Ghrelin plays key roles in energy homeostasis by central and peripheral actions that include effects on insulin signalling pathways in liver. Insulin is an important inhibitor of production by hepatocytes of insulin-like growth factor-binding protein-1 (IGFBP-1) which has an endocrine role to inhibit IGF availability. The effects of ghrelin, insulin, an AMPK activator, and an AMPK inhibitor on IGFBP-1 secretion were studied in H4-II-E rat liver cells. Ghrelin (100？nM) blocked the inhibitory effect of a maximally effective concentration of insulin (10？ng/mL) on IGFBP-1 secretion during a 5？h incubation period ( ) in the absence and presence of an AMPK inhibitor. Ghrelin, alone, had no effect on IGFBP-1 production, but enhanced secretion independently of insulin under conditions of AMPK activation ( ). In conclusion, IGFBP-1 is identified as a novel target of ghrelin action in liver that may contribute to its metabolic effects in obesity. 1. Introduction Insulin-like growth factor-binding protein-1 (IGFBP-1) is a member of a family of six IGFBPs, which have effects on cell metabolism, motility, growth, and survival via IGF-dependent and -independent mechanisms [1]. Liver is the most important source of IGFBP-1 in the human circulation and hepatic Igfbp1 transcription is inhibited by the action of portal insulin [2]. As a consequence, there is an inverse relationship between circulating insulin and IGFBP-1 concentrations [2, 3]. This relationship is preserved in obesity [4]. In adults with type 2 diabetes, however, there is an upward shift in the regression line so that IGFBP-1 levels are higher than expected for a given insulin concentration [3]. This is consistent with a decrease in hepatic insulin sensitivity or a reduction in hepatic insulin extraction [3], or an increase in factors that stimulate IGFBP-1 directly, including pro-inflammatory cytokines [5]. Although IGFBP-1 levels in simple obesity are appropriately low for the prevailing hyperinsulinemia, in patients with obesity due to the Prader-Willi syndrome, IGFBP-1 concentrations are not suppressed [6]. Interestingly, circulating levels of the gut peptide ghrelin are also elevated in this syndrome [7, 8], whilst they are low in simple obesity [9, 10]. Like IGFBP-1 [11], ghrelin has a glucose counter-regulatory role [12]. Ghrelin is essential for blood glucose control in starvation [13, 14]. These metabolic effects are mediated in part by a central stimulatory effect of ghrelin on appetite and GH release and in part by peripheral actions on insulin secretion and insulin sensitivity, and hepatic
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