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Abstract.: Otsuka Long-Evans Tokushima Fatty (OLETF) rats lack cholecystokinin-A receptor (CCK-AR) because of a genetic abnormality. We observed that body temperature homeostasis in response to changes in ambient temperature was deteriorated in OLETF rats, while the functions of the signal outputs from the hypothalamus to effectors were not impaired. Deteriorated homeostasis was also seen in CCK-AR deficient (−/−) mice. In the present study, we examined whether the sensory pathway involved in transmitting signals about temperature from the skin to the brain was impaired in OLETF rats. To elucidate the involvement of CCK-AR function, we conducted the same experiment in CCK-AR(−/−) mice. Responses to thermal pain were assessed using the Hargreaves’ plantar test apparatus. Shortening of withdrawal latency was observed in OLETF rats compared to control rats, indicating thermal hyperalgesia. Behavioral responses following paw withdrawal were disturbed in OLETF rats. The 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid contents in the hippocampus and frontal cortex of OLETF rats were significantly higher than in those of the controls. CCK-AR(−/−) mice did not show any differences from wild-type mice. In conclusion, OLETF rats showed thermal hyperalgesia and disturbed responses to thermal pain, and an alteration of 5-HT function might have a role in this disturbance. Keywords:: thermal pain, plantar test, knockout mouse, 5-hydroxytryptamine, Otsuka Long-Evans Tokushima Fatty (OLETF) rat

Aging is associated with a progressive decrease in appetite and food intake. Both A and B orexins, expressed in specific neurons of the lateral hypothalamic area, have been implicated in the regulation of sleep and feeding. In this study, the stimulatory effect of intracerebroventricular administration of the orexins on food intake was compared between young (4-mo-old) and old (25- to 27-too-old) male Wistar rats. A stainless steel cannula was implanted stereotactically into the left lateral ventricle. After a 7-day recovery period, different doses (0-30 nmol) of orexins were injected into the left lateral ventricle without anesthesia. Food and water consumptions were measured at 1, 2, and 4 h after injection. The protein levels of orexin receptors, a specific receptor for orexin-A (OX1R) and a receptor for both orexin-A and -B (OX2R), in the hypothalamus were determined by Western blot analysis and compared between young and old rats. Intracerebroventricular administration of orexin-A stimulated food intake in a dose-dependent manner in young rats. However, no effects were observed at any dose in old rats. The protein level of OX 1R in the hypothalamus was significantly lower in old rats than in young rats, although the protein level of OX2R was comparable between groups. Results of the present study indicate that the function of the orexin system is diminished in old rats. The decrease in the OX1R protein level in the hypothalamus could be responsible for orexin-A's lack of stimulation of food intake in old rats. age; anorexia of aging; brain; hypothalamus; orexin receptor

The circadian rhythm of the body core temperature ([T.sub.c]) and the effects of changes in ambient temperatures on the homeostasis of [T.sub.c] in Otsuka Long Evans Tokushima Fatty (OLETF) rats, which are naturally occurring cholecystokinin (CCK)-A receptor (CCK-AR) gene knockout (-/-) rats, were examined. In addition, the peripheral responses to warming or cooling of the preoptic and anterior hypothalamic region (PO/AH) were determined. The circadian rhythm of [T.sub.c] in OLETF rats was similar to that in Long-Evans Tokushima (LETO) rats; this rhythm was characterized by a higher [T.sub.c] during the dark period and a lower [T.sub.c] during the light period. When the ambient temperature was changed within the limits of 0[degrees]C to 30[degrees]C, the changes in [T.sub.c] of LETO rats were associated with the changes in ambient temperature, whereas those in OLETF rats were dissociated from the temperature changes. The OLETF rats showed a large hysteresis. The peripheral responses to warming or cooling of PO/AH, including shivering of the neck muscle and changes in skin temperature of the tail and footpad, were similar in OLETF and LETO rats. To confirm the role of CCK-AR in the regulation of body temperature, the values of [T.sub.c] in the CCK-AR(-/-) mice were compared with those in CCK-B receptor (CCK-BR) (-/-), CCK-AR(-/-)BR (-/-), and wild-type mice. In the mice, the circadian rhythms of [T.sub.c] were the same, regardless of the genotype. Mice without CCK-AR showed larger hysteresis than mice with CCK-AR. From these results, we conclude that the lack of CCK-AR causes homeostasis of [T.sub.c] in rats and mice to deteriorate. knockout mice

Increased lymphatic lipid transport in genetically diabetic obese rats. Am J Physiol Gastrointest Liver Physiol 282: G69-G76, 2002.--Otsuka Long-Evans Tokushima fatty (OLETF) rats are a model for noninsulin-dependent diabetes mellitus (NIDDM), which is first manifested at 18 wk of age. We assessed age-related changes in lymphatic lipid transport in the intestine of OLETF rats and compared them with those of control Long-Evans Tokushima Otsuka (LETO) rats. Olive oil was infused into the rats with a mesenteric lymph fistula, which was created under ethrane anesthesia. A significant increase in lymphatic triglyceride (TG) transport in OLETF rats was observed at 18-19 wk compared with under 17 wk, but no age-related change was observed in LETO rats. Food restriction, exercise training, or troglitazone treatment in OLETF rats prevented the age-related increase in lipid transport. Biliary phosphatidylcholine concentration was higher in OLETF rats than in LETO rats, but no difference was seen in bile acid concentrations or the activity of microsomal TG transfer protein between the two strains. This study shows that increased lipid transport in the intestine may occur in NIDDM. lymph fistula rats; noninsulin-dependent diabetes mellitus; triglyceride; biliary phosphatidylcholine; troglitazone

A study was conducted to analyze changes in the levels of novel luminal cholecystokinin-releasing factor (LCRF) in the small intestinal lumen before and after bile-pancreatic juice diversions in rats. A specific radioimmunoassay was utilized to carry out the analysis. Anti-LCRF antiserum was raised in rabbits as a sensitive radioimmunoassay was established.The locationalization of LCRF was then analyzed by immunohistochemistry.

Second filial generation crosses of the Otsuka Long-Evans Tokushima (OLETF) rats were used in the genetic analyses of two loci postulated to cause diabetes in rats. OLETF rats show characteristics of human non-insulin dependent diabetes mellitus. Results of the breeding studies reveal that rats containing the knock out cholecystokinin type A receptor (CCKAR) had high plasma glucose levels. This gene was mapped close to the ODB2 gene, one of two genes that cause diabetes. The CCKAR gene appears to act synergistically with the ODB1 gene to induce diabetes.

Research was conducted to study the function and peripheral mechanism of action of central dopamine on basal pancreatic exocrine secretion in rats. Bile and pancreatic juices were collected for 30-min periods while dopamine was intracerebroventricular administered in vagotomized rats. Results indicated that propranolol inhibited basal pancreatic fluid and protein secretion while bretylium and phentolamine had no effect. They also showed that the inhibitory effect of dopamine was inhibited by phentolamine.

The effects of somatostatin on exocrine pancreatic secretion stimulated by vagal nerve efferent excitation was analyzed in conscious Wistar rats. Intracerebroventricular injections of somatostatin in rats inhibited pancreatic secretions that were induced by thyrotropin-releasing hormones (TRH). Somatostatin also inhibited vagal afferent nerve excitation that was mediated by TRH. Furthermore, 2-deoxy-D-glucose and TRH promote pancreatic secretion by stimulating the vagal efferent nerve via distinct pathways.

Background. Cholecystokinin (CCK) is an important bioactive peptide which stimulates pancreatic enzyme secretion and is also a neuromodulator in the central nervous system. We examined whether CCK release from the central and peripheral tissues was decreased in old animals, and whether there were sex-related differences. Methods. Young (5-10-month-old) and old (25-29-month-old) male and female Wistar rats were used. Synaptosomes were prepared from the cerebral cortex, and the vasculary perfused duodenojejunum was isolated to examine central and peripheral CCK release, respectively. In some young female rats, 21 days after bilateral ovariectomy, the peripheral CCK release and the changes in CCK mRNA levels were examined. Results. The central CCK release was impaired in response to the higher concentration of KCI, and the peripheral CCK response to the highest dose of neuromedin C was impaired in old male rats. However, no aging effect was observed in female rats, and ovariectomy did not affect CCK release or CCK mRNA level. Conclusions. CCK release from both central and peripheral tissues was decreased in old male rats, but not in old female rats.

Abstract Background The frequency of Japanese subjects over 20 years old with metabolic syndrome is 45.6% in men but just 16.7% in women. The reason why Japanese male subjects are more susceptible to metabolic syndrome than women is unknown. One possibility is the higher frequency of Japanese male subjects (40–70 years old) who had a drinking habit (67%), while that of female subjects was only 25%. In addition, daily fat intake was markedly increased in Japanese subjects (from 9% to 25%), and cholesterol cholelithiasis is one of the most rapidly increasing digestive diseases during the past 50 years. The object of this study is to examine whether a potential sex-related risk factor exists in the manifestation of metabolic syndrome as well as gallstone formation. Methods Gallbladder dysmotility accerelates gallstone formation and gallbladder contraction depends on cholecystokinin (CCK) and its receptor (CCK-1R). We developed CCK-1R gene knockout (-/-) mice. The effects of the fat- and protein- enriched diet OA-2 on body weight, hyperlipidemia, and frequencies of sludge and gallstone formation were examined, and compared between wild-type and CCK-1R(-/-) male and female mice. The OA-2 diet contains slightly higher protein and fat (7.9 % fat and 27.6 % protein) compared with a standard diet (CRF-1) (5.6 % fat and 22.6 % protein), but their total energies are similar. After weaning, CRF-1 was provided until 3 months of age in all animals. Administration of an OA-2 diet was started when age-matched CCK-1R(-/-) and wild-type male and female mice reached maturity, at 3 months of age. Administration of CRF-1 was continued in the rest of the animals. Mice were sacrificed by guillotine at 6 and 12 months of age and the blood was collected to measure plasma levels of triglyceride and cholesterol. The gallbladder was removed and classified as normal (clear gallbladder), clouded (sludge formation), and/or containing gallstone formations. Results As long as CRF-1 was provided, the frequency of sludge and/or gallstone formation in CCK-1R(-/-) male mice was 3 of 8 (35%) and 4 of 9 (45%) in females at 12 months of age, whereas no gallstone formation was observed at 6 months of age. On the other hand, male mice fed OA-2 increased their body weight and plasma lipid concentrations, compared with those fed CRF-1 regardless of genotype. Under the OA-2 diet, sludge and gallstone formation was observed at 6 months of age, not only in CCK-1R(-/-) male mice but also in wild-type male mice. In contrast, parameters in female mice did not differ between the two diets. Conclusion Male mice were more susceptible to protein- and fat-enriched diet-induced obesity than female mice, and hyper-nutritional status accelerated sludge and gallstone formation in male mice.