Little or No Expression of the Cholecystokinin-A Receptor Gene in the Pancreas of Diabetic Rats (Otsuka Long-Evans Tokushima Fatty=OLETF Rats)

Funakoshi, Akihiro; Miyasaka, Kyoko; Jimi, Atsuo; Kawanai, Takuya; Takata, Yutaka; Kono, Akira

doi:10.1006/bbrc.1994.1254

Cited by 94 publications

(54 citation statements)

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“…In studies of mice deficient in endothelin and its receptor, newborn mutants died with a failure of the normal development of several neural crest-derived cell lineages, indicating that the physiological roles of the mitogenic activity in adults are poorly understood (38,39). Although the diabetic rat OLEFT congenitally lacks CCK-A receptors, the pathophysiological significance of the mitogenic effect of the CCK-A receptor has not been reported (40 (47,48). Thus, the decreased mature parietal cells in CCKBR'1-mice might also affect the growth of other cell types in the gastric mucosa.…”

Section: Discussionmentioning

confidence: 99%

G protein-coupled cholecystokinin-B/gastrin receptors are responsible for physiological cell growth of the stomach mucosa in vivo.

Nagata

Ito

Iwata

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

213

160

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Many peptide hormone and neurotransmitter receptors belonging to the seven membrane-spanning G protein-coupled receptor family have been shown to transmit ligand-dependent mitogenic signals in vitro. However, the physiological roles of the mitogenic activity through G protein-coupled receptors in vivo remain to be elucidated. Here we have generated G protein-coupled cholecystokinin (CCK)-B/ gastrin receptor deficient-mice by gene targeting. The homozygous mice showed a remarkable atrophy of the gastric mucosa macroscopically, even in the presence of severe hypergastrinemia. The atrophy was due to a decrease in parietal cells and chromogranin A-positive enterochromaffin-like cells expressing the H+,K+-ATPase and histidine decarboxylase genes, respectively. Oral administration of a proton pump inhibitor, omeprazole, which induced hypertrophy of the gastric mucosa with hypergastrinemia in wild-type littermates, did not eliminate the gastric atrophy of the homozygotes. These results clearly demonstrated that the G protein-coupled CCK-B/gastrin receptor is essential for the physiological as well as pathological proliferation of gastric mucosal cells in vivo.Cell proliferation and differentiation are regulated by a wide array of factors such as growth factors, cytokines, and hormones (1). Several peptide hormones such as bombesin/ gastrin-releasing peptide, angiotensin, and endothelin, and neurotransmitters such as serotonin and adrenaline have been shown to stimulate cell proliferation through their own seventransmembrane, heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors in vitro (2-5). Certain serotonin, acetylcholine, or adrenergic receptor subtypes were reported not only to stimulate cell proliferation but also to transform 3T3 fibroblasts in a ligand-dependent manner as do growth factor receptors (3-5). Very recently, G proteincoupled receptors have also been shown to involve tyrosine kinases and the Ras-mitogen-activating protein kinase pathway in their intracellular signaling as do growth factor and cytokine receptors (6-9). Although some peptides could promote the proliferation of a variety of human tumor cell lines in vivo as well as in vitro (10,11), the physiological significance of the mitogenic activity through the G protein-coupled receptor superfamily remains to be clarified.The peptide hormone, gastrin, is well characterized as a stimulant of gastric acid secretion. In addition, there is circumstantial evidence that gastrin presumably functions as a trophic factor for the gastrointestinal tissues (11, 12). Another peptide hormone, cholecystokinin (CCK), is also isolated as a stimulant of enzyme secretion by the pancreas (13). Because of the abundant expression of CCK in the central nervous system as well as in digestive organs, this hormone is also thought to act as a neurotransmitter or modulator in the brain (14). Moreover, the specific receptors for CCK and/or gastrin have been pharmacologically shown to be expressed in various human tumor cells and to stimulat...

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Section: Discussionmentioning

confidence: 99%

G protein-coupled cholecystokinin-B/gastrin receptors are responsible for physiological cell growth of the stomach mucosa in vivo.

Nagata

Ito

Iwata

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

213

160

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“…Little or no expression of CCK-1 receptor mRNA could be detected in the pancreas of OLETF rats by Northern blot using total RNA (Funakoshi et al 1994), RT-PCR or southern blot hybridization (Funakoshi et al 1995). These results were specific to CCK-1 receptor expression, because CCK-2 receptor expression was shown to be normal in OLETF rats.…”

Section: Oletf Ratsmentioning

confidence: 92%

Hyperphagia and obesity in OLETF rats lacking CCK-1 receptors

Moran

2006

Phil. Trans. R. Soc. B

113

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The brain-gut peptide cholecystokinin (CCK) inhibits food intake following peripheral or site directed central administration. Peripheral exogenous CCK inhibits food intake by reducing the size and duration of a meal. Antagonist studies have demonstrated that the actions of the exogenous peptide mimic those of endogenous CCK. Antagonist administration results in increased meal size and meal duration. The feeding inhibitory actions of CCK are mediated through interactions with CCK-1 receptors. The recent identification of the Otsuka-Long-Evans-Tokushima Fatty (OLETF) rat as a spontaneous CCK-1 receptor knockout model has allowed a more comprehensive evaluation of the feeding actions of CCK. OLETF rats become obese and develop non-insulin dependent diabetes mellitus (NIDDM). Consistent with the absence of CCK-1 receptors, OLETF rats do not respond to exogenous CCK. OLETF rats are hyperphagic and their increased food intake is characterized by a large increase in meal size with a decrease in meal frequency that is not sufficient to compensate for the meal size increase. Deficits in meal size control are evident in OLETF rats as young as 2 days of age. OLETF obesity is secondary to the increased food intake. Pair feeding to amounts consumed by intact control rats normalizes body weight, body fat and elevated insulin and glucose levels. Hypothalamic arcuate nucleus peptide mRNA expression in OLETF rats is appropriate to their obesity and is normalized by pair feeding. In contrast, pair fed and young pre-obese OLETF rats have greatly elevated dorsomedial hypothalamic (DMH) neuropeptide Y (NPY) mRNA expression. Elevated DMH NPY in OLETF rats appears to be a consequence of the absence of CCK-1 receptors. In intact rats NPY and CCK-1 receptors colocalize to neurons within the compact subregion of the DMH and local CCK administration reduces food intake and decreases DMH NPY mRNA expression. We have proposed that the absence of DMH CCK-1 receptors significantly contributes to the OLETF's inability to compensate for their meal size control deficit leading to their overall hyperphagia. Access to a running wheel and the resulting exercise normalizes food intake and body weight in OLETF rats. When given access to running wheels for 6 weeks shortly after weaning, OLETF rats do not gain weight to the same degree as sedentary OLETF rats and do not develop NIDDM. Exercise also prevents elevated levels of DMH NPY mRNA expression, suggesting that exercise exerts an alternative, non-CCK mediated, control on DMH NPY. The OLETF rat is a valuable model for characterizing actions of CCK in energy balance and has provided novel insights into interactions between exercise and food intake.

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“…Hybridization was performed at 42°C for 20 h in 50% formamide, ϫ5 standard saline citrate (SSC), 20 mmol/l sodium phosphate buffer (pH 6.5), 0.2% SDS, ϫ2 Denhardts solution, 5% dextran sulfate and 200 g/ml denatured salmon sperm DNA. After hybridization, the filters were washed with decreasing concentrations of SSC to a final concentration of ϫ0.1 SSC with 0.1% SDS at 65°C, and then autoradiographed [2]. Autoradiograms were analyzed with a computer scanner (Sharp JX-32F3, Sharp Electric Co., Osaka) and an NIH image program on a Macintosh computer (Apple Computer Inc., CA).…”

Section: Materials and Chemicals Silastic Medicalmentioning

confidence: 99%

“…In an original report by Kawano et al (1992) [1], rats were divided to three groups after an oral glucose tolerance test (OGTT) was conducted. Glucose (2 g/kg) solution was given orally, and plasma levels of glucose were measured before and 30, 60, 90, and 120 min later: (1) diabetic rats had a peak plasma glucose level of Ͼ16.8 mM and a level of plasma glucose at 120 min Ͼ11.2 mM-only rats that showed both conditions by OGTT were diagnosed with clinical DM; (2) in that either one of the two conditions observed was diagnosed with impaired glucose tolerance (IGT); and (3) normal type, where neither DM nor IGT was present. The characteristic features of OLETF rats are late onset of hyperglycemia at about 18 weeks of age, followed by insulin deficiency at about 65 weeks of age [1].…”

Section: -10mentioning

confidence: 99%

“…The characteristic features of OLETF rats are late onset of hyperglycemia at about 18 weeks old, followed by insulin deficiency at about 65 weeks old [1]. We recently found [2][3][4] that OLETF rats lack cholecystokinin (CCK)-A receptor because of a genetic abnormality. The CCK-A receptor gene of rats is approximately 10 kb in length and consists of five exons interrupted by four introns [5].…”

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confidence: 99%

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Mechanism of Delayed Gastric Emptying in Naturally Occurring CCK-A Receptor Gene Knockout (OLETF) Rats.

Ohta

Kanai²,

Sato³

et al. 2000

JJP

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Otsuka Long Evans Tokushima Fatty (OLETF) ratswere developed as a model of non-insulin-dependent diabetes mellitus (NIDDM) [1]. The characteristic features of OLETF rats are late onset of hyperglycemia at about 18 weeks old, followed by insulin deficiency at about 65 weeks old [1]. We recently found [2][3][4] that OLETF rats lack cholecystokinin (CCK)-A receptor because of a genetic abnormality. The CCK-A receptor gene of rats is approximately 10 kb in length and consists of five exons interrupted by four introns [5]. Two exons including the promoter area are deleted in OLETF rats [4].CCK is known to be an important gastrointestinal hormone stimulating pancreatic enzyme secretion and producing gallbladder contraction. It is also an important neurotransmitter [6]. Two types of CCK receptors (type A "alimentary" and type B "brain") have been cloned [7]. The CCK-A receptors were expressed dominantly in the pancreas (in mice and rats, not in humans), in the stomach and in the vagal afferent nerve terminals of the gastrointestinal tract [7].Gastric emptying is delayed via CCK-A receptors of vagal afferent nerve [7,8]. Thus, it was suggested that the lack of CCK-A receptor might result in enhanced gastric emptying. However, Shoji et al. [9] reported the delayed gastric emptying in OLETF rats. The administration of CCK inhibited gastric emptying in LETO rats, while no effect was observed in OLETF rats [9]. The inhibitory effects of atropine and corticotropin-releasing factor (CRF) were not impaired in either strain [9].In the present study we tried to elucidate the mech- Key words: CCK-A receptor, OLETF rat, gastric emptying. Abstract:We recently found a specific strain of rats (OLETF rats) in which CCK-A receptor gene expression is lacking because of a genetic abnormality. As delayed gastric emptying has been reported in this strain, we examined its mechanism. A liquid gastric load containing phenol red was administered using an orogastric tube into the stomach in OLETF and control (LETO) rats. The stomach was removed 0, 15, 30 and 45 min after meal ingestion and the content of phenol red was measured to estimate the rate of gastric emptying. Pretreatment of reserpine enhanced gastric emptying in both strains. A tenfold dose of reserpine was required in OLETF rats to induce a similar effect to LETO rats. The plasma noradrenalin level was significantly higher in OLETF than LETO rats. When the smooth muscle of the stomach was isolated and contraction in vitro was examined, the smooth muscle functions were not deteriorated in OLETF rats. The thickness of muscle determined by hematoxylin-eosin staining was not different between strains. It is suggested that the delayed gastric emptying in OLETF rats may be due to increased sympathetic nerve function.

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Little or No Expression of the Cholecystokinin-A Receptor Gene in the Pancreas of Diabetic Rats (Otsuka Long-Evans Tokushima Fatty=OLETF Rats)

Cited by 94 publications

References 0 publications

G protein-coupled cholecystokinin-B/gastrin receptors are responsible for physiological cell growth of the stomach mucosa in vivo.

G protein-coupled cholecystokinin-B/gastrin receptors are responsible for physiological cell growth of the stomach mucosa in vivo.

Hyperphagia and obesity in OLETF rats lacking CCK-1 receptors

Mechanism of Delayed Gastric Emptying in Naturally Occurring CCK-A Receptor Gene Knockout (OLETF) Rats.

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