Peroxisome proliferator-activated receptor-alpha regulates lipid homeostasis, but is not associated with obesity - Studies with congenic mouse lines

Considerable controversy exists in determining the role of peroxisome proli ferator-activated receptor-a (PPAR alpha) in obesity. Two purebred congenic strains of PPAR alpha -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 alpha -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 grea ter in both strains of male and female PPAR alpha -null mice. Hepatic accum ulation of lipids was greater in both strains and sexes of PPAR alpha -null mice compared with wild-type controls. Administration of the peroxisome pr oliferator WY-14643 caused hepatomegaly, alterations in mRNAs encoding prot eins that regulate lipid metabolism, and reduced serum triglycerides in a P PAR alpha -dependent mechanism. Constitutive differences in serum cholester ol and triglycerides in PPAR alpha -null mice were found between genetic ba ckgrounds. Results from this work establish that PPAR alpha is a critical m odulator of lipid homeostasis in two congenic mouse lines. This study demon strates that disruption of the murine gene encoding PPAR alpha results in s ignificant alterations in constitutive serum, hepatic, and adipose tissue l ipid metabolism. However, an overt, obese phenotype in either of the two co ngenic strains was not observed. In contrast to earlier published work, thi s study establishes that PPAR alpha is not associated with obesity in mice.