TY - JOUR
T1 - Compartmentalized metabolism supports midgestation mammalian development
AU - Solmonson, Ashley
AU - Faubert, Brandon
AU - Gu, Wen
AU - Rao, Aparna
AU - Cowdin, Mitzy A.
AU - Menendez-Montes, Ivan
AU - Kelekar, Sherwin
AU - Rogers, Thomas J.
AU - Pan, Chunxiao
AU - Guevara, Gerardo
AU - Tarangelo, Amy
AU - Zacharias, Lauren G.
AU - Martin-Sandoval, Misty S.
AU - Do, Duyen
AU - Pachnis, Panayotis
AU - Dumesnil, Dennis
AU - Mathews, Thomas P.
AU - Tasdogan, Alpaslan
AU - Pham, An
AU - Cai, Ling
AU - Zhao, Zhiyu
AU - Ni, Min
AU - Cleaver, Ondine
AU - Sadek, Hesham A.
AU - Morrison, Sean J.
AU - DeBerardinis, Ralph J.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/4/14
Y1 - 2022/4/14
N2 - Mammalian embryogenesis requires rapid growth and proper metabolic regulation1. Midgestation features increasing oxygen and nutrient availability concomitant with fetal organ development2,3. 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 cycle4,5. 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.
AB - Mammalian embryogenesis requires rapid growth and proper metabolic regulation1. Midgestation features increasing oxygen and nutrient availability concomitant with fetal organ development2,3. 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 cycle4,5. 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.
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U2 - 10.1038/s41586-022-04557-9
DO - 10.1038/s41586-022-04557-9
M3 - Article
C2 - 35388219
AN - SCOPUS:85127691241
SN - 0028-0836
VL - 604
SP - 349
EP - 353
JO - Nature
JF - Nature
IS - 7905
ER -