Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Jan 1;310(1):R87-93.
doi: 10.1152/ajpregu.00356.2015. Epub 2015 Oct 21.

Activation of placental insulin and mTOR signaling in a mouse model of maternal obesity associated with fetal overgrowth

Fredrick J Rosario  1 , Theresa L Powell  2 , Thomas Jansson  3
Affiliations

Activation of placental insulin and mTOR signaling in a mouse model of maternal obesity associated with fetal overgrowth

Fredrick J Rosario et al. Am J Physiol Regul Integr Comp Physiol. .

Abstract

Fetal overgrowth is common in obese women and is associated with perinatal complications and increased risk for the child to develop metabolic syndrome later in life. Placental nutrient transport capacity has been reported to be increased in obese women giving birth to large infants; however, the underlying mechanisms are not well established. Obesity in pregnancy is characterized by elevated maternal serum insulin and leptin, hormones that stimulate placental amino acid transporters in vitro. We hypothesized that maternal obesity activates placental insulin/IGF-I/mTOR and leptin signaling pathways. We tested this hypothesis in a mouse model of obesity in pregnancy that is associated with fetal overgrowth. C57BL/6J female mice were fed a control (C) or a high-fat/high-sugar (HF/HS) pelleted diet supplemented by ad libitum access to sucrose (20%) solution. Placentas were collected at embryonic day 18.5. Using Western blot analysis, placental mTOR activity was determined along with energy, inflammatory, leptin, and insulin signaling pathways (upstream modulators of mTOR). Phosphorylation of S6 ribosomal protein (S-235/236), 4E-BP1 (T-37/46), Insulin receptor substrate 1 (Y-608), Akt (T-308), and STAT-3 (Y-705) was increased in obese dams. In contrast, expression of placental caspase-1, IкBα, IL-1β, and phosphorylated-JNK(p46/54-T183/Y185) was unaltered. Fetal amino acid availability is a key determinant of fetal growth. We propose that activation of placental insulin/IGF-I/mTOR and leptin signaling pathways in obese mice stimulates placental amino acid transport and contributes to increased fetal growth.

Keywords: fetal growth; fetal programming; intracellular signaling proteins; maternal-fetal exchange; pregnancy.

PubMed Disclaimer

Figures

Fig. 1.
Fig. 1.
Placental S6 phosphorylation in mice fed a control (C) or high-fat/high-sugar (HF/HS) diet. A: representative Western blots of S6 (S-235/236) and total S6 in homogenates of mice placenta at E18.5. B: summary of the Western blot data. After normalization to β-actin, the mean density of control samples was assigned an arbitrary value of 1. Subsequently, individual control and HF/HS density values were expressed relative to this mean. Values are given as means ± SE; n = 12/each group, *P < 0.05 vs. control, using unpaired Student's t-test.
Fig. 2.
Fig. 2.
Placental 4E-BP1 phosphorylation in mice fed a control (C) or HF/HS diet. A: representative A: Western blots of 4E-BP1 (T-37/46) and total 4E-BP1 in homogenates of mice placenta at E18.5. B: summary of the Western blot data. After normalization to β-actin, the mean density of control samples was assigned an arbitrary value of 1. Subsequently, individual control and HF/HS density values were expressed relative to this mean. Values are given as means ± SE; n = 12/each group, *P < 0.05 vs. control, using unpaired Student's t-test.
Fig. 3.
Fig. 3.
Placental AMPK phosphorylation in mice fed a control (C) or HF/HS diet. A: representative Western blots of AMPK (T-172) and total AMPK in homogenates of mice placenta at E18.5. B: summary of the Western blot data. After normalization to β-actin, the mean density of control samples was assigned an arbitrary value of 1. Subsequently, individual control and HF/HS density values were expressed relative to this mean. Values are given as means ± SE; n = 12/each group, *P < 0.05 vs. control, using unpaired Student's t-test.
Fig. 4.
Fig. 4.
Placental IRS-1 and Akt phosphorylation in mice fed a control (C) or HF/HS diet. A: representative Western blots of IRS-1 (Y-608), Akt (T-308), and total IRS-1/Akt in homogenates of mice placenta at E18.5. B: summary of the Western blot data. After normalization to β-actin, the mean density of control samples was assigned an arbitrary value of 1. Subsequently, individual control and HF/HS density values were expressed relative to this mean. Values are given as means ± SE; n = 12/each group, *P < 0.05 vs. control, using unpaired Student's t-test.
Fig. 5.
Fig. 5.
Placental of caspase-1, IκBα, JNKp46/54-T183/Y185 and IL-1β expression mice fed a control (C) or HF/HS diet. A: representative Western blots of caspase-1, IκBα, JNKp46/54-T183/Y185, and IL-1β in homogenates of mice placenta at E18.5. B: summary of the Western blot data. After normalization to β-actin, the mean density of control samples was assigned an arbitrary value of 1. Subsequently, individual control and HF/HS density values were expressed relative to this mean. Values are given as means ± SE; n = 12/each group.
Fig. 6.
Fig. 6.
Placental phosphorylated STAT-3 expression in mice fed a control (C) or HF/HS diet. A: representative Western blots of STAT-3 (Y-705) and total STAT-3 in homogenates of mice placenta at E18.5. B: summary of the Western blot data. After normalization to β-actin, the mean density of control samples was assigned an arbitrary value of 1. Subsequently, individual control and HF/HS density values were expressed relative to this mean. Values are given as means ± SE; n = 12/each group. *P < 0.05 vs. control, using unpaired Student's t-test.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ahlsson FS, Diderholm B, Ewald U, Gustafsson J. Lipolysis and insulin sensitivity at birth in infants who are large for gestational age. Pediatrics 120: 958–965, 2007. - PubMed
    1. Alfaradhi MZ, Ozanne SE. Developmental programming in response to maternal overnutrition. Front Genet 2: 27, 2011. - PMC - PubMed
    1. Arroyo JA, Brown LD, Galan HL. Placental mammalian target of rapamycin and related signaling pathways in an ovine model of intrauterine growth restriction. Am J Obstet Gynecol 201: 616e 611–617, 2009. - PMC - PubMed
    1. Aye IL, Gao X, Weintraub ST, Jansson T, Powell TL. Adiponectin inhibits insulin function in primary trophoblasts by PPARα-mediated ceramide synthesis. Mol Endocrinol 28: 512–524, 2014. - PMC - PubMed
    1. Aye IL, Lager S, Ramirez VI, Gaccioli F, Dudley DJ, Jansson T, Powell TL. Increasing maternal body mass index is associated with systemic inflammation in the mother and the activation of distinct placental inflammatory pathways. Biol Reprod 90: 129, 2014. - PMC - PubMed

Publication types

MeSH terms