Growth hormone (GH)-induced STAT5-mediated signaling in liver of growing mice

SOTELO ANA I, MARTINEZ CAROLINA S, MIQUET JOHANNA G, PIAZZA VERÓNICA G, RATNER LAURA D, RULLI SUSANA, GONZÁLEZ LORENA, TURYN DANIEL

Houston

Congreso; 94th Annual Meeting of The Endocrine Society; 2012

The Endocrine Society

 Growth hormone (GH) is the principal endocrine regulator of postnatal body growth. Signal transducer and activator of transcription 5b (STAT5b) is the main GH-signaling mediator, related to IGF1 synthesis and somatic growth. Glucocorticoid receptor (GR) and hepatocyte nuclear factor 1 (HNF1) are STAT5 coactivators, whereas suppressors of cytokine signaling (SOCS-2,-3 and CIS) and phospho-tyrosine phosphatases (PTP-1B, SHP1 and SHP2) contribute to signaling termination. Rodents exhibit two instances of rapid postnatal growth: the first is perinatal and independent of growth hormone (GH), the second takes place around weaning and is controlled by GH. The objective of the present study was to assess differential sensitivity to growth hormone during the growth period. For that purpose, GH-induced STAT5 signaling and the ontogeny of modulators that regulate this pathway were determined in the liver of growing mice. Three representative ages were chosen: 1 week animals in the GH-independent phase of growth-, 2.5 week mice at the onset of the GH-dependent phase of growth-, and 9 week young adults, used as reference. Since GH secretion is sexually dimorphic, both genders were analyzed in parallel. Animals received an ip GH bolus (1µg/g BW) or saline and were sacrificied 7.5 min later. Liver protein content was assessed by immunoblotting and by immunohistochemistry. One week old animals presented low GH-induced STAT5 phosphorylation, associated with lower hepatic receptor content and with high levels of the signaling suppressor CIS and phosphatase PTP-1B, whereas the abundance of glucocorticoid receptor and HNF-1 was low. Maximal GH-induced STAT5 activation was found for 2.5 week animals, which could be related with higher STAT5 protein levels at that age, and with an age-dependent decline of CIS and PTP-1B. On the other hand, SOCS2 and SOCS3 achieved higher levels in the 9 week control than at earlier ages. GR and HNF1 also exhibited a maximum at adulthood, while phosphatases SHP1 and 2 did not present any age variation. Although GH secretion is sexually dimorphic, no gender difference was observed for the proteins studied. We conclude GH-induced STAT5 signaling presents age-dependent activity in the liver of growing mice, with its maximum coinciding with the onset of the GH-dependent phase of growth, accompanied by age-related changes in the pathway modulators.