Maternal influence of prolyl endopeptidase on fat mass of adult progeny

Background: Maternal genotype has lifetime effects on progeny, but few specific genes, and no proteases, are known to underlie maternal effects. Prolyl endopeptidase (PREP) is a serine protease with putative substrates that regulate appetite or milk production. Objective: To test effects of PREP on obesity phenotypes in mice. Design: Mice with a gene trap (GT) of PREP (PREP gt/gt ) on the C57BL/6J (B6) background were generated. Minimal PREP protein was detected by western blot. In Experiment 1, direct effects of PREP were measured in littermate mice derived from intercrosses of heterozygotes (PREP WT/gt ). In Experiment 2, maternal effects of PREP were measured in reciprocal crosses of heterozygous (PREP WT/gt ) and wild-type (WT) (PREP WT/WT ) males and females. Diets: Mice were fed either low-fat (LF, Experiments 1 and 2) or high-fat (HF, Experiment 1) defined diets. Measurements: Adiposity index (AI) was calculated from body weight (BW) and weights of four fat depots measured in 120-day-old mice. Fasting plasma glucose, insulin and leptin were measured. In vivo plasma α-MSH levels were measured by targeted quantitative peptidomics. Results: Experiment 1-In intercross mice, there were significant diet effects, but few genotype effects. There were no genotype effects on BW or AI in males or females on either diet. Experiment 2-In contrast, reciprocal crosses of heterozygous males or females with WT B6 revealed highly significant parent of origin effects on all traits except body length. Progeny (WT and heterozygous genotypes and both sexes) born to female PREP WT/gt heterozygotes had fat pads that weighed as much as -twofold more at 120 days old than progeny born to male heterozygotes. Conclusion: Heterozygosity for PREP GT results in highly significant maternal effects, whereas homozygosity for the PREP gt/gt mutation has a much more limited direct effect.