Growth hormone action in hypothyroid infant rats
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Published on: October 6, 2023
J T Humbert1, P L Bergad, O Masha
1Department of Pediatrics, University of Minnesota, Minneapolis 55455, USA.
Insights
Growth hormone (GH) is inactive in 2-day-old rats but becomes active by day 7, coinciding with increased GH receptor and Stat5. This study reveals a critical developmental window for GH action in neonatal rats.
Area of Science:
- Endocrinology
- Developmental Biology
- Molecular Biology
Background:
- Serine protease inhibitors (SPIs) 2.1 and 2.3 mRNA expression peaks early in neonatal rats, coinciding with circulating growth hormone (GH) levels.
- The role of GH in perinatal life and its developmental regulation remain incompletely understood.
Purpose of the Study:
- To investigate the role of GH in SPI mRNA induction during early neonatal development.
- To test the hypothesis that GH is active in perinatal life and to identify factors contributing to developmental changes in GH sensitivity.
Main Methods:
- A rat model of GH deficiency was induced via maternal/neonatal hypothyroidism using methimazole.
- Hypothyroid neonates were treated with GH or saline at postnatal days 2 or 7.
- SPI 2.1 and 2.3 mRNA levels, GH receptor, IGF-I mRNA, and signal transducer and activator of transcription 5 (Stat5) nuclear abundance were analyzed.
Main Results:
- GH administration induced SPI 2.1 and 2.3 mRNA in 7-day-old neonates but not in 2-day-old neonates.
- GH treatment did not increase GH receptor or IGF-I mRNA; however, a slight GH-independent increase in these was observed by day 7.
- Electromobility shift assays and immunoblotting demonstrated GH-dependent Stat5 binding and increased nuclear Stat5 abundance in 7-day-old neonates compared to 2-day-old neonates.
Conclusions:
- Neonatal rats exhibit apparent insensitivity to GH at day 2 of life, which resolves by day 7.
- This developmental remission of GH insensitivity correlates with increased GH receptor and nuclear Stat5 abundance, suggesting a critical window for GH action during early development.
Abstract:
In neonatal rats, expression of serine protease inhibitors 2.1 and 2.3 mRNA peaks on d 2 of life and declines shortly thereafter, coinciding with levels of circulating GH. To evaluate the role of GH in this increase and to test the hypothesis that GH is active in perinatal life, we studied GH action in a model of GH deficiency. Maternal/neonatal hypothyroidism with consequent GH deficiency was induced by methimazole administration to pregnant dams. The resultant hypothyroid neonates were treated at d 2 or 7 of age with GH or saline for 1 h before exsanguination. In d-7 neonates, but not at d 2, GH administration resulted in significant serine protease inhibitors 2.1 and 2.3 mRNA induction. This treatment did not result in increased production of either GH receptor or IGF-I mRNA at either age. There was a slight GH-independent increase in GH receptor and IGF-I mRNA expression by d 7. Electromobility shift assays using hepatic nuclear extracts from these neonates and the GH response element from the serine protease inhibitor 2.1 promoter showed signal transducer and activator of transcription 5 (Stat5) binding in response to GH in extracts from d-7 rats only. Immunoblots of these extracts showed twice as much Stat5 in the nuclei of d-7 treated neonates compared with d-2 treated neonates. We conclude that there is apparent insensitivity to GH treatment in d-2 neonates that remits by d 7 and that this remission correlates with increased abundance of GH receptor and Stat5.
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