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Cited by 40Birth, Development, and HealthOvarian function and disordersSexual Differentiation and Disorders

Developmental Programming: Prenatal Testosterone Excess and Insulin Signaling Disruptions in Female Sheep1

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Lu, Chunxia, Cardoso, Rodolfo C., Puttabyatappa, Muraly, Padmanabhan, Vasantha·2016·Biology of Reproduction
DOI 10.1095/biolreprod.115.136283PMC PMC4939741
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Abstract

Women with polycystic ovary syndrome often manifest insulin resistance. Using a sheep model of polycystic ovary syndrome-like phenotype, we explored the contribution of androgen and insulin in programming and maintaining disruptions in insulin signaling in metabolic tissues. Phosphorylation of AKT, ERK, GSK3beta, mTOR, and p70S6K was examined in the liver, muscle, and adipose tissue of control and prenatal testosterone (T)-, prenatal T plus androgen antagonist (flutamide)-, and prenatal T plus insulin sensitizer (rosiglitazone)-treated fetuses as well as 2-yr-old females. Insulin-stimulated phospho (p)-AKT was evaluated in control and prenatal T-, prenatal T plus postnatal flutamide-, and prenatal T plus postnatal rosiglitazone-treated females at 3 yr of age. GLUT4 expression was evaluated in the muscle at all time points. Prenatal T treatment increased mTOR, p-p70S6K, and p-GSK3beta levels in the fetal liver with both androgen antagonist and insulin sensitizer preventing the mTOR increase. Both interventions had partial effect in preventing the increase in p-GSK3beta. In the fetal muscle, prenatal T excess decreased p-GSK3beta and GLUT4. The decrease in muscle p-GSK3beta was partially prevented by insulin sensitizer cotreatment. Both interventions partially prevented the decrease in GLUT4. Prenatal T treatment had no effect on basal expression of any of the markers in 2-yr-old females. At 3 yr of age, prenatal T treatment prevented the insulin-stimulated increase in p-AKT in liver and muscle, but not in adipose tissue, and neither postnatal intervention restored p-AKT response to insulin stimulation. Our findings provide evidence that prenatal T excess changes insulin sensitivity in a tissue- and development-specific manner and that both androgens and insulin may be involved in the programming of these metabolic disruptions.

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  • In experimental animals, excess androgen exposure in utero or in early neonatal life programmes the female offspring to have changes in adipose tissue biology.

    “As shown in Table 7, work in experimental animals has shown that excess androgen exposure in utero or in early neonatal life programmes the female offspring to have changes in adipose tissue biology [132–135].”

    From Developmental programming of offspring adipose tissue biology and obesity risk (2021) · cites this paper as [135]

    Results (Study 1; page unavailable) report altered mTOR markers in fetal adipose tissue after prenatal testosterone exposure, supporting a change in adipose biology. But the Discussion reports no change in adipose insulin sensitivity in fetal or three-year-old female sheep. This paper also does not study early neonatal androgen exposure, so it does not establish the claim across both exposure periods. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Lu, C., Cardoso, R. C., Puttabyatappa, M., & Padmanabhan, V.
Affiliations
University of Michigan (US)
Corresponding author
Padmanabhan, Vasantha
ORCID
Venue
Biology of Reproduction
Publisher
Oxford University Press (OUP)
Published
2016-05-01
Volume
94
Issue
5
Pages
113-113
ISSN
  • 0006-3363 (ISSN-L)
  • 1529-7268
DOI
10.1095/biolreprod.115.136283
PMC
PMC4939741
OpenAlex
W2315591776
Cited by
40
References
5
Citations by year
2026: 2 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 2 · 2021: 3 · 2020: 10 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 1
FWCI
4.65
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Biology of Reproduction (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • BioOne Complete (BioOne) (submittedVersion)
Funders
  • University of Michigan
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK020572)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD044232)
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
Keywords
developmental programming, insulin signaling, polycystic ovary syndrome, insulin resistance, androgen antagonists, flutamide, insulin sensitizers, rosiglitazone, mTOR, GSK3β, p70S6K, Akt, ERK, GLUT4, liver, skeletal muscle, adipose tissue, ewes, metabolic tissues
MeSH terms
Animals, Animals, Newborn, Disease Models, Animal, Female, Insulin, Polycystic Ovary Syndrome, Pregnancy, Prenatal Exposure Delayed Effects, Sheep, Testosterone, Signal Transduction, Embryonic Development, Oncogene Protein v-akt

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