Ghrelin, a gastric hormone, provides a hunger signal to the central nervous system to stimulate food intake. Mammalian target of rapamycin (mTOR) is an intracellular fuel sensor critical for cellular energy homeostasis. Here we showed the reciprocal relationship of gastric mTOR signaling and ghrelin during changes in energy status. mTOR activity was down-regulated, whereas gastric preproghrelin and circulating ghrelin were increased by fasting. In db/db mice, gastric mTOR signaling was enhanced, whereas gastric preproghrelin and circulating ghrelin were decreased. Inhibition of the gastric mTOR signaling by rapamycin stimulated the expression of gastric preproghrelin and ghrelin mRNA and increased plasma ghrelin in both wild-type and db/db mice. Activation of the gastric mTOR signaling by l-leucine decreased the expression of gastric preproghrelin and the level of plasma ghrelin. Overexpression of mTOR attenuated ghrelin promoter activity, whereas inhibition of mTOR activity by overexpression of TSC1 or TSC2 increased its activity. Ghrelin receptor antagonist d-Lys-3-GH-releasing peptide-6 abolished the rapamycin-induced increment in food intake despite that plasma ghrelin remained elevated. mTOR is therefore a gastric fuel sensor whose activity is linked to the regulation of energy intake through ghrelin.

Ghrelin, a 28 amino acid gut brain peptide, acts as an endogenous ligand for its receptor, the growth hormone secretagogue receptor, to exercise a variety of functions ranging from stimulation of growth hormone secretion, regulation of appetite and energy metabolism, and cell protection to modulation of inflammation. This review summarizes the advance in the regulation of ghrelin expression and secretion. We introduce the structure of ghrelin promoter, the processing and modification of ghrelin precursor, and the regulation mechanism in these processes. Then we discuss factors found to be important in the regulation of ghrelin production, including nutrients, hormones, and autonomic nervous system. Finally, we outline the alteration in the level of ghrelin in certain physiological and pathological status.

Background: Ghrelin, the only identified circulating orexigenic signal, is unique in structure in which a specific acyl-modification of its third serine occurs. This acylation is necessary for ghrelin to bind to its receptor and to exert its biologic activity, which is catalyzed by ghrelin O-acyltransferase (GOAT). Although ghrelin is mainly secreted from gastric X/A like endocrine cells, it is also expressed in pancreatic islet cells and regulates insulin secretion. In this study, we examined the expression and regulation of GOAT in pancreas. Methods: GOAT mRNA and immunoreactivity were examined in pancreatic islets and INS-1 cells by RT-PCR and immunofluorescent staining or Western blotting. Results: Insulin inhibits the expression of GOAT mRNA and GOAT promoter activity in a dose and time-dependent manner. The mammalian target of rapamycin (mTOR) is activated by insulin. Blocking mTOR signaling by either rapamycin or overexpression of its negative regulator tuberous sclerosis complex 1 (TSC1) or TSC2 attenuates the inhibitory effect of insulin on the transcription and translation of GOAT. Conclusion: Our study suggests that GOAT is present in pancreatic islet cells and that insulin inhibits the expression of GOAT via the mediation of mTOR signaling.

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.

It has been shown that angiotensin II (Ang II) is involved in cardiac remodeling mediated by NADPH oxidase-dependent reactive oxygen species (ROS). Accordingly, NADPH oxidase-dependent ROS may play a role in cardiac hypertrophy induced by pressure overload. In the present study, we sought to determine whether inhibition of NADPH oxidase prevents cardiac hypertrophy. After abdominal aorta banding to induce cardiac hypertrophy, rats were treated for 8 weeks with apocynin (Apo) or captopril (Cap). Measures of cardiac hypertrophy were evaluated. Treatment with Cap or Apo reduced the left ventricle/body weight ratio (LV/BW), LV transnuclear myocyte diameter, and atrial natriuretic factor (ANF) mRNA expression relative to those of untreated rats subjected to aorta banding. The activity of NADPH oxidase and the ROS levels were decreased in treated animals. Cap, but not Apo, decreased Ang II levels and inhibited expression of p22phox and p67phox in LVs. In conclusion, local expression of Ang II appears to contribute to pressure overload-induced cardiac hypertrophy by upregulating NADPH oxidase expression and promoting ROS synthesis. Inhibition of NADPH oxidase and elimination of ROS may prevent or repair damage due to cardiac hypertrophy.