Abstract
BackgroundGhrelin modulates many physiological processes. However, the effects of intestinal ghrelin on hepatic glucose production (HGP) are still unclear. The current study was to explore the roles of intestinal ghrelin on glucose homeostasis and insulin signaling in the liver.MethodsThe system of intraduodenal infusion and intracerebral microinfusion into the nucleus of the solitary tract (NTS) in the normal chow-diet rats and pancreatic-euglycemic clamp procedure (PEC) combined with [3-3H] glucose as a tracer were used to analyze the effect of intestinal ghrelin. Intraduodenal co-infusion of ghrelin, tetracaine and Activated Protein Kinase (AMPK) activator (AICAR), or pharmacologic and molecular inhibitor of N-methyl-D-aspartate receptors within the dorsal vagal complex, or hepatic vagotomy in rats were used to explore the possible mechanism of the effect of intestinal ghrelin on HGP.ResultsOur results demonstrated that gut infusion of ghrelin inhibited duodenal AMP-dependent protein kinase (AMPK) signal pathways, increased HGP and expression of gluconeogenic enzymes, and decreased insulin signaling in the liver of the rat. Intraduodenal co-infusion of ghrelin receptor antagonist [D-Lys3]-GHRP-6 and AMPK agonist with ghrelin diminished gut ghrelin-induced increase in HGP and decrease in glucose infusion rate (GIR) and hepatic insulin signaling. The effects of gut ghrelin were also negated by co-infusion with tetracaine, or MK801, an N-methyl-D-aspartate (NMDA) receptor inhibitor, and adenovirus expressing the shRNA of NR1 subunit of NMDA receptors (Ad-shNR1) within the dorsal vagal complex, and hepatic vagotomy in rats. When ghrelin and lipids were co-infused into the duodenum, the roles of gut lipids in increasing the rate of glucose infusion (GIR) and lowering HGP were reversed.ConclusionsThe current study provided evidence that intestinal ghrelin has an effect on HGP and identified a neural glucoregulatory function of gut ghrelin signaling.
Highlights
Duodenal ghrelin increases hepatic glucose production To examine whether growth hormone secretagogue receptor 1a (GHS-R1a) was expressed in the duodenum, GHS-R1a immunoreactivity was performed in the duodenum tissue of rat
To investigate whether gut ghrelin can regulate hepatic glucose production (HGP) (Fig. 1c), we activated gut ghrelin signaling via direct intraduodenal ghrelin infusion in vivo
We infused ghrelin (0, 5, 25, 50 pmol/kg/min) into the duodenum of rat and the glucose infusion rate (GIR) demonstrated a dose-dependent decrease during pancreatic-euglycemic clamp (PEC) (Fig. 1e)
Summary
The current study was to explore the roles of intestinal ghrelin on glucose homeostasis and insulin signaling in the liver. It is well established that nutrients can stimulate the release of gut hormones, such as cholecystokinin and glucagon-like-peptide, which are involved in the modulation of feeding and gastrointestinal function [1,2,3]. Ghrelin is a 28-amino acid peptide originally identified in human and rat stomachs as an endogenous natural ligand of growth hormone secretagogue receptor 1a (GHS-R1a). It is produced in X/A-like cells of oxyntic mucosa [6]. We have investigated the roles of gut ghrelin to modulate HGP via a neuronal network
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