Abstract
Glucose homeostasis is an important biological process that involves a variety of regulatory mechanisms. This study aimed to determine whether ghrelin, a multifunctional gut-brain hormone, modulates intestinal glucose transport in goldfish (Carassius auratus). Three intestinal glucose transporters, the facilitative glucose transporter 2 (GLUT2), and the sodium/glucose co-transporters 1 (SGLT1) and 2 (SGLT2), were studied. Immunostaining of intestinal sections found colocalization of ghrelin and GLUT2 and SGLT2 in mucosal cells. Some cells containing GLUT2, SGLT1 and SGLT2 coexpressed the ghrelin/growth hormone secretagogue receptor 1a (GHS-R1a). Intraperitoneal glucose administration led to a significant increase in serum ghrelin levels, as well as an upregulation of intestinal preproghrelin, ghrelin O-acyltransferase and ghs-r1 expression. In vivo and in vitro ghrelin treatment caused a concentration- and time-dependent modulation (mainly stimulatory) of GLUT2, SGLT1 and SGLT2. These effects were abolished by the GHS-R1a antagonist [D-Lys3]-GHRP-6 and the phospholipase C inhibitor U73122, suggesting that ghrelin actions on glucose transporters are mediated by GHS-R1a via the PLC/PKC signaling pathway. Finally, ghrelin stimulated the translocation of GLUT2 into the plasma membrane of goldfish primary intestinal cells. Overall, data reported here indicate an important role for ghrelin in the modulation of glucoregulatory machinery and glucose homeostasis in fish.
Highlights
In fish, the mechanisms of carbohydrate absorption are believed to be very similar to those described in mammals
Quantification of immunoreactive cells demonstrated that glucose transporter 2 (GLUT2)-like cells are the most abundant (51.5%) of the three glucose transporters studied, followed by sodium/glucose co-transporters 1 (SGLT1)-like cells (30.8%) and SGLT2-like cells (17.7%) (Fig. 1d)
We observed the presence of GLUT2 in the basolateral border and of SGLT1 in the brush border of the mucosal cells, consistent with the putative location previously suggested for these two transporters within the fish enterocyte[48], and in agreement with the classical model of intestinal glucose absorption in mammals: SGLT1 mediates glucose absorption from the intestinal lumen, whereas GLUT2 provides basolateral exit[3,49]
Summary
The mechanisms of carbohydrate absorption are believed to be very similar to those described in mammals. Fish exhibit a wide range of natural feeding habits and consume herbivorous, carnivorous and omnivorous diets These diverse feed composition determine different capabilities of the intestinal uptake process, and different glucose absorption rates depending on the species[9,17,18,19]. The role of ghrelin in glucose metabolism, in mammals, is mainly associated with an elevation in blood glucose levels due to a decrease in insulin secretion, exerting an insulinostatic action[28,29]. Different subtypes of ghrelin receptors have been described in mammals and fish[36,37], among which GHS-R1a seems to be the one mediating most physiological functions of ghrelin[37,38,39] This receptor predominantly triggers the phospholipase C (PLC)/protein kinase C (PKC) and/or the adenylyl cyclase (AC)/protein kinase A (PKA) intracellular pathways for signal transduction[39,40,41]. Other molecular pathways, including the AMP-activated protein kinase (AMPK)[42], the mitogen-activated protein kinase (MAPK)[43,44] and the mechanistic target of rapamycin (mTOR)[45] pathways, have been associated to actions mediated by GHS-R1a
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