DEFECTS OF CHOLECYSTOKININ (CCK)-A RECEPTOR GENE-EXPRESSION AND CCK-ARECEPTOR-MEDIATED BIOLOGICAL FUNCTIONS IN OTSUKA-LONG-EVANS-TOKUSHIMA-FATTY (OLETF) RATS

Recent studies in genetically obese and diabetic Otsuka Long-Evans Tok ushima Fatty (OLETF) rats suggest defects of cholecystokinin (CCK)-A r eceptor gene expression and CCK-A receptor-mediated biological functio ns such as pancreatic juice, protein, and gastric acid secretion. The present studies were undertaken to further examine CCK-A receptor gene expression and CCK-A receptor-mediated biological functions in the pa ncreas, stomach, and brain of OLETF rats. Expression of the CCK-A rece ptor gene could not be detected in the stomach, pancreas and brain by the reverse-transcription polymerase chain reaction (RT-PCR) method an d Southern blotting of the PCR products. Southern blot analysis of gen omic DNA from OLETF and control Long-Evans Tokushima Otsuka (LETO) rat s with CCK-A receptor fragment as a probe revealed different restricti on bands. Expression of the CCK-B receptor gene was observed in the st omach, pancreas, and brain in both OLETF and LETO rats by the RT-PCR m ethod, with expression of the CCK-B receptor gene markedly enhanced in OLETF rats compared with that in LETO rats. Consistent with the defec t of CCK-A receptor gene expression, CCK-A receptor-mediated biologica l functions were not observed in these organs. Perfused exocrine and e ndocrine pancreas of OLETF rats were insensitive to CCK stimulation bu t not to carbamylcholine stimulation. Basal gastric acid and pepsinoge n secretions in OLETF rats were higher than in LETO rats. OLETF rats s howed a significantly higher average daily food intake, gained body we ight faster? and were heavier than LETO rats. The present study confir med that OLETF rats have CCK-A receptor gene anomalies and demonstrate d deficient CCK-A receptor-mediated biological function in the pancrea s, stomach, and brain.