Peroxisome Proliferator-activated Receptor- Regulates Lipid Homeostasis, but Is Not Associated with Obesity

Considerable controversy exists in determining the role of peroxisome proliferator-activated receptor(PPAR) in obesity. Two purebred congenic strains of PPAR-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 PPAR-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 PPAR-null mice. Hepatic accumulation of lipids was greater in both strains and sexes of PPAR-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 PPAR-dependent mechanism. Constitutive differences in serum cholesterol and triglycerides in PPAR-null mice were found between genetic backgrounds. Results from this work establish that PPAR is a critical modulator of lipid homeostasis in two congenic mouse lines. This study demonstrates that disruption of the murine gene encoding PPAR 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 PPAR is not associated with obesity in mice.