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Maternal influence of prolyl endopeptidase on fat mass of adult progeny.

Warden CH, Fisler JS, Espinal G, Graham J, Havel PJ, Perroud B - Int J Obes (Lond) (2009)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Rowe Program in Genetics, University of California, Davis, CA 95616, USA. chwarden@ucdavis.edu

ABSTRACT

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 alpha-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.

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Reciprocal cross (Experiment 2). Body weight and adiposity index (AI) of male and female pups with either wild-type (PREPWT/WT, WT) or heterozygous (PREPWT/gt, H) mothers in the reciprocal cross and categorized by either the pup genotype or the maternal genotype. Pups were fed LF diet only. Data are means ± SE. See Figure 2 legend for methods. 3-Way ANOVA for both body weight and AI: effect of gender, p<0.0001; effect of pup genotype, NS; effect of maternal genotype, p<0.0001; all interactions, NS.
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Figure 5: Reciprocal cross (Experiment 2). Body weight and adiposity index (AI) of male and female pups with either wild-type (PREPWT/WT, WT) or heterozygous (PREPWT/gt, H) mothers in the reciprocal cross and categorized by either the pup genotype or the maternal genotype. Pups were fed LF diet only. Data are means ± SE. See Figure 2 legend for methods. 3-Way ANOVA for both body weight and AI: effect of gender, p<0.0001; effect of pup genotype, NS; effect of maternal genotype, p<0.0001; all interactions, NS.

Mentions: We examined the hypothesis that heterozygotes for the PREP gene-trap mutation will have a parent of origin effect on obesity. We performed reciprocal crosses of PREPWT/gt × PREPWT/WT using mice that were at generation N8 of backcross. All animals were phenotyped by the same protocol as for the intercross, but using only the LF diet (Figure 5 and Table 2). Pup genotype had no effect on phenotypes in either gender (Figure 5) and the pups of both genotypes were combined for analysis of maternal effects. Progeny of heterozygous PREPWT/gt females weighed significantly more and had significant greater fat mass (AI) than progeny of wild-type PREPWT/WT mothers. Pups born to heterozygous PREPWT/gt mothers also had higher body mass index and organ weights but not anal nasal length than pups born to wild-type PREPWT/WT mothers (Table 2).


Maternal influence of prolyl endopeptidase on fat mass of adult progeny.

Warden CH, Fisler JS, Espinal G, Graham J, Havel PJ, Perroud B - Int J Obes (Lond) (2009)

Reciprocal cross (Experiment 2). Body weight and adiposity index (AI) of male and female pups with either wild-type (PREPWT/WT, WT) or heterozygous (PREPWT/gt, H) mothers in the reciprocal cross and categorized by either the pup genotype or the maternal genotype. Pups were fed LF diet only. Data are means ± SE. See Figure 2 legend for methods. 3-Way ANOVA for both body weight and AI: effect of gender, p<0.0001; effect of pup genotype, NS; effect of maternal genotype, p<0.0001; all interactions, NS.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2743752&req=5

Figure 5: Reciprocal cross (Experiment 2). Body weight and adiposity index (AI) of male and female pups with either wild-type (PREPWT/WT, WT) or heterozygous (PREPWT/gt, H) mothers in the reciprocal cross and categorized by either the pup genotype or the maternal genotype. Pups were fed LF diet only. Data are means ± SE. See Figure 2 legend for methods. 3-Way ANOVA for both body weight and AI: effect of gender, p<0.0001; effect of pup genotype, NS; effect of maternal genotype, p<0.0001; all interactions, NS.
Mentions: We examined the hypothesis that heterozygotes for the PREP gene-trap mutation will have a parent of origin effect on obesity. We performed reciprocal crosses of PREPWT/gt × PREPWT/WT using mice that were at generation N8 of backcross. All animals were phenotyped by the same protocol as for the intercross, but using only the LF diet (Figure 5 and Table 2). Pup genotype had no effect on phenotypes in either gender (Figure 5) and the pups of both genotypes were combined for analysis of maternal effects. Progeny of heterozygous PREPWT/gt females weighed significantly more and had significant greater fat mass (AI) than progeny of wild-type PREPWT/WT mothers. Pups born to heterozygous PREPWT/gt mothers also had higher body mass index and organ weights but not anal nasal length than pups born to wild-type PREPWT/WT mothers (Table 2).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Rowe Program in Genetics, University of California, Davis, CA 95616, USA. chwarden@ucdavis.edu

ABSTRACT

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 alpha-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.

Show MeSH
Related in: MedlinePlus