Rewiring of embryonic glucose metabolism via suppression of PFK-1 and aldolase during mouse chorioallantoic branching.

Hidenobu Miyazawa,Kurara Honda,Yoshifumi Yamaguchi,Koki Kondo,Masayuki Miura,Fumio Matsuda,Yuki Sugiura,Takehiro Yamamoto,Makoto Suematsu

doi:10.1242/dev.138545

Hidenobu Miyazawa, Kurara Honda + Show 7 more

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https://doi.org/10.1242/dev.138545

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Abstract

Adapting the energy metabolism state to changing bioenergetic demands is essential for mammalian development accompanying massive cell proliferation and cell differentiation. However, it remains unclear how developing embryos meet the changing bioenergetic demands during the chorioallantoic branching (CB) stage, when the maternal-fetal exchange of gases and nutrients is promoted. In this study, using metabolome analysis with mass-labeled glucose, we found that developing embryos redirected glucose carbon flow into the pentose phosphate pathway via suppression of the key glycolytic enzymes PFK-1 and aldolase during CB. Concomitantly, embryos exhibited an increase in lactate pool size and in the fractional contribution of glycolysis to lactate biosynthesis. Imaging mass spectrometry visualized lactate-rich tissues, such as the dorsal or posterior neural tube, somites and head mesenchyme. Furthermore, we found that the heterochronic gene Lin28a could act as a regulator of the metabolic changes observed during CB. Perturbation of glucose metabolism rewiring by suppressing Lin28a downregulation resulted in perinatal lethality. Thus, our work demonstrates that developing embryos rewire glucose metabolism following CB for normal development.

Highlights

Understanding how cellular metabolism is coordinated with various biological processes at the tissue or organismal level has been a challenge for modern biology (Boroughs and DeBerardinis, 2015; Pavlova and Thompson, 2016; Vander Heiden et al, 2009)
Tissue distribution of glycolytic and tricarboxylic acid (TCA) cycle intermediates within embryos revealed by imaging mass spectrometry We explored which embryonic structures contribute to the increased lactate level during chorioallantoic branching (CB)
We found that perturbation of glucose metabolism rewiring by Lin28a overexpression during CB led to perinatal lethality at postnatal day (P)0 without obvious morphological defects (Fig. 8D)

Summary

Introduction

Understanding how cellular metabolism is coordinated with various biological processes at the tissue or organismal level has been a challenge for modern biology (Boroughs and DeBerardinis, 2015; Pavlova and Thompson, 2016; Vander Heiden et al, 2009). Received 29 April 2016; Accepted 19 November 2016 and cell differentiation; actively dividing cells favor glycolysis for efficient biomass production, whereas terminally differentiated cells mainly rely on oxidative phosphorylation (OXPHOS) for efficient energy production (Agathocleous and Harris, 2013; Christofk et al, 2008; Folmes et al, 2011; Vander Heiden et al, 2009). This seems to be the case during development, when cell proliferation and cell differentiation occur concurrently (Agathocleous et al, 2012; Tennessen et al, 2011). Embryos harboring mutations in key regulators of energy metabolic pathways exhibit defects around these stages of development (Bamforth et al, 2001; Davis et al, 1993; Iyer et al, 1998; Larsson et al, 1998)

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