PMID- 35388219
OWN - NLM
STAT- MEDLINE
DCOM- 20220415
LR  - 20220716
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 604
IP  - 7905
DP  - 2022 Apr
TI  - Compartmentalized metabolism supports midgestation mammalian development.
PG  - 349-353
LID - 10.1038/s41586-022-04557-9 [doi]
AB  - Mammalian embryogenesis requires rapid growth and proper metabolic regulation(1). 
      Midgestation features increasing oxygen and nutrient availability concomitant 
      with fetal organ development(2,3). Understanding how metabolism supports 
      development requires approaches to observe metabolism directly in model organisms 
      in utero. Here we used isotope tracing and metabolomics to identify evolving 
      metabolic programmes in the placenta and embryo during midgestation in mice. 
      These tissues differ metabolically throughout midgestation, but we pinpointed 
      gestational days (GD) 10.5-11.5 as a transition period for both placenta and 
      embryo. Isotope tracing revealed differences in carbohydrate metabolism between 
      the tissues and rapid glucose-dependent purine synthesis, especially in the 
      embryo. Glucose's contribution to the tricarboxylic acid (TCA) cycle rises 
      throughout midgestation in the embryo but not in the placenta. By GD12.5, 
      compartmentalized metabolic programmes are apparent within the embryo, including 
      different nutrient contributions to the TCA cycle in different organs. To 
      contextualize developmental anomalies associated with Mendelian metabolic 
      defects, we analysed mice deficient in LIPT1, the enzyme that activates 
      2-ketoacid dehydrogenases related to the TCA cycle(4,5). LIPT1 deficiency 
      suppresses TCA cycle metabolism during the GD10.5-GD11.5 transition, perturbs 
      brain, heart and erythrocyte development and leads to embryonic demise by GD11.5. 
      These data document individualized metabolic programmes in developing organs in 
      utero.
CI  - (c) 2022. The Author(s).
FAU - Solmonson, Ashley
AU  - Solmonson A
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
FAU - Faubert, Brandon
AU  - Faubert B
AUID- ORCID: 0000-0002-2886-886X
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
AD  - Section of Hematology and Oncology, Department of Medicine, The University of 
      Chicago, Chicago, IL, USA.
FAU - Gu, Wen
AU  - Gu W
AUID- ORCID: 0000-0002-3003-8945
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
FAU - Rao, Aparna
AU  - Rao A
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
FAU - Cowdin, Mitzy A
AU  - Cowdin MA
AUID- ORCID: 0000-0003-0549-2473
AD  - Department of Molecular Biology, University of Texas Southwestern Medical Center, 
      Dallas, TX, USA.
FAU - Menendez-Montes, Ivan
AU  - Menendez-Montes I
AUID- ORCID: 0000-0001-5252-9502
AD  - Division of Cardiology, Department of Internal Medicine, University of Texas 
      Southwestern Medical Center, Dallas, TX, USA.
FAU - Kelekar, Sherwin
AU  - Kelekar S
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
FAU - Rogers, Thomas J
AU  - Rogers TJ
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
FAU - Pan, Chunxiao
AU  - Pan C
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
FAU - Guevara, Gerardo
AU  - Guevara G
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
FAU - Tarangelo, Amy
AU  - Tarangelo A
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
FAU - Zacharias, Lauren G
AU  - Zacharias LG
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
FAU - Martin-Sandoval, Misty S
AU  - Martin-Sandoval MS
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
FAU - Do, Duyen
AU  - Do D
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
FAU - Pachnis, Panayotis
AU  - Pachnis P
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
FAU - Dumesnil, Dennis
AU  - Dumesnil D
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
FAU - Mathews, Thomas P
AU  - Mathews TP
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
FAU - Tasdogan, Alpaslan
AU  - Tasdogan A
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
AD  - Department of Dermatology, University Hospital Essen and German Cancer 
      Consortium, Partner Site Essen, Essen, Germany.
FAU - Pham, An
AU  - Pham A
AD  - Department of Pediatrics, University of Texas Southwestern Medical Center, 
      Dallas, TX, USA.
FAU - Cai, Ling
AU  - Cai L
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
AD  - Quantitative Biomedical Research Center, Department of Population and Data 
      Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
FAU - Zhao, Zhiyu
AU  - Zhao Z
AUID- ORCID: 0000-0001-6308-6997
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
FAU - Ni, Min
AU  - Ni M
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
FAU - Cleaver, Ondine
AU  - Cleaver O
AD  - Department of Molecular Biology, University of Texas Southwestern Medical Center, 
      Dallas, TX, USA.
FAU - Sadek, Hesham A
AU  - Sadek HA
AUID- ORCID: 0000-0002-4745-366X
AD  - Department of Molecular Biology, University of Texas Southwestern Medical Center, 
      Dallas, TX, USA.
AD  - Division of Cardiology, Department of Internal Medicine, University of Texas 
      Southwestern Medical Center, Dallas, TX, USA.
FAU - Morrison, Sean J
AU  - Morrison SJ
AUID- ORCID: 0000-0003-1587-8329
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA.
AD  - Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 
      Dallas, TX, USA.
FAU - DeBerardinis, Ralph J
AU  - DeBerardinis RJ
AUID- ORCID: 0000-0002-2705-7432
AD  - Children's Medical Center Research Institute, University of Texas Southwestern 
      Medical Center, Dallas, TX, USA. ralph.deberardinis@utsouthwestern.edu.
AD  - Department of Pediatrics, University of Texas Southwestern Medical Center, 
      Dallas, TX, USA. ralph.deberardinis@utsouthwestern.edu.
AD  - Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 
      Dallas, TX, USA. ralph.deberardinis@utsouthwestern.edu.
LA  - eng
GR  - F30 CA254150/CA/NCI NIH HHS/United States
GR  - K00 CA212230/CA/NCI NIH HHS/United States
GR  - R35 CA22044901/CE/NCIPC CDC HHS/United States
GR  - K99 CA237724/CA/NCI NIH HHS/United States
GR  - R35 CA220449/CA/NCI NIH HHS/United States
GR  - F32 HD096786/HD/NICHD NIH HHS/United States
GR  - K00 CA234650/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20220406
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - *Citric Acid Cycle
MH  - Embryo, Mammalian/metabolism
MH  - Female
MH  - *Fetal Development
MH  - Glucose/metabolism
MH  - Mammals/metabolism
MH  - *Metabolomics
MH  - Mice
MH  - *Placenta/metabolism
MH  - Pregnancy
PMC - PMC9007737
COIS- R.J.D. is an advisor for Agios Pharmaceuticals and Vida Ventures and a co-founder 
      of Atavistik Bio. The other authors declare no competing interests.
EDAT- 2022/04/08 06:00
MHDA- 2022/04/16 06:00
PMCR- 2022/04/06
CRDT- 2022/04/07 05:30
PHST- 2021/03/01 00:00 [received]
PHST- 2022/02/08 00:00 [accepted]
PHST- 2022/04/08 06:00 [pubmed]
PHST- 2022/04/16 06:00 [medline]
PHST- 2022/04/07 05:30 [entrez]
PHST- 2022/04/06 00:00 [pmc-release]
AID - 10.1038/s41586-022-04557-9 [pii]
AID - 4557 [pii]
AID - 10.1038/s41586-022-04557-9 [doi]
PST - ppublish
SO  - Nature. 2022 Apr;604(7905):349-353. doi: 10.1038/s41586-022-04557-9. Epub 2022 
      Apr 6.