Fenofibrate is a selective peroxisome proliferator-activated receptor alpha (PPARalpha) activator and is prescribed to treat hyperlipidemia. The mechanism through which PPARalpha agonists reduce food intake, body weight, and adiposity remains unclear. One explanation for the reduction of food intake is that fenofibrate promotes fatty acid oxidation and increases the production of ketone bodies upon a standard experimental dose of the drug (100~300 mg/kg/day). We observed that low-dose treatment of fenofibrate (30 mg/kg/day), which does not cause significant changes in ketone body synthesis, reduced food intake in Long-Evans Tokushima (LETO) rats. LETO rats are the physiologically normal controls for Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which are obese and cholecystokinin (CCK)-A receptor deficient. We hypothesized that the reduced food intake by fenofibrate-treated LETO rats may be associated with CCK production. To investigate the anorexic effects of fenofibrate in vivo and to determine whether CCK production may be involved, we examined the amount of food intake and CCK production. Fenofibrate-treated OLETF rats did not significantly change their food intake while LETO rats decreased their food intake. Treatment of fenofibrate increased CCK synthesis in the duodenal epithelial cells of both LETO and OLETF rats. The absence of a change in the food intake of OLETF rats, despite the increase in CCK production, may be explained by the absence of CCK-A receptors. Contrary to the OLETF rats, LETO rats, which have normal CCK receptors, presented a decrease in food intake and an increase in CCK production. These results suggest that reduced food intake by fenofibrate treatment may be associated with CCK production.
Adiposity ; Animals ; Body Weight ; Cholecystokinin ; Diethylpropion ; Eating ; Epithelial Cells ; Fenofibrate ; Hyperlipidemias ; Ketone Bodies ; PPAR alpha ; Rats ; Rats, Inbred OLETF ; Receptor, Cholecystokinin A ; Receptors, Cholecystokinin

OBJECTIVE: This study aimed to test the possible association between Cholecystokinin B receptor (CCKBR) promoter gene and panic disorder. METHODS: 262 patients with panic disorder and 76 healthy controls participated in this study. Genotyping was performed by polymerase chain reaction-based method. RESULTS: Allele distribution of CT repeat polymorphism in patients with panic disorder was not different from those of the controls. However, after excluding the patients with panic disorder comorbid with major depressive disorder and other anxiety disorder, we found out the significant association of CCKBR (CT)n repeat with the panic disorder without comorbidities. And we analysed the data as a di-allelic polymorphism with a short (140-162 bp) and a long (164-180 bp) allele. In the di-allelic analysis, there was an excess of the shorter allele in patients with panic disorder. CONCLUSION: The present study suggested that the CCKBR promoter dinucleotide polymorphism may have a potential role for susceptibility to panic disorder in the Korean population and thus calls for consecutive studies in order to pile up the data with larger different ethnic background.
Alleles ; Anxiety Disorders ; Cholecystokinin* ; Comorbidity ; Depressive Disorder, Major ; Diagnosis* ; Drug Therapy* ; Humans ; Panic Disorder* ; Panic* ; Receptor, Cholecystokinin B*

PURPOSE: Gastrin and cholecystokinin (CCK) have been reported to play a role in the development and growth stimulation of gastrointestinal cancers including pancreatic cancer. METHODS: We investigated the effects of gastrin and CCK on the growth of pancreatic and biliary tract cancer cell lines established at the Cancer Research Institute of Seoul National University College of Medicine, using reverse transcription-polymerase chain reaction (RT-PCR) and slot blot hybridization, to examine the expressions of hormonal receptors in these cell lines. RESULTS: Of the six biliary tract, and five pancreatic, cancer cell lines, SNU-308 showed a growth stimulated effect due to gastrin-17, as did SNU-478 to both gastrin-17 and CCK-8. The trophic effect of these two hormones was completely blocked by specific antagonists (L-365, 260 for gastrin and L-364, 718 for CCK). The other cell lines did not respond to either the gastrin or the CCK. From the RT-PCR, the presence of the CCK-A receptor and the CCK-B/gastrin receptor mRNA was detected in all the biliary and pancreatic cancer cell lines. From the slot blot hybridization, although the cell lines that responded to the hormones showed high level of expression for receptor mRNA, so did some of those not responding to the hormones. CONCLUSION: This study suggests that gastrin and CCK exert a trophic action on some biliary tract cancers due to their specific receptors. However, further studies investigating the functional and structural variation among these receptors, in relation to their subtypes and mutation/polymorphism are requisite prior to their clinical usage for adjunctive hormonal or antihormonal therapy can be recommended.
Academies and Institutes ; Bile Duct Neoplasms ; Biliary Tract ; Biliary Tract Neoplasms ; Cell Line* ; Cholecystokinin* ; Gallbladder Neoplasms ; Gastrins* ; Gastrointestinal Neoplasms ; Growth and Development ; Pancreatic Neoplasms ; Receptor, Cholecystokinin A ; RNA, Messenger ; Seoul ; Sincalide

OBJECTIVETo find the risk loci on cholecystokinin A receptor gene (CCKAR) - a schizophrenia candidate gene by using the deep sequencing and then analyze the variations.

METHODSIn the present study, 8 schizophrenia patients and 8 healthy controls were recruited. After DNA extraction from peripheral blood, we conducted deep sequencing on CCKAR region by HaloPlex Target Enrichment System (Agilent). We used Unphased software to exclude the false positive.

RESULTSAfter deep sequencing, we got 103 loci, among which 30 were located in CCKAR gene. Besides, the SNP rs191275118 was found to be associated with schizophrenia.

CONCLUSIONSA new variation that may be associated with schizophrenia was found. The deep sequencing is effective to find genetic variation.

Adult ; Case-Control Studies ; Female ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Receptor, Cholecystokinin A ; genetics ; Schizophrenia ; genetics ; Sequence Analysis, DNA

Base Sequence ; Haplotypes ; Humans ; Molecular Sequence Data ; Polymerase Chain Reaction ; Polymorphism, Restriction Fragment Length ; Receptor, Cholecystokinin A ; genetics ; Schizophrenia ; genetics

PURPOSE: Gastrin, a peptide hormone produced by the G cells of the gastric antrum, plays a major role in regulating acid secretion in the stomach, and acts as a trophic factor in the gastrointestinal tract. The relationship between gastrin and the development of colorectal cancer remains controversial. To study its possible role in development or proliferation of colorectal cancer, we evaluated the expression of gastrin and gastrin/CCK-B receptor mRNA in cancer and normal tissue from colorectal cancer patients. We also reviewed clinical records to evaluate the correlations between gastrin receptor expression and clinical characteristics of colorectal cancer. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) was used to evaluate mRNA expression for gastrin and gastrin/CCK-B receptor in 26 surgical specimens of colorectal cancer. RESULTS: The mRNA expression of gastrin was detected in 24 out of 26 cancer specimens and 9 out of 26 normal colon specimens (p<0.05). The mRNA expression of gastrin/ CCK-B receptor was detected in 18 out of 26 cancer specimens and 17 out of 26 normal colon specimens (p>0.05). There was no significant correlation between gastrin receptor expression and clinical characteristics of colorectal cancer. CONCLUSIONS: The gastrin gene products might be more important than gastrin/CCK-B receptor in development or proliferation of colorectal cancer, which supports the hypothesis that gastrin gene products play a role in proliferation of colorectal cancer as an autocrine factor.
Colon ; Colorectal Neoplasms ; Gastrin-Secreting Cells ; Gastrins* ; Gastrointestinal Tract ; Humans ; Intestine, Large* ; Pyloric Antrum ; Receptor, Cholecystokinin B* ; RNA, Messenger* ; Stomach

The paradigm for the control of feeding behavior has changed significantly. In this review, we present evidence that the separation of function in which cholecystokinin (CCK) controls short-term food intake and leptin regulate long-term eating behavior and body weight become less clear. In addition to the hypothalamus, the vagus nerve is critically involved in the control of feeding by transmitting signals arising from the upper gut to the nucleus of the solitary tract. Among the peripheral mediators, CCK is the key peptide involved in generating the satiety signal via the vagus. Leptin receptors have also been identified in the vagus nerve. Studies in the rodents clearly indicate that leptin and CCK interact synergistically to induce short-term inhibition of food intake and long-term reduction of body weight. The synergistic interaction between vagal CCK-A receptor and leptin is mediated by the phosphorylation of signal transducer and activator of transcription3 (STAT3), which in turn, activates closure of K+ channels, leading to membrane depolarization and neuronal firing. This involves the interaction between CCK/SRC/phosphoinositide 3-kinase cascades and leptin/Janus kinase-2/phosphoinositide 3-kinase/STAT3 signaling pathways. It is conceivable that malfunctioning of these signaling molecules may result in eating disorders.
Appetite ; Body Weight ; Cholecystokinin ; Eating ; Feeding and Eating Disorders ; Feeding Behavior ; Fires ; Hypothalamus ; Leptin ; Membranes ; Neurons ; Nodose Ganglion ; Phosphorylation ; Receptor, Cholecystokinin A ; Receptors, Leptin ; Rodentia ; Signal Transduction ; Solitary Nucleus ; Transducers ; Vagus Nerve

OBJECTIVETo investigate the expression of gastrin in human gastric cancer cell line SGC-7901 and the effects of gastrin-17 and anti-gastrin mAb on its growth.

METHODSThe expression of gastrin was determined by immunohistochemistry with anti-gastrin mAb prepared by our group. In a series of experiments, the growth of SGC-7901 cells was evaluated by MTT assay on cells grown in serum-free medium and treated with gastrin-17 and/or anti-gastrin mAb.

RESULTSImmunohistochemical examination of SGC-7901 cells revealed a specific gastrin immunoreactivity. Gastrin-17 significantly stimulated cell growth at the concentrations of 1 x 10(-9) mol/L approximately 1 x 10(-5) mol/L in a dose-dependent manner. The growth of SGC-7901 cells treated with anti-gastrin mAb, either alone or in combination with gastrin-17 (1 x 10(-7) mol/L), was significantly inhibited.

CONCLUSIONGrowth of human gastric cancer cells SGC-7901 can be stimulated in an autocrine fashion. The gastrin-stimulated growth of gastric cancer cells can be blocked by anti-gastrin mAb bound specifically with gastrin. Further study on the significance of anti-gastrin mAb in designing immunotherapy targeting to gastrin or gastrin receptor is warranted.

Antibodies, Monoclonal ; pharmacology ; Cell Line, Tumor ; Cell Proliferation ; Gastrins ; biosynthesis ; genetics ; immunology ; Humans ; Receptor, Cholecystokinin B ; biosynthesis ; genetics ; Stomach Neoplasms ; metabolism ; pathology

This study was conducted to explore whether cholecystokinin-B/gastrin receptor (CCKBRwt) gene and its alternative splicing variant (CCKBRi4sv) are expressed in human gastric carcinomas cell line and tissues, and to find out their relationship with the development and progression of human gastric carcinoma. The mRNA expression levels of CCKBRwt and CCKBRi4sv were detected in 30 human gastric carcinomas and normal tissues adjacent to cancer, 10 gastritis specimens, 2 autopsied normal stomach specimens as well as in a gastric carcinoma cell line SGC-7901 cells. The results revealed that the transcripts of CCKBRwt and CCKBRi4sv were observed in all of the human gastric specimens tested, but only CCKBRwt was expressed in gastric cancer cell line SGC-7901 cells. The expression levels of the two receptors were not correlated with the differentiation and metastases of gastric cancers. From the results, we infer that human gastric tissues simultaneously express CCKBRwt and CCKBRi4sv, and CCKBRi4sv may have unknown physiological functions in gastric epithelial cells.
Base Sequence ; Epithelial Cells ; metabolism ; Gastric Mucosa ; metabolism ; Gastrins ; biosynthesis ; genetics ; Gastritis ; genetics ; metabolism ; Humans ; Molecular Sequence Data ; RNA, Messenger ; biosynthesis ; genetics ; Receptor, Cholecystokinin B ; biosynthesis ; genetics ; Stomach ; metabolism ; Stomach Neoplasms ; genetics ; metabolism ; Tumor Cells, Cultured

The tubby mouse is characterized by progressive retinal and cochlear degeneration and late-onset obesity. These phenotypes are caused by a loss-of-function mutation in the tub gene and are shared with several human syndromes, suggesting the importance of tubby protein in central nervous system (CNS) functioning. Although evidence suggests that tubby may act as a transcription factor mediating G-protein coupled receptor (GPCR) signaling, any downstream gene regulated by tubby has yet to be identified. To explore potential target genes of tubby with region-specific transcription patterns in the brain, we performed a microarray analysis using the cerebral cortex and hypothalamus of tubby mice. We also validated the changes of gene expression level observed with the microarray analysis using real-time RT-PCR. We found that expression of erythroid differentiation factor 1 (Erdr1) and caspase 1 (Casp1) increased, while p21-activated kinase 1 (Pak1) and cholecystokinin 2 receptor (Cck2r) expression decreased in the cerebral cortex of tubby mice. In the hypothalamic region, Casp 1 was up-regulated and micro-crystallin (CRYM) was down-regulated. Based on the reported functions of the differentially expressed genes, these individual or grouped genes may account for the phenotype of tubby mice. We discussed how altered expression of genes in tubby mice might be understood as the underlying mechanism behind tubby phenotypes.
Activins ; Animals ; Brain ; Caspase 1 ; Central Nervous System ; Cerebral Cortex ; Gene Expression ; GTP-Binding Proteins ; Humans ; Hypothalamus ; Mice ; Microarray Analysis ; Negotiating ; Obesity ; p21-Activated Kinases ; Phenotype ; Receptor, Cholecystokinin B ; Retinaldehyde ; Transcription Factors