Fetal manipulation of maternal metabolism is a critical function of the imprinted Igf2 gene

Fetal manipulation of maternal metabolism is a critical function of the imprinted Igf2 gene

Cell Metabolism

10.1016/j.cmet.2023.06.007

https://doi.org/10.1016/j.cmet.2023.06.007

Jorge Lopez-Tello, Hannah E.J. Yong, Ionel Sandovici, Georgina K.C. Dowsett, Efthimia R. Christoforou, Esteban Salazar-Petres, Rebecca Boyland, Tina Napso, Giles S.H. Yeo, Brian Y.H. Lam, Miguel Constancia, Amanda N. Sferruzzi-Perri

11 July 2023

Lopez-Tello, J., Yong, H. E. J., Sandovici, I., Dowsett, G. K. C., Christoforou, E. R., Salazar-Petres, E., Boyland, R., Napso, T., Yeo, G. S. H., Lam, B. Y. H., Constancia, M., & Sferruzzi-Perri, A. N. (2023). Fetal manipulation of maternal metabolism is a critical function of the imprinted Igf2 gene. Cell Metabolism, 35(7), 1195-1208.e6. https://doi.org/10.1016/j.cmet.2023.06.007

Maternal-offspring interactions in mammals involve both cooperation and conflict. The fetus has evolved ways to manipulate maternal physiology to enhance placental nutrient transfer, but the mechanisms involved remain unclear. The imprinted Igf2 gene is highly expressed in murine placental endocrine cells. Here, we show that Igf2 deletion in these cells impairs placental endocrine signaling to the mother, without affecting placental morphology. Igf2 controls placental hormone production, including prolactins, and is crucial to establish pregnancy-related insulin resistance and to partition nutrients to the fetus. Consequently, fetuses lacking placental endocrine Igf2 are growth restricted and hypoglycemic. Mechanistically, Igf2 controls protein synthesis and cellular energy homeostasis, actions dependent on the placental endocrine cell type. Igf2 loss also has additional long-lasting effects on offspring metabolism in adulthood. Our study provides compelling evidence for an intrinsic fetal manipulation system operating in placenta that modifies maternal metabolism and fetal resource allocation, with long-term consequences for offspring metabolic health.

Attribution 4.0 International (CC BY 4.0)

J.L.-T. currently holds a Sir Henry Wellcome Postdoctoral Fellowship from the Wellcome Trust (220456/Z/20/Z) and previously a Newton International Fellowship from the Royal Society (NF170988/RG90199) and an Early Career Grant from the Society for Endocrinology. H.E.J.Y. was supported by an A*STAR International Fellowship from the Agency for Science, Technology and Research. E.S.-P. was supported by a Beca-Chile, ANID Postdoctoral Scholarship (74190055). E.R.C. was supported by a Cambridge-Rutherford PhD Scholarship from the Cambridge Trust and Rutherford Foundation. T.N. was supported by an EU Marie Sk1odowska-Curie Fellowship (PlaEndo/703160) and an Early Career Grant from the Society for Endocrinology. G.K.C.D. is funded by a BBSRC CASE 4-year PhD studentship co-funded by Novo Nordisk. G.S.H.Y. and B.Y.H.L. are funded by MRC Metabolic Diseases Unit (MC_UU_00014/1). A.N.S.-P. was supported by a Royal Society Dorothy Hodgkin Research Fellowship, Academy of Medical of Sciences Springboard Grant, Isaac Newton Trust Grant, Lister Institute Research Prize grant, and the Medical Research Council (DH130036/RG74249, SBF002/ 1028/RG88501, RG97390, RG93692, and MR/R022690/1/RG93186, respectively). M.C.’s research was supported by the Biotechnology and Biological Sciences Research Council grant (BB/H003312/1) and the Medical Research Council (MRC_MC_UU_12012/4 to M.C.; MRC_MC_UU_12012/5 to the MRC Metabolic Diseases Unit). The MRC MDU is supported by the MRC (MC_UU_00014/5). Next-generation sequencing was performed by the IMS Genomics and Transcriptomics Core Facility, which is supported by MRC (MC_UU_00014/5), Wellcome (208363/Z/17/Z), and the Cancer Research UK Cambridge Institute Genomics Core.

https://oar.a-star.edu.sg/communities-collections/articles/21984

1550-4131

Institute for Human Development and Potential