Generation of mice with the PPARγ P465L mutation. (A) Crossovers (indicated by the large X marks) between the wild-type mouse Pparg locus with Pro465 in exon 6 (6P) (top diagram) and targeting construct with Leu465 (6L) (second diagram) resulted in the targeted allele in ES cells (third diagram). The ACN (Cre-Neo) cassette, flanked by loxP sequences, was excised out of the mutant allele upon germline transmission (bottom diagram). B, X, Xb, and St indicate the BamHI, XhoI, XbaI, and StuI restriction enzyme sites, respectively. tAce, testis-specific Ace promoter; TK, thymidine kinase. (B) Southern blot analysis of genomic DNA. The targeted allele was identified by a 5′ probe that hybridizes to an 11-kb fragment in wild-type (+/+) DNA and to a 7.7-kb fragment in heterozygous DNA that includes the P465L mutation (L/+). (C) PPARγ mRNA of the wild-type (white bars) and mutant allele (black bar) in gonadal adipose tissue from wild-type and PpargP465L/+ mice (n = 8 each). The PPARγ mRNA amount is expressed relative to that of wild-type allele in wild-type mice. (D) Rosiglitazone-induced PEPCK expression in gonadal adipose tissue explants. Tissues isolated from four wild-type (open squares) and four PpargP465L/+ (filled squares) mice were incubated in cultured media containing various concentrations of PPARγ agonist rosiglitazone as indicated. The levels of PEPCK mRNA are relative to the wild-type basal level. *P < 0.01 and **P < 0.005 compared with the respective basal levels.