Abstract
Considerable controversy exists in determining the role of peroxisome proliferator-activated receptor-alpha (PPARalpha) in obesity. Two purebred congenic strains of PPARalpha-null mice were developed to study the role of this receptor in modulating lipid transport and storage. Weight gain and average body weight in wild-type and PPARalpha-null mice on either an Sv/129 or a C57BL/6N background were not markedly different between genotypes from 3 to 9 months of age. However, gonadal adipose stores were significantly greater in both strains of male and female PPARalpha-null mice. Hepatic accumulation of lipids was greater in both strains and sexes of PPARalpha-null mice compared with wild-type controls. Administration of the peroxisome proliferator WY-14643 caused hepatomegaly, alterations in mRNAs encoding proteins that regulate lipid metabolism, and reduced serum triglycerides in a PPARalpha-dependent mechanism. Constitutive differences in serum cholesterol and triglycerides in PPARalpha-null mice were found between genetic backgrounds. Results from this work establish that PPARalpha is a critical modulator of lipid homeostasis in two congenic mouse lines. This study demonstrates that disruption of the murine gene encoding PPARalpha results in significant alterations in constitutive serum, hepatic, and adipose tissue lipid metabolism. However, an overt, obese phenotype in either of the two congenic strains was not observed. In contrast to earlier published work, this study establishes that PPARalpha is not associated with obesity in mice.
Highlights
From the ‡Laboratory of Metabolism, NCI, National Institutes of Health, Bethesda, Maryland 20892, §UR545 INSERM, Departement d’Atherosclerose, Institut Pasteur, 59019 Lille, France, the ¶Veterinary and Tumor Pathology Section, Office of Laboratory Animal Resources, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702, the ʈInstitut de Genetique et Biologie Moleculaire et Cellulaire, CNRS, INSERM, Universite Louis Pasteur, 67400 Illkirch, France, the **Department of Biochemistry, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, and the ‡‡Department of Veterinary Science, Center for Molecular Toxicology, Pennsylvania State University, University Park, Pennsylvania 16802-4401
Constitutive expression of peroxisomal and microsomal lipid-metabolizing enzymes was not influenced by targeted disruption of the PPAR␣ gene, hepatic accumulation of lipids was described in PPAR␣-null mice, suggesting that constitutive lipid homeostasis is altered in the absence of a functional PPAR␣ [3]
Evidence that constitutive gene expression is altered in PPAR␣-null mice on an Sv/129 background was provided by the report that mRNAs encoding mitochondrial fatty acid-metabolizing enzymes are reduced compared with wildtype mice, whereas constitutive expression of mRNAs encoding peroxisomal and microsomal fatty acid-metabolizing enzymes is unaffected [5]
Summary
From the ‡Laboratory of Metabolism, NCI, National Institutes of Health, Bethesda, Maryland 20892, §UR545 INSERM, Departement d’Atherosclerose, Institut Pasteur, 59019 Lille, France, the ¶Veterinary and Tumor Pathology Section, Office of Laboratory Animal Resources, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702, the ʈInstitut de Genetique et Biologie Moleculaire et Cellulaire, CNRS, INSERM, Universite Louis Pasteur, 67400 Illkirch, France, the **Department of Biochemistry, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, and the ‡‡Department of Veterinary Science, Center for Molecular Toxicology, Pennsylvania State University, University Park, Pennsylvania 16802-4401. Administration of peroxisome proliferators to rodents results in numerous hepatic alterations, including an increase in the number and size of peroxisomes; hepatomegaly; increased expression of genes encoding peroxisomal, mitochondrial, and microsomal fatty acid-metabolizing enzymes; and subsequent modulation of lipid homeostasis characterized by increased oxidation of fatty acids, decreased serum lipids, and reduced adipose stores [1]. All of these effects are mediated by PPAR␣1 since PPAR␣-null mice are refractory to these changes when administered the prototypical peroxisome proliferator WY-14643 [3,4,5]. For the PPAR␣-null mouse line, the Sv/129 mouse was the source of the genomic DNA library used to construct a targeting vector and the embryonic stem cells used for transfection of a targeting vector, whereas the C57BL/6N mouse (NIH substrain) was the source of donor blastocysts used for microinjecting the heterozygous embryonic stem cells
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