Insulin and insulin-like growth factor-1 modulate the lipolytic action of growth hormone by altering signal pathway linkages

Abstract

Growth hormone (GH) has many actions in vertebrates, including the regulation of two disparate metabolic processes: growth promotion (anabolic) and the mobilization of stored lipids (catabolic). Our previous studies showed that GH stimulated IGF-1 production in hepatocytes from fed rainbow trout, but in cells from fasted fish GH stimulated lipolysis. In this study, we used rainbow trout (Oncorhynchus mykiss) to elucidate regulation of the mechanisms that enable cells to alter their lipolytic responsiveness to GH. In the first experiment, cells were removed from either fed or fasted fish, conditioned in medium containing serum (10%) from either fed or fasted fish, then challenged with GH. GH stimulated the expression of hormone sensitive lipase (HSL), the primary lipolytic enzyme, in cells from fasted fish conditioned with "fasted serum" but not in cells from fasted fish conditioned in "fed serum." Pretreatment of cells from fed fish with "fasted serum" resulted in GH-stimulated HSL expression, whereas GH-stimulated HSL expression in cells from fasted fish was blocked by conditioning in "fed serum." The nature of the conditioning serum governed the signaling pathways activated by GH irrespective of the nutritional state of the animals from which the cells were removed. When hepatocytes were pretreated with "fed serum," GH activated JAK2, STAT5, Akt, and ERK pathways; when cells were pretreated with "fasted serum," GH activated PKC and ERK. In the second study, we examined the direct effects of insulin (INS) and insulin-like growth factor (IGF-1), two nutritionally-regulated hormones, on GH-stimulated lipolysis and signal transduction in isolated hepatocytes. GH only stimulated HSL mRNA expression in cells from fasted fish. Pretreatment with INS and/or IGF-1 abolished this lipolytic response to GH. INS and/or IGF-1 augmented GH activation of JAK2 and STAT5 in cells from fed and fasted fish. However, INS and/or IGF-1 eliminated the ability of GH to activate PKC and ERK from fasted cells. These results indicate that INS and IGF-1 determine the signaling pathways activated by GH and whether or not a lipolytic response ensues. Such hormone-receptor-signal pathway linkages provide insight into the molecular basis of GH multifunctionality and into how cellular responses to GH can be adjusted to meet physiological (e.g., nutritional), developmental, or other conditions.

Social status regulates the hepatic miRNAome in rainbow trout: Implications for posttranscriptional regulation of metabolic pathways

“…Here, we report a significant increase in hepatic mRNA abundance of a paralogue of hormone sensitive lipase ( hsl ), providing further evidence for lipolytic activity in SS fish. In rainbow trout, hepatic hsl has been shown to be strongly regulated by nutritional and endocrine stimuli [41–42], and our finding of hsl upregulation in SS fish, which experience little or no food intake during social interactions, is consistent with data previously reported for hsl paralogues observed in trout in a comparable fasted state [41–42].…”

Update on the synergistic effect of HSL and insulin in the treatment of metabolic disorders

“…A recent study performed by Bergan-Roller and colleagues 38 provided novel insights into the various functions of growth hormone (GH) and helped clarify its lipolytic actions. The authors have confirmed that, during feeding, the growth-promoting actions of GH result from GH receptors (GHRs) linked to Akt/PI3K and JAK/STAT pathways that are activated by insulin and IGF-1.…”

Ultrasound measurement of fetal abdominal subcutaneous tissue thickness as a predictor of large versus small fetuses for gestational age

“…Fetal growth is a process of complex interactions between several maternal, fetal, and placental factor [1]. Proper fetal weight assessment leads to better management of high-risk pregnancies as fetal weight is an important determinant of neonatal survival [2].…”