Received for publication September 15, 2004.
Revised November 26, 2004.
Accepted for publication November 29, 2004.

Constitutive Expression of Peroxisome Proliferator-Activated Receptor -Regulated Genes in Dwarf Mice

Abstract

Defects in growth hormone (GH) secretion or signaling in mice are associated with decreased body weights (dwarfism), increased longevity, increased resistance to stress and decreases in factors which contribute to cardiovascular disease and cancer. Peroxisome proliferators (PP) alter a subset of these changes in wild-type mice through activation of the nuclear receptor family member, PP-activated receptor (PPAR). We tested the hypothesis that an overlap in the transcriptional programs between untreated dwarf mice and PP-treated wild-type mice underlies these similarities. Using transcript profiling, we observed a statistically significant overlap in the expression of genes differentially regulated in control Snell dwarf mice (Pit-1^dw) compared to phenotypically normal heterozygote (+/dw) controls and those altered by the PP, WY-14,643 (WY) in +/dw mice. The genes included those involved in - and -oxidation of fatty acids (Acox1, Cyp4a10, Cyp4a14) and those involved in stress responses (the chaperonin, T-complex protein 1e) and cardiovascular disease (fibrinogen). The levels of some of these gene products were also altered in other dwarf mouse models including Ames, Little and growth hormone receptor-null mice. The constitutive increases in PPAR-regulated genes may be partly due to increased expression of PPAR mRNA and protein as observed in the livers of control Snell dwarf mice. These results indicate that some of the beneficial effects associated with the dwarf phenotype may be due to constitutive activation of PPAR and regulated genes.

Key words: PPARs, Pharmacogenomic analyses, Regulation of gene expression, Regulation - transcriptional