Gut ghrelin regulates hepatic glucose production and insulin signaling via a gut-brain-liver pathway

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.Electronic supplementary materialThe online version of this article (10.1186/s12964-019-0321-y) contains supplementary material, which is available to authorized users.

Elevated chemerin induces insulin resistance in human granulosa‐lutein cells from polycystic ovary syndrome patients

“…The phosphorylation of IRS1 at Ser307 site has been shown to impair insulin signaling (12,13), which was reported as one of the major postreceptor factors involved in IR in skin fibroblasts and skeletal muscle cells from patients with PCOS (3,9,32). The phosphorylation of IR-b Tyr1150/115, the phosphorylation of IRS1/2 Tyr612, and the phosphorylation of Akt Ser473 were important insulin signaling molecules (33)(34)(35)(36)(37). Here, we found that the insulin-induced Ser307 19).…”

Mechanisms controlling hormone secretion in human gut and its relevance to metabolism

“…2012). Perhaps the most well-known of the gut-derived hormones released during fasting is ghrelin, with intraduodenal infusion increasing hepatic glucose production via GSH-R1a receptors on vagal afferents signalling to the NTS (Lin et al . 2019).…”

Activation of N-methyl-D-aspartate receptor regulates insulin sensitivity and lipid metabolism

“…It has been reported that gut infusion of ghrelin inhibited increased hepatic glucose production and expression of gluconeogenic enzymes and decreased insulin signaling in the rat liver. Co-infusion with the NMDAR inhibitor negated gut ghrelin effects within the dorsal vagal complex 53 . However, further studies are required to assess whether NMDA-induced insulin resistance is dependent on the activation of NMDAR in the liver.…”