Activation of mTORC1 signaling in gastric X/A-like cells induces spontaneous pancreatic fibrosis and derangement of glucose metabolism by reducing ghrelin production

Abstract

BackgroundPancreatic fibrosis is a pathophysiological process associated with excessive deposition of extracellular matrix in pancreas, leading to reduced insulin secretion and derangement of glucose metabolism. X/A-like cells, a group of unique endocrine cells in gastric oxyntic mucosa, produce and secret ghrelin to influence energy balance. Whether gastric X/A-like cells affect pancreatic fibrosis and subsequent glucose homeostasis remains unclear.MethodsWe established a Ghrl-cre transgene in which the cre enzyme is expressed in X/A-like cells under the control of ghrelin-promoter. TSC1flox/flox mice were bred with Ghrl-cre mice to generate Ghrl-TSC1−/− (TG) mice, within which mTORC1 signaling was activated in X/A-like cells. Pancreatic fibrosis and insulin secretion were analyzed in the TG mice.FindingsActivation of mTORC1 signaling by deletion of TSC1 gene in gastric X/A-like cells induced spontaneous pancreatic fibrosis. This alteration was associated with reduced insulin expression and secretion, as well as impaired glucose metabolism. Activation of mTORC1 signaling in gastric X/A-like cells reduced gastric and circulating ghrelin levels. Exogenous ghrelin reversed pancreatic fibrosis and glucose intolerance induced by activation of mTORC1 signaling in these cells. Rapamycin, an inhibitor of mTOR, reversed the decrease of ghrelin levels and pancreatic fibrosis.InterpretationActivation of mTORC1 signaling in gastric X/A-like cells induces spontaneous pancreatic fibrosis and subsequently impairs glucose homeostasis via suppression of ghrelin.

mTOR Pathway is Involved in Energy Homeostasis Regulation as a Part of the Gut–Brain Axis

“…These findings are supported by several in vitro studies showing that mTOR signaling is activated in the presence of increased intracellular ATP levels [ 52 ]. In pathological states, increased activity of the mTOR signaling has been associated with obesity [ 39 ] and, accordingly, the knockout mice for the mTOR downstream S6kinase 1 are protected against diet-induced obesity [ 53 ].…”

“…It was reported that the components of the mTOR pathway are expressed in different endocrine cells, including X/A-like cells and with lower expression in G cells [ 54 ]. Specifically, in X/A-like cells, one of the most abundant types of gastric endocrine cells, the mTOR pathway is involved in the secretion of different gastrokines with a relevant role in metabolism regulation such as ghrelin and nesfatin-1 [ 53 ]. Consequently, this pathway has been proposed as a component of the gut–brain axis by modulating the gastric production of different stomach-derived signals involved in energy homeostasis [ 49 , 50 , 51 ].…”

“…In fact, pancreatic fibrosis and insulin intolerance are reversed after replacement of ghrelin by exogenous administration. In the same way, by administering rapamycin, which inhibits mTORC1, it was possible to reverse the decreased ghrelin levels and pancreatic fibrosis [ 53 ].…”

“…To highlight the importance of decreased ghrelin production in the mice after mTOR activation in X/A, this effect was reverted after administration of ghrelin exogenously to the mice. This treatment reversed the circulating low levels of acyl ghrelin described in the animal model, together with an increase in food intake, which indicates that the activation of mTOR in X/A induces a decrease in food intake that is mediated by the reduction in gastric ghrelin production [ 53 ]. This finding is supported by previous articles showing the gastric mechanism regulating appetite and body weight, led by the interaction between ghrelin and mTOR [ 25 , 50 ].…”

A Novel Stomach-Pancreas Connection: More than Physical

“…Interestingly, although the stomach and pancreas are physically connected and share common autonomic innervations, very few humoral mechanisms have been described by which the stomach impacts the exocrine pancreas. It is thus noteworthy that Yu et al [ 1 ], as reported in EBioMedicine , have identified a novel gastric-pancreas humoral axis active in health.…”