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. 2022 Jul 1:10:928210.
doi: 10.3389/fcell.2022.928210. eCollection 2022.

Ablation of PI3K-p110alpha Impairs Maternal Metabolic Adaptations to Pregnancy

Jorge Lopez-Tello  1 , Esteban Salazar-Petres  1 , Liam Webb  1 , Abigail L Fowden  1 , Amanda N Sferruzzi-Perri  1
Affiliations

Ablation of PI3K-p110alpha Impairs Maternal Metabolic Adaptations to Pregnancy

Jorge Lopez-Tello et al. Front Cell Dev Biol. .

Abstract

Pregnancy 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.

Keywords: PI3K; metabolism; mitochondria; pregnancy; signalling.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
PI3K-p110α regulates maternal bodyweight and fetal growth. (A) Female starting weights (n = 9–15 mice; two-way ANOVA) (B) Hysterectomised weights (after removal of the uterus) of the pregnant mice (n = 11–15 mice; two-way ANOVA). (C) Weight of the gravid uterus (n = 11–15 mice; unpaired Student’s t-test). (D) Litter size (n = 11–15 mice; unpaired Student’s t-test). (E) Fetal weights obtained from 11 to 15 dams (each dot represents a litter mean; one-way ANOVA). (F) Fetal weight divided by maternal weight at the start of pregnancy (each dot represents a litter mean; one-way ANOVA). (G) Placental weight obtained from 11 to 15 dams (each dot represents a litter mean; one-way ANOVA). Data are individual-litter values and mean ± SEM.*p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001. NS (not significant), NP (non-pregnant).
FIGURE 2
FIGURE 2
PI3K-p110α regulates glucose homeostasis and participates in the expansion of pancreatic β-cell mass in response to pregnancy. (A) Fasted glucose levels in non-pregnant (NP) and pregnant mice (n > 5/group; two-way ANOVA). (B) Glucose tolerance test and area under the curve (AUC) after intraperitoneal injection of glucose (n = 5/group; GTT curve analysed by two-way repeated measures ANOVA; AUC analysed by two-way ANOVA). (C) Fasted insulin levels for GTT animals before administration of glucose at time 0 and 15 min after intraperitoneal injection of glucose (n = 4–5/group; two-way MIXED ANOVA). (D) Insulin tolerance test and area above the curve (AAC) after intraperitoneal injection of insulin (n = 4–5/group; ITT curve analysed by two-way repeated measures ANOVA; AAC analysed by two-way ANOVA). (E) Pancreas weight (n = 9–15/group; two-way ANOVA). (F) Representative images of insulin staining using DAB for pancreas islet detection (scale bar = 250 μm) and β-cell mass (n = 6–7/group; two-way ANOVA). (G) Distribution of islets sizes per area analysed (n = 6–7/group; two-way ANOVA). Data are individual values and/or mean ± SEM. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001. For B and D, the definitions for *, @, $ and # are provided within the figure.
FIGURE 3
FIGURE 3
PI3K-p110α regulates adiposity levels and mitochondrial function. (A) Adipose depot weights in non-pregnant (NP) and pregnant mice (n = 9–15/group; two-way ANOVA). (B) Histological analysis of adipocyte size (n = 5–6/group; two-way ANOVA) (scale bar = 100 μm). (C) Western blot analysis of metabolic signalling proteins: insulin receptor β subunit (Insulin Rβ), phosphoinositide-3-kinase subunits (PI3K-p85α and PI3K-p110α), total and phosphorylated protein kinase B (Total AKT and P-AKTSer473) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). (n = 6/group; un-paired Student’s t-test). (D) Western blot analysis of mitochondrial related proteins; citrate synthase, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and peroxisome proliferator-activated receptor gamma (PPAR-γ). (n = 6/group; un-paired Student’s t-test). (E) Mitochondrial respiration rates. Information about substrate/inhibitor in relation to complex activation can be found in Supplementary Table S1. Maximum electron transfer system capacity (Total ETS) and fatty acid oxidation (FAO). (n = 5–6/group; two-way ANOVA). Data in (B–E) are from the retroperitoneal fat pad. Data are individual values and/or mean ± SEM. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.
FIGURE 4
FIGURE 4
PI3K-p110α regulates myofibre size and mitochondrial metabolism. (A) Skeletal muscle fibre size in non-pregnant (NP) and pregnant mice (n = 4–6/group; two-way ANOVA) (scale bar = 50 μm). (B,C) Western blot analysis of metabolic signalling pathways in the skeletal muscle: insulin receptor β subunit (Insulin Rβ), phosphoinositide-3-kinase subunits (PI3K-p85α and PI3K-p110α), total and phosphorylated protein kinase B (Total AKT and P-AKTSer473) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), mitochondrial brown fat uncoupling protein 1 (UCP1) and mitochondrial dynamin like GTPase (OPA1) (n = 6/group; un-paired Student’s t-test). (D) Mitochondrial respirometry (n = 5–6/group; two-way ANOVA). Information about substrate/inhibitor in relation to complex activation can be found in Supplementary Table S1. Maximum electron transfer system capacity (Total ETS) and fatty acid oxidation (FAO). Data are individual values and/or mean ± SEM. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.
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