Exendin-4 Inhibits the Secretion of Ghrelin from Primary Culture of Rat Gastric Mucosal Cells

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 824-833-GI Regulatory Peptides
Bench to Bedside
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-826
Jeffrey Dennis Gagnon*1 and Younes Anini2
1Dalhousie University, Halifax, NS, Canada, 2Dalhousie Univ
Ghrelin is an appetite stimulating, stomach derived peptide hormone. Ghrelin administration in both humans and rodents causes hyperphagia and increases adiposity. Furthermore, ghrelin inhibits glucose-stimulated insulin release. In contrast, the intestinal derived glucagon-like peptide-1 (GLP-1) potentiates glucose-induced insulin secretion. On this basis, degradation resistant GLP-1 analogues like exendin-4 (Ex-4) are being used for the treatment of type 2 diabetes. Interestingly, Ex4 has also been demonstrated to reduce the levels of circulating ghrelin in humans. The goal of the present study was to elucidate if Ex-4 can modulate ghrelin secretion by acting directly on stomach ghrelin cells, and if so, through what cellular mechanisms. To achieve this, we used our recently developed rat primary stomach cell culture system which was shown to secrete ghrelin in a regulated manner. Primary stomach mucosal cells were harvested from 8 day old mixed gender pups using enzymatic disassociation. Ex-4 (10nM) significantly reduced 4 hour ghrelin secretion to 60% of control (p<0.05). Ex-4 (10 nM) treatment also resulted in an increase in phosphorylated AKT. Furthermore, the inhibitory effect of Ex-4 on ghrelin secretion was blocked by the phosphoinositide 3-kinase (PI3K) inhibitor wortmannin. These results provide direct evidence that Ex-4 suppresses ghrelin release from the stomach through the activation of the PI3K / AKT pathway. They also further support how Ex-4 treatment, in addition to the incretin effects on the β cells of the pancreas, may reduce appetite and body weight.

1. Gagnon J, Anini Y. Glucagon Stimulates Ghrelin Secretion Through the Activation of MAPK and EPAC and Potentiates the Effect of Norepinephrine. Endocrinology. 2013 Jan 10. [Epub ahead of print] 2. Gagnon J, Sheppard E and Anini Y. Metformin Directly Inhibits Ghrelin Secretion Through AMP-Activated Protein Kinase in Rat Primary Gastric Cells. Diabetes Obes Metab. 2012 Oct 5. doi: 10.1111/dom.12021. [Epub ahead of print]   3.  Gagnon J and Anini Y. Insulin and Norepinephrine Directly Regulate Ghrelin Secretion from a Rat Primary Stomach Cell Culture. Endocrinology 2012. 153:3646-56.

Nothing to Disclose: JDG, YA

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Dr. Anini’s laboratory is supported by grants from the Canadian Institutes of Health Research (MOP-82795), Canada foundation for innovation and the IWK Research Foundation. J. G. was supported by studentships from the Natural Sciences and Engineering Research Council, the Nova Scotia Heart and Stroke foundation and the IWK Research Foundation.