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

SOTELO AI; MARTINEZ CS; MIQUET JG; PIAZZA VG; RATNER LD; RULLI S; GONZÁLEZ L; TURYN D

Houston

Congreso; The Endocrine Society?s 94th Annual Meeting & Expo; 2012

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 GH-induced 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 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 levels gradually increased to achieve 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 that 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.