Maternal Hyperglycemia Activates an ASK1–FoxO3a–Caspase 8 Pathway That Leads to Embryonic Neural Tube Defects

Yang, Peixin; Li, Xuezheng; Xu, Cheng; Eckert, Richard L.; Reece, E. Albert; Zielke, H. Ronald; Wang, Fang

doi:10.1126/scisignal.2004020

Cited by 86 publications

(208 citation statements)

References 57 publications

(108 reference statements)

Supporting

Mentioning

196

Contrasting

Order By: Relevance

“…Increased pool size of lactate and TCA cycle metabolites following CB Although glucose metabolism is known to be crucial for embryonic development during CB (Hunter and Tugman, 1995;Yang et al, 2013), it remains to be fully understood how embryonic glucose metabolism changes at this stage. Our metabolome data showed that intracellular metabolites in the TCA cycle increased significantly from E8.5 to E10.5 (Fig.…”

Section: Transition Of Embryonic Metabolome Profiles During Cbmentioning

confidence: 99%

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

Miyazawa¹,

Yamaguchi²,

Honda³

et al. 2017

Journal of Cell Science

View full text Add to dashboard Cite

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.

show abstract

Section: Transition Of Embryonic Metabolome Profiles During Cbmentioning

confidence: 99%

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

Miyazawa¹,

Yamaguchi²,

Honda³

et al. 2017

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…Western blotting was performed as described previously (17,57). Briefly, E12.5 embryonic hearts were sonicated in ice-cold RIPA lysis buffer (Millipore, Bedford, MA).…”

Section: Mice and Reagentsmentioning

confidence: 99%

“…Mouse models of maternal diabetes-induced embryonic malformations were described previously (18,57). Briefly, 10-wk-old WT and Ask1 Ϫ/Ϫ female mice were intravenously injected daily with 75 mg/kg STZ over 2 days to induce diabetes.…”

Section: Mice and Reagentsmentioning

confidence: 99%

“…Maternal diabetes induces oxidative stress in the developing embryo (6,9,26,45,48,53,58,59) and activates apoptosis signal-regulating kinase 1 (ASK1), a mitogen-activated protein kinase (MAPK) kinase, in neurulation stage embryos (47,57). ASK1 responds to oxidative stress and induces apoptosis via the activation of c-Jun NH 2 -terminal kinase 1/2 (JNK) and/or p38 MAPK (42).…”

mentioning

confidence: 99%

See 1 more Smart Citation

ASK1 mediates the teratogenicity of diabetes in the developing heart by inducing ER stress and inhibiting critical factors essential for cardiac development

Wang¹,

Wu²,

Quon³

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

View full text Add to dashboard Cite

show abstract

“…Immunoblotting was performed as previously described (2,(29)(30)(31)(32)(33)(34). Briefly, ovaries from different experimental groups were sonicated in lysis buffer containing a protease inhibitor cocktail (Sigma-Aldrich, St. Louis, MO, USA).…”

Section: Methodsmentioning

confidence: 99%

Effect of high-fat diet-induced obesity on the Akt/FoxO/Smad signaling pathway and the follicular development of the mouse ovary

Zhang

Liao

et al. 2016

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. Obesity has a negative effect on ovarian functions, which is reported to increase the risk of infertility. The mechanism underlying obesity-induced infertility is not yet clear. The present study established a high-fat diet (HFD)-induced obesity mouse model to elucidate the mechanisms underlying the effect of HFD-induced obesity on follicular development in the mouse ovary. The 4-week-old female mice were fed with HFD or normal control (NC) diet for 15 or 20 weeks. Body mass index was used to demonstrate that the mice were obese following HFD treatment. The follicular development of the ovaries from the HFD group mice was retarded in a time-dependent manner, as demonstrated by morphological and histological examination of the ovaries. Further investigation via western blot analysis demonstrated that the activity of the transcription factor, forkhead box O3a (FoxO3a), was increased by HFD through downregulated FoxO3a phosphorylation, which may contribute to the inhibited development of ovarian follicles. To determine the regulatory mechanism of FoxO3 on the follicular development, the expression levels of FoxO3a target protein, Smad1/5/8, were also determined and there was significant decrease in phosphorylated Smad1/5/8 in the ovaries from the HFD group compared with the NC group, indicating that FoxO3a/Smad1/5/8 may be important in the regulation of follicular development. The expression levels of the upstream regulator of FoxO3a, Akt, were also examined and it was demonstrated that Akt phosphorylation was significantly reduced in the HFD group compared with the NC group, indicating that Akt/FoxO3a may be also involved in follicular development. Together, the experiments demonstrated that HFD-induced obesity affected the activity of the Akt/FoxO3a/Smad1/5/8 signaling pathway in a time-dependent manner during the follicular development of the mouse ovary, leading to abnormal follicular development. These findings may provide part of a theoretical basis for the clinical prevention and treatment of obesity-associated female infertility.

show abstract

Maternal Hyperglycemia Activates an ASK1–FoxO3a–Caspase 8 Pathway That Leads to Embryonic Neural Tube Defects

Cited by 86 publications

References 57 publications

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

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

ASK1 mediates the teratogenicity of diabetes in the developing heart by inducing ER stress and inhibiting critical factors essential for cardiac development

Effect of high-fat diet-induced obesity on the Akt/FoxO/Smad signaling pathway and the follicular development of the mouse ovary

Contact Info

Product

Resources

About