| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2005: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Research Abstract |
Ghrelin, an appetite-promoting peptide secreted from the stomach, is reported to enhance the pre-prandial acid output possibly through the stimulation of cephalic phase, and is also supposed to be affected by parasympathetic, presumably muscarinic signaling. Among five subtypes (M_1-M_5) of muscarinic acetylcholine receptors, M_3 is known to be expressed on the surface of parietal cells, which are located in the vicinity of the ghrelin-producing A-like cells. The present study was designed to clarify the dynamics of the ghrelin in mice with genetically knockout (KO) of H_2 receptor (H_2R) or M_3 receptor (M_3R) on the basolateral membrane of the parietal cell. Methods. Fifteen-and 54-week-old H_2R-KO mice and 25-week-old M_3R KO mice were compared with their littermates. After evaluating the levels of food intakes and body weight increment, mice were sacrificed to examine the plasma active and total ghrelin levels, gastric active and total ghrelin levels by RIA, and the gastric preprog
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hrelin mRNA expression by quantitative RT-PCR. Furthermore, some stomach specimens were evaluated by immunohistochemistry and transmission electron microscopy for ghrelin. Results. The levels of food intakes and body weight gain of the H_2R-K0 mice were higher than those of wild type mice. The gastric pH in the 54-week-old H_2R-K0 mice was lower than those of 15-week-old mice. Gastric preproghrelin mRNA expression, plasma ghrelin level and percentage of ghrelin-immunoreactive cells in the gastric mucosa of the H_2R-K0 mice were significantly increased as compared with those of wild types. Ghrelin-positive immunogold density in the electron micrograph was significantly reduced in A-like cells of H_2R-KO mouse stomach. On the other hand, although body weight of M_3R KO mice was significantly decreased, which possibly reflected its malnutrition, their plasma ghrelin levels and numbers of ghrelin-immunoreactive cells in the gastric mucosa were not significantly elevated as compared with those of wild type mice. On the other hand, preproghrelin mRNA expression and gastric ghrelin contents were significantly increased in M_3R-KO mice as compared with those of wild types. Conclusion. While ghrelin production and secretion from A-like cells in the gastric fundus are upregulated in mice with genetically H_2R-KO as a compensatory mechanism for H_2R blockade, only the ghrelin production, not but its secretion from A-like cells, are upregulated in mice with M_3R-KO. These results suggest that H_2R blockade affects the ghrelin dynamics through the inhibition of acid secretion and that M_3R plays an important and direct role for ghrelin secretion from A-like cells of the stomach. Less
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