Abstract
In mammals, insulin is known to modify growth hormone (GH)-induced IGF-I expression at the hepatic level, which also contributes to the functional crosstalk between energy homeostasis and somatotropic axis. However, the studies on the comparative aspects of this phenomenon are limited and the mechanisms involved have not been fully characterized. Using a serum-free culture of grass carp hepatoctyes, the functional interaction between GH and insulin on hepatic expression of IGF-I and -II was examined in a fish model. In carp hepatocytes, GH could up-regulate IGF-I and -II mRNA expression via the JAK2/STAT5, MEK/ERK and PI3K/Akt pathways. These stimulatory effects were mimicked by insulin via activation of the PI3K/Akt but not MEK/ERK and P38 MAPK cascades. Although insulin did not activate JAK2 and STAT5 at hepatocyte level, insulin-induced IGF-I and -II mRNA expression were highly dependent on the normal functioning of JAK2/STAT5 pathway. In parallel experiments, insulin co-treatment was found to markedly enhance IGF-I and -II responses induced by GH and these potentiating effects were mediated by insulin receptor (InsR) but not IGF-I receptor. Interestingly, co-treatment with GH also enhanced insulin-induced InsR phosphorylation with a current elevation in protein:protein interaction between GH receptor and phosphorylated InsR and these stimulatory effects were noted with further enhancement in STAT5, ERK1/2 and Akt phosphorylation at hepatocyte level. Consistent with these findings, the potentiating effects of GH and insulin co-treatment on IGF-I and -II mRNA expression were found to be suppressed/abolished by inhibiting JAK2/STAT5, MEK/ERK and PI3K/Akt but not P38 MAPK pathways. These results, as a whole, suggest that insulin and GH can act in a synergistic manner in the carp liver to up-regulate IGF-I and -II expression through protein:protein interaction at the receptor level followed by potentiation in post-receptor signaling.
Highlights
Growth hormone (GH) secreted from the pituitary is essential for body growth, metabolism and tissue maintenance/repairing
GH was shown to induce rapid phosphorylation of Janus kinase 2 (JAK2), Signal transducer and activator of transcription 5 (STAT5), Mitogen-activated protein kinase kinase 1/2 (MEK1/2), Extracellular signal-regulated kinase 1/2 (ERK1/2), P38 P38 Mitogenactivated protein kinase (MAPK), and Protein kinase B (Akt) in grass carp hepatocytes [27], suggesting that the JAK2/STAT5, MAPK and Phosphoinositide 3-kinase (PI3K)/Akt pathways may play a role in hepatic functions of GH in carp species
This idea is supported by the current study with the same cell model under a serumfree culture condition, in which GH-induced insulin-like growth factor (IGF)-I and -II mRNA expression could be negated by (i) inhibiting JAK2 and STAT5, (ii) blocking MEK1/2 and ERK1/2, and (iii) inactivating PI3K and Akt
Summary
Growth hormone (GH) secreted from the pituitary is essential for body growth, metabolism and tissue maintenance/repairing. These biological effects are mediated mainly by insulin-like growth factor (IGF) produced at the hepatic level, which forms the basis of the “somatomedin hypothesis” for GH action [1]. IGF-I and -II are readily detectable at the tissue level, especially in the liver [6], and unlike mammals, IGF-I and -II production/secretion at the hepatic level can be up-regulated by GH treatment, e.g., in tilapia [7] and salmon [8], which lend support to the idea that the two IGFs are both involved in the somatotropic actions of GH in fish species [9]. Gonadal expression of IGF-III is not affected by GH treatment, e.g., in tilapia [11], and its functional role in GH action/signaling is questionable
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