Exendin-4 decreases ghrelin levels through mTOR signaling. (5th December 2016) - Hong, Xiaosi
Abstract: Exendin-4 (EX-4), a long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist, regulates feeding behavior through its ability to inhibit gastric emptying. Ghrelin, a gastric hormone, provides a hunger signal to the central nervous system to stimulate appetite. Here, we report that EX-4 suppresses ghrelin production through the mTORC1-dependent mechanism. Central administration of EX-4 reduces gastric, hypothalamic and plasma ghrelin in both C57BL/6J mice and diet induced obese mice. These changes were associated with a significant increase in mTORC1 activity. Both GLP-1 and EX-4 suppressed the expression and secretion of ghrelin in cultured mHypoE-42 cells, a hypothalamic cell line. These effects were associated with significant changes in mTOR signaling. Inhibition of mTORC1 activity by mTOR siRNA or rapamycin abolished the suppression of ghrelin production induced by GLP-1 and EX-4 in mHypoE-42 cells. Our results identify mTORC1 as a critical signaling pathway for the downregulation of ghrelin induced by activation of GLP-1R. Highlights: Exendin-4 attenuates ghrelin synthesis and secretion through mTOR signaling. Central EX-4 reduces ghrelin production in both lean and DIO C57BL/6J mice. GLP-1 and EX-4 suppress the expression and secretion of ghrelin in mHypoE-42 cells. Rapamycin and mTOR siRNA abolish the suppression of ghrelin by GLP-1 and EX-4.