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Ablation of PI3K-p110alpha Impairs Maternal Metabolic Adaptations to Pregnancy.

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cam.depositDate2022-06-10
cam.issuedOnline2022-07
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cam.orpheus.successWed Aug 03 09:45:49 BST 2022 - Embargo updated
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dc.contributor.authorLopez-Tello, Jorge
dc.contributor.authorSalazar-Petres, Esteban
dc.contributor.authorWebb, Liam
dc.contributor.authorFowden, Abigail L
dc.contributor.authorSferruzzi-Perri, Amanda N
dc.date.accessioned2022-06-10T23:31:05Z
dc.date.available2022-06-10T23:31:05Z
dc.date.issued2022
dc.date.updated2022-06-10T15:13:13Z
dc.description.abstractPregnancy requires adaptations in maternal metabolism to support fetal growth. The phosphoinositol-3-kinase (PI3K) signalling pathway controls multiple biological processes and defects in this pathway are linked to metabolic disorders including insulin resistance and glucose intolerance in non-pregnant animals. However, relatively little is known about the contribution of PI3K signalling to the maternal metabolic adaptations during pregnancy. Using mice with partial inactivation of the PI3K isoform, p110α (due to a heterozygous dominant negative mutation; Pik3ca-D933A), the effects of impaired PI3K-p110α signalling on glucose and insulin handling were examined in the pregnant and non-pregnant states and related to the morphological, molecular, and mitochondrial changes in key metabolic organs. The results show that non-pregnant mice lacking PI3K-p110α are glucose intolerant but exhibit compensatory increases in pancreatic glucose-stimulated insulin release and adipose tissue mitochondrial respiratory capacity and fatty acid oxidation. However, in pregnancy, mutant mice failed to show the normal increment in glucose intolerance and pancreatic β-cell mass observed in wild-type pregnant dams and exhibited further enhanced adipose tissue mitochondrial respiratory capacity. These maladaptations in pregnant mutant mice were associated with fetal growth restriction. Hence, PI3K-p110α is a key regulator of metabolic adaptations that support fetal growth during normal pregnancy.
dc.description.sponsorshipJL-T holds a Sir Henry Wellcome Postdoctoral Fellowship (220456/Z/20/Z). ESP was supported by a Beca-Chile, ANID Postdoctoral Scholarship: 57774190055. ANSP is supported by a MRC New Investigator Grant (MR/R022690/1 / RG93186) and Lister Institute of Preventative Medicine Research Prize (RG93692).
dc.identifier.doi10.17863/CAM.85421
dc.identifier.eissn2296-634X
dc.identifier.issn2296-634X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338016
dc.language.isoeng
dc.publisherFrontiers Media
dc.publisher.departmentDepartment of Physiology, Development And Neuroscience
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectPI3K
dc.subjectmetabolism
dc.subjectmitochondria
dc.subjectpregnancy
dc.subjectsignalling
dc.titleAblation of PI3K-p110alpha Impairs Maternal Metabolic Adaptations to Pregnancy.
dc.typeArticle
dcterms.dateAccepted2022-06-10
prism.publicationNameFront Cell Dev Biol
pubs.funder-project-idWellcome Trust (220456/Z/20/Z)
pubs.funder-project-idMedical Research Council (MR/R022690/1)
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
pubs.licence-identifierapollo-deposit-licence-2-1
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.3389/fcell.2022.928210

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