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Maternal influence of prolyl endopeptidase on fat mass of adult progeny

International Journal of Obesity volume 33, pages 1013–1022 (2009)Cite this article

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 (PREPgt/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 (PREPWT/gt). In Experiment 2, maternal effects of PREP were measured in reciprocal crosses of heterozygous (PREPWT/gt) and wild-type (WT) (PREPWT/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 PREPWT/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 PREPgt/gt mutation has a much more limited direct effect.

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Acknowledgements

This work was supported by a NIH grants R01-DK69978, DK52581 (CHW) and R01-HL075675, R01-HL091333, R21-AT002599, R21-AT002993, R21-AT003645 (PJH) and the American Diabetes Association. We acknowledge the UC Davis Genome Center Proteomics Core for MS quantitative targeted peptidomics work. We also acknowledge Ella Nunez for assistance with the insulin assays.

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Authors and Affiliations

  1. Rowe Program in Genetics, University of California, Davis, CA, USA

    C H Warden & G Espinal

  2. Department of Pediatrics, Section of Neurobiology, Physiology and Behavior, University of California, Davis, CA, USA

    C H Warden

  3. Department of Nutrition, University of California, Davis, CA, USA

    J S Fisler, J Graham & P J Havel

  4. Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA

    J Graham & P J Havel

  5. Genome Center, University of California, Davis, CA, USA

    B Perroud

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  1. C H Warden
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Correspondence to C H Warden.

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Warden, C., Fisler, J., Espinal, G. et al. Maternal influence of prolyl endopeptidase on fat mass of adult progeny. Int J Obes 33, 1013–1022 (2009). https://doi.org/10.1038/ijo.2009.129

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