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ORIGINAL ARTICLE

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

CIIT Centers for Health Research, Research Triangle Park, North Carolina (A.J.S., A.L., R.A.S., J.C.C., C.S.); Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine, Grand Forks, North Dakota (H.B.B.); National Cancer Institute and National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (J.L., M.P.W.), Toxicology and Mycotoxin Research Unit, Agricultural Research Service, United States Department of Agriculture, Athens, Georgia (K.A.V.), Department of Biomedical Sciences, College of Osteopathic Medicine and Edison Biotechnology Institute, Ohio University, Athens, Ohio (J.J.K.), and ToxicoGenomics, Chapel Hill, North Carolina (J.C.C.)

Abstract

Defects in growth hormone secretion or signaling in mice are associated with decreased body weights (dwarfism), increased longevity, increased resistance to stress, and decreases in factors that 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 with phenotypically normal heterozygote (+/dw) control mice and those altered by the PP 4-chloro-6-(2,3-xylidino)-2-pyrimidinyl)thioacetic acid (WY-14,643) 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 protein1) 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 caused by 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 caused by constitutive activation of PPAR and regulated genes.

Address correspondence to: J. Christopher Corton, ToxicoGenomics, 209 Silver Creek Tr., Chapel Hill, NC 27514. E-mail: ccorton{at}msn.com

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