Metabolic induction and early responses of mouse blastocyst developmental programming following maternal low protein diet affecting life-long health

PLoS One. 2012;7(12):e52791. doi: 10.1371/journal.pone.0052791. Epub 2012 Dec 27.

Abstract

Previously, we have shown that a maternal low protein diet, fed exclusively during the preimplantation period of mouse development (Emb-LPD), is sufficient to induce by the blastocyst stage a compensatory growth phenotype in late gestation and postnatally, correlating with increased risk of adult onset cardiovascular disease and behavioural dysfunction. Here, we examine mechanisms of induction of maternal Emb-LPD programming and early compensatory responses by the embryo. Emb-LPD induced changes in maternal serum metabolites at the time of blastocyst formation (E3.5), notably reduced insulin and increased glucose, together with reduced levels of free amino acids (AAs) including branched chain AAs leucine, isoleucine and valine. Emb-LPD also caused reduction in the branched chain AAs within uterine fluid at the blastocyst stage. These maternal changes coincided with an altered content of blastocyst AAs and reduced mTORC1 signalling within blastocysts evident in reduced phosphorylation of effector S6 ribosomal protein and its ratio to total S6 protein but no change in effector 4E-BP1 phosphorylated and total pools. These changes were accompanied by increased proliferation of blastocyst trophectoderm and total cells and subsequent increased spreading of trophoblast cells in blastocyst outgrowths. We propose that induction of metabolic programming following Emb-LPD is achieved through mTORC1signalling which acts as a sensor for preimplantation embryos to detect maternal nutrient levels via branched chain AAs and/or insulin availability. Moreover, this induction step associates with changes in extra-embryonic trophectoderm behaviour occurring as early compensatory responses leading to later nutrient recovery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / blood
  • Animals
  • Blastocyst / metabolism*
  • Blood Glucose
  • Corticosterone / blood
  • Diet, Protein-Restricted / adverse effects*
  • Embryonic Development*
  • Estrogens / blood
  • Female
  • Health
  • Insulin / blood
  • Male
  • Maternal Nutritional Physiological Phenomena
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes
  • Phenotype
  • Phosphorylation
  • Pregnancy
  • Prenatal Exposure Delayed Effects / metabolism*
  • Protein Processing, Post-Translational
  • Proteins / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Uterus / metabolism

Substances

  • Amino Acids
  • Blood Glucose
  • Estrogens
  • Insulin
  • Multiprotein Complexes
  • Proteins
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases
  • Corticosterone