Maternal Diabetes Leads to Adaptation in Embryonic Amino Acid Metabolism during Early Pregnancy.

Jacqueline Gürke,René Thieme,Frank Hirche,Bernd Fischer,Maria Schindler,Elisa Haucke,Anne Navarrete Santos,Gabriele I Stangl,Claudia Kappen

doi:10.1371/journal.pone.0127465

Jacqueline Gürke, René Thieme + Show 7 more

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https://doi.org/10.1371/journal.pone.0127465

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Journal: PloS one	Publication Date: May 28, 2015
Citations: 56	License type: CC BY 4.0

Affiliation: Martin Luther University Halle-Wittenberg

Abstract

During pregnancy an adequate amino acid supply is essential for embryo development and fetal growth. We have studied amino acid composition and branched chain amino acid (BCAA) metabolism at day 6 p.c. in diabetic rabbits and blastocysts. In the plasma of diabetic rabbits the concentrations of 12 amino acids were altered in comparison to the controls. Notably, the concentrations of the BCAA leucine, isoleucine and valine were approximately three-fold higher in diabetic rabbits than in the control. In the cavity fluid of blastocysts from diabetic rabbits BCAA concentrations were twice as high as those from controls, indicating a close link between maternal diabetes and embryonic BCAA metabolism. The expression of BCAA oxidizing enzymes and BCAA transporter was analysed in maternal tissues and in blastocysts. The RNA amounts of three oxidizing enzymes, i.e. branched chain aminotransferase 2 (Bcat2), branched chain ketoacid dehydrogenase (Bckdha) and dehydrolipoyl dehydrogenase (Dld), were markedly increased in maternal adipose tissue and decreased in liver and skeletal muscle of diabetic rabbits than in those of controls. Blastocysts of diabetic rabbits revealed a higher Bcat2 mRNA and protein abundance in comparison to control blastocysts. The expression of BCAA transporter LAT1 and LAT2 were unaltered in endometrium of diabetic and healthy rabbits, whereas LAT2 transcripts were increased in blastocysts of diabetic rabbits. In correlation to high embryonic BCAA levels the phosphorylation amount of the nutrient sensor mammalian target of rapamycin (mTOR) was enhanced in blastocysts caused by maternal diabetes. These results demonstrate a direct impact of maternal diabetes on BCAA concentrations and degradation in mammalian blastocysts with influence on embryonic mTOR signalling.

Highlights

Amino acids are essential nutrients for embryo and fetal development and growth [1]
As in maternal plasma, the branched chain amino acids (BCAA) showed the strongest differences in Blastocyst cavity fluid (BCF) of embryos from diabetic rabbits in comparison to the controls
The lowest expression level of all enzymes was found in the skeletal muscle (Bcat2: 13±1, branched chain ketoacid dehydrogenase (Bckdha): 2±0.09, dehydrolipoyl dehydrogenase (Dld): 408±41, Dbt: 26±3 molecules per 105 glyceraldehyde 3-phosphate dehydrogenase (GAPDH) molecules) and the highest in liver (Bcat2: 104±11, Bckdha: 123±10, Dld: 38090± 2800, Dbt: 14757±1225 molecules per 105 GAPDH molecules) and adipose tissue (Bcat2: 275± 25, Bckdha: 1666±88, Dld: 19041±1488, Dbt: 3839±172 molecules per 105 GAPDH molecules)

Summary

Introduction

Amino acids are essential nutrients for embryo and fetal development and growth [1]. Amino Acid Metabolism in Rabbit Preimplantation Embryos trophoblast differentiation and implantation [2,3]. In 1966, Gwatkin reported that an absence of the amino acids leucine and arginine in culture medium led to inhibited trophoblast growth [9]. The branched chain amino acids (BCAA) leucine, isoleucine and valine are of great importance for fetal growth. They are preferentially transported to the embryo via system L [10] and spread quickly across the placenta [11]. BCKDHC consists of three catalytic components; the branched chain ketoacid dehydrogenase (BCKDH; alpha and beta subunit), dehydrolipoyl dehydrogenase (DLD) and dehydrolipoyl transacylase (DBT)

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