Regulation of gastric hormones by systemic rapamycin

Abstract

The mammalian target of rapamycin (mTOR), an evolutionarily conserved serine-threonine kinase, is an intracellular fuel sensor critical for cellular energy homeostasis. Gastrointestinal endocrine cells play a vital role in the regulation of energy balance by secreting hormones that inform the brain about energy supply. Here we showed the localization of mTOR signaling molecules in more than 90 % of gastric ghrelin cells and 36 ± 3% of gastrin cells, while no somatostatin-positive cell showed phospho-S6K1 immunoreactivity. Inhibition of mTOR significantly stimulated expression of gastric ghrelin mRNA and protein, and the concentration of plasma ghrelin (2.06±0.34 vs. 12.53±3.9 ng/ml, p<0.05), inhibited gastrin synthesis and secretion (75.01±6.71 vs. 54.04±3.65 pg/ml, p<0.05), but had no effect on somatostatin production (165.2±25.07 vs. 178.9±29.14 pg/ml, p=0.73). Gastric mTOR is a gastric sensor whose activity is linked to the differential regulation of gastric hormone production and release.

Ghrelin, a Gastric Hormone with Diverse Functions

“…Our studies suggest that gastric mammalian target of rapamycin (mTOR) activity is critical for the modulation of ghrelin production (Xu et al, 2009;Xu et al, 2010).…”

Gastric mammalian target of rapamycin signaling, hormone production and energy metabolism

“…No mTOR activity is detected in somatostatin positive cells. Furthermore, inhibition of gastric mTOR signaling by rapamycin demonstrates no effect on the synthesis and secretion of somatostatin [20] . All of this evidence supports that mTOR signaling selectively modulates the production of gastric hormones.…”

“…A series of studies have identified mTOR as a potential candidate of fuel sensor in the gastric mucosa because of its expression in a distinct group of the gastric endocrine cells, its reciprocal relationship with energy status and its role in the regulation of gastric hormone production [1,5,20] .…”

“…The majority of the mTOR positive endocrine cells are ghrelin positive with a small fraction of cells stained positive for gastrin immunoreactivity. No mTOR signaling molecule is located within somatostatin immunoreactive cells [20] . These studies suggest that mTOR signaling may selectively influence the function of a subpopulation of gastric endocrine cells.…”

“…Gastric mTOR signaling may be involved in the regulation of gastrin synthesis and secretion in a proportion of gastric G cells. Only 1/3 of gastrin cells contain mTOR signaling molecules, suggesting that regulation of gastrin synthesis and secretion may involve multiple mechanisms [20] . Somatostatin: Somatostatin was originally isolated as a hypothalamic somatotropin-release inhibiting factor [49] and was soon found to potently inhibit the secretion of multiple hormones, including gastrin [50] .…”