice, inconsistent with its recently proposed role in the establishment of colorectal tumors. Together, these observations reveal specific roles for PPARdelta in embryo development and adipocyte physiology, but not cancer.
Proceedings of the National Academy of Sciences 01/2002; 99(1):303-8. DOI:10.1073/pnas.012610299 · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Obesity is a growing threat to global health by virtue of its association with insulin resistance, glucose intolerance, hypertension, and dyslipidemia, collectively known as the metabolic syndrome or syndrome X. The nuclear receptors PPARalpha and PPARgamma are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively, and drugs that modulate these receptors are currently in clinical use. More recent work on the less-described PPAR isotype PPARdelta has uncovered a dual benefit for both hypertriglyceridemia and insulin resistance, highlighting the broad potential of PPARdelta in the treatment of metabolic disease. PPARdelta enhances fatty acid catabolism and energy uncoupling in adipose tissue and muscle, and it suppresses macrophage-derived inflammation. Its combined activities in these and other tissues make it a multifaceted therapeutic target for the metabolic syndrome with the potential to control weight gain, enhance physical endurance, improve insulin sensitivity, and ameliorate atherosclerosis.
[Show abstract][Hide abstract] ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate the expression of many genes involved in lipid metabolism. The biological roles of PPARalpha and PPARgamma are relatively well understood, but little is known about the function of PPARbeta. To address this question, and because PPARbeta is expressed to a high level in the developing brain, we used reaggregated brain cell cultures prepared from dissociated fetal rat telencephalon as experimental model. In these primary cultures, the fetal cells initially form random aggregates, which progressively acquire a tissue-specific pattern resembling that of the brain. PPARs are differentially expressed in these aggregates, with PPARbeta being the prevalent isotype. PPARalpha is present at a very low level, and PPARgamma is absent. Cell type-specific expression analyses revealed that PPARbeta is ubiquitous and most abundant in some neurons, whereas PPARalpha is predominantly astrocytic. We chose acyl-CoA synthetases (ACSs) 1, 2, and 3 as potential target genes of PPARbeta and first analyzed their temporal and cell type-specific pattern. This analysis indicated that ACS2 and PPARbeta mRNAs have overlapping expression patterns, thus designating the ACS2 gene as a putative target of PPARbeta. Using a selective PPARbeta activator, we found that the ACS2 gene is transcriptionally regulated by PPARbeta, demonstrating a role for PPARbeta in brain lipid metabolism.
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