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Biomedical subjects

Tamotsu Shibasaki

Publications and source records attributed to Tamotsu Shibasaki.

At least 19 recordsLinked to original sources
PubMed2006

[Eating disorders].

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Cognition Disorders↗
PubMed2006

Growth hormone-releasing hormone (GHRH) neurons in the arcuate nucleus (Arc) of the hypothalamus are decreased in transgenic rats whose expression of ghrelin receptor is attenuated: Evidence that ghrelin receptor is involved in the up-regulation of GHRH expression in the arc.

GH secretagogue (GHS)/ghrelin stimulates GH secretion by binding mainly to its receptor (GHS-R) on GHRH neurons in the arcuate nucleus (Arc) of the hypothalamus. GHRH, somatostatin, and neuropeptide Y (NPY) in the hypothalamus are involved in the regulatory mechanism of GH secretion. We previously created transgenic (Tg) rats whose GHS-R expression is reduced in the Arc, showing lower body weight and shorter nose-tail length. GH secretion is decreased in female Tg rats. To clarify how GHS-R affects GHRH expression in the Arc, we compared the numbers of GHS-R-positive, GHRH, and NPY neurons between Tg and wild-type rats. Immunohistochemical analysis showed that the numbers of GHS-R-positive neurons, GHRH neurons, and GHS-R-positive GHRH neurons were reduced in Tg rats, whereas the numbers of NPY neurons and GHS-R-positive NPY neurons did not differ between the two groups. The numbers of Fos-positive neurons and Fos-positive GHRH neurons in response to KP-102 were decreased in Tg rats. Competitive RT-PCR analysis of GHRH mRNA expression in the cultured hypothalamic neurons showed that KP-102 increased NPY mRNA expression level and that NPY decreased GHRH mRNA expression level. KP-102 increased GHRH mRNA expression level in the presence of anti-NPY IgG. GH increased somatostatin mRNA expression. Furthermore, GH and somatostatin decreased GHRH mRNA expression, whereas KP-102 showed no significant effect on somatostatin mRNA expression. These results suggest that GHS-R is involved in the up-regulation of GHRH and NPY expression and that NPY, somatostatin, and GH suppress GHRH expression. It is also suggested that the reduction of GHRH neurons of Tg rats is induced by a decrease in GHS-R expression.

Animals↗
PubMed2005

Urocortin 2 induces tyrosine hydroxylase phosphorylation in PC12 cells.

Urocotins (Ucns) are newly discovered members of the corticotropin-releasing factor (CRF) neuropeptide family. Ucn 2 is expressed in the adrenal medulla, and its receptor, CRF2 receptor, is also expressed in the adrenal gland. To predict the physiological significance of Ucn 2 expression in the adrenal medulla, we examined the effects of Ucn 2 on catecholamine secretion and intracellular signaling using PC12 cells, a rat pheochromocytoma cell line. PC12 cells were found to express CRF2 receptor, but not CRF1 receptor. Treatment with Ucn 2 increased noradrenaline secretion and induced phosphorylation of PKA and Erk1/2. Tyrosine hydroxylase (TH), a rate-limiting enzyme for catecholamine synthesis, was also phosphorylated by Ucn 2. Pretreatment with a PKA inhibitor blocked Ucn 2-induced NA secretion, and Erk1/2 and TH phosphorylation. Pretreatment with a MEK inhibitor did not block Ucn 2-induced noradrenaline secretion or PKA phosphorylation, although TH phosphorylation was blocked. Thus, Ucn 2 induces noradrenaline secretion and TH phosphorylation through the PKA pathway and the PKA-Erk1/2 pathway, respectively. These results suggest Ucn 2 in the adrenal gland may be involved in the regulation of catecholamine release and synthesis.

Animals↗
PubMed2004

Both corticotropin-releasing factor receptor type 1 and type 2 are involved in stress-induced inhibition of food intake in rats.

RATIONALE: Stress-induced inhibition of food intake is reportedly blocked by a selective corticotropin-releasing factor (CRF) type 1 receptor (CRF1) antagonist, suggesting the involvement of CRF1 in the inhibitory mechanism. CRF1 and CRF2 are considered to function in the inhibition of food intake by CRF-related peptides with different time courses. OBJECTIVES: This study was designed to clarify whether CRF2 is also involved in stress-induced inhibition of food intake and to examine the relation of CRF1to CRF2 in the inhibitory mechanism. METHODS: Antisauvagine-30 (AS-30), a selective CRF2 antagonist, and/or CRA1000, a selective CRF1 antagonist, were pre-administered intracerebroventricularly and intraperitoneally, respectively, to male Wistar rats deprived of food for 24 h before the animals were exposed to a 1-h period of stressors and food intake in 1 h after stress exposure was examined. The effect of both antagonists on locomotor activity was also examined. RESULTS: Pre-administration of 5-30 microg of AS-30 attenuated inhibition of food intake induced by restraint, electric footshock or emotional stress using a communication box. CRA1000 also attenuated the restraint-induced inhibition of food intake at doses of 5 and 10 mg/kg body weight. The reversal of restraint-induced inhibition of food intake by co-administration of AS-30 and CRA1000 was not larger than that by AS-30 or CRA1000 alone. Both antagonists did not affect locomotor activity. CONCLUSIONS: These results suggest that not only CRF1, but also CRF2, are involved in stress-induced inhibition of food intake, and that both subtypes of CRF receptor function probably in series in 1 h after stress exposure.

Animals↗
PubMed2004

Effects of food restriction on peroxisome proliferator-activated receptor-gamma and glucocorticoid receptor signaling in adipose tissues of normal rats.

In adipocytes, peroxisome proliferator-activated receptor (PPAR)-gamma activates adipocyte differentiation and glucocorticoid (GC) stimulates the expression of PPAR-gamma mRNA. The local tissue concentrations of GC, in turn, are modulated by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). To clarify the change of energy metabolism in condition of reduced energy intake, we investigated whether food restriction alters the adipocyte size and levels of PPAR-gamma, GC receptor (GR), and 11beta-HSD1 mRNA expression in the white adipose tissues of normal rats. Male Wistar rats weighing 340 g were housed under free feeding or 20% reduction of food intake for 2 or 14 days. We found that 2-day food restriction did not cause any change in the mean size or number of adipocytes in the omentum, while 14-day food restriction decreased the size and increased the number of adipocytes. In addition, the levels of PPAR-gamma2, GR, and 11beta-HSD1 mRNA expression in the omentum were lower in the food-restricted rats after 2 days, while they did not differ after 14 days. Also, after both 2 and 14 days, plasma concentrations of free fatty acid (FFA) were higher in the food-restricted rats than in control rats. Finally, plasma concentrations of adrenocorticotropin (ACTH) and corticosterone were the same in the both groups after 2 days, although they were higher in the food-restricted rats after 14 days. These results suggest that adipocyte differentiation in the omentum of food-restricted rats is attenuated after 2 days but recovers after 14 days, resulting in an increase in the number of small adipocytes. It is also likely that lipolysis induced during the 14-day period of food restriction decreased the size of adipocytes. Further, food restriction may affect the efficiency of local GC effects by altering GR and 11beta-HSD1 mRNA expression. Also, higher levels of plasma GC and recovery of GR and 11beta-HSD1 mRNA expression may contribute to the recovery of the levels of PPAR-gamma2 mRNA expression in the omentum and result in the recovery of adipocyte differentiation.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2004

Effects of urocortin 2 and 3 on motor activity and food intake in rats.

Urocortin 2 (Ucn 2) and Ucn 3 are new members of the corticotropin-releasing factor (CRF) family and bind selectively to the CRF type 2 receptor (CRF2). The effects of these peptides on behavioral changes induced by CRF were examined in rats. In a familiar environment, intracerebroventricular injection of Ucn 2 attenuated the stimulatory effect of CRF on motor activity, although it alone produced no effect. Ucn 3 suppressed motor activity and attenuated the stimulatory effect of CRF. In an open field, CRF decreased locomotion and rearing but increased grooming behavior. Ucn 2 attenuated the inhibition of locomotor activity induced by CRF without affecting other activities, such as rearing or grooming behavior. Ucn 3 had no effect on the behavioral changes induced by CRF, although it alone decreased locomotion and rearing in a manner similar to CRF. Ucn 2 was thus found to have an antagonistic effect on bi-directional motor activation induced by CRF, while Ucn 3 had a suppressive effect on motor activity. Both Ucn 2 and Ucn 3 suppressed food intake in freely-fed rats, but not immediately after injection. These results suggest that the CRF2 receptor is involved in motor suppressive effects as well as anxiolytic and anorectic effects of Ucn 2 and Ucn 3.

Animals↗
PubMed2004

Plasma levels of intact and degraded ghrelin and their responses to glucose infusion in anorexia nervosa.

Octanoylated ghrelin (1-28) (intact ghrelin) is rapidly and easily degraded to desoctanoyl forms or smaller fragments (degraded ghrelin). Plasma levels of intact and degraded ghrelin were examined in 30 patients with anorexia nervosa (AN) (body mass index, 8.81-22.4 kg/m(2)) and 16 age-matched healthy women using several assay methods. Plasma levels of ghrelin measured using immunocomplex transfer-enzyme immunoassay, which specifically detects intact ghrelin, were lower in AN than controls. Plasma ghrelin levels in AN measured using the active ghrelin ELISA kit, which is advertised as specifically detecting intact ghrelin, did not differ significantly from controls. Plasma levels of desoctanoyl ghrelin using the desacyl-ghrelin ELISA kit, N-terminus ghrelin using the ghrelin active RIA kit, and C-terminus ghrelin using the ghrelin total RIA kit were significantly higher in AN than controls, and displayed significant negative correlations with body mass index. Plasma levels of ghrelin determined using immunocomplex transfer-enzyme immunoassay or active ghrelin ELISA during iv glucose infusion were suppressed in both AN and controls, whereas plasma levels of degraded ghrelin levels were not significantly decreased in AN. Plasma levels of intact ghrelin are therefore not higher in AN than controls, whereas degraded forms of ghrelin are elevated in AN. Rapid suppression of plasma intact ghrelin, but not degraded ghrelin, occurs in AN in response to glucose infusion. The profiles of intact and degraded forms of ghrelin in plasma of AN patients differ from those of healthy women.

Adolescent↗
PubMed2003

Intermittent foot shock stress prolongs the telogen stage in the hair cycle of mice.

Stress significantly influences skin diseases and cutaneous functions. Recently, interactions between stress and skin conditions have been studied in animal models using various systemic stressors. Here, we studied the effect of intermittent foot shock stress on the hair cycle of C57BL/6 mice. After a 2-week period of intermittent foot shock stress, we examined the changes in the depilation-synchronized hair cycle macroscopically and histologically and we also measured the plasma levels of corticosterone. We found that foot shock stress prolonged the telogen stage and delayed the subsequent anagen induction in the hair cycle. The distribution patterns of corticotrophin releasing factor or corticotrophin releasing factor receptor positive cells in the skin of stressed or of control mice were identical with those in the ordinal hair cycle. It is noteworthy that corticotrophin releasing factor positive keratinocytes were observed in the telogen follicles of the stressed mice but were negative in the telogen follicles of the non-stressed mice in this study. Plasma corticosterone levels were significantly higher in the stressed group than in the control group. These results suggest that increased levels of plasma corticosterone may be involved in the mechanism underlying the stress-induced delay of the hair cycle.

Animals↗
PubMed2003

Corticotropin-releasing factor receptor type 1 is involved in the stress-induced exacerbation of chronic contact dermatitis in rats.

Cutaneous diseases such as psoriasis and atopic dermatitis are worsened by psychic stress. We attempted to clarify the involvement of the corticotropin-releasing factor (CRF) receptor (CRFR) in stress-induced exacerbation of chronic contact dermatitis in rats. Male Wistar rats, in which chronic contact dermatitis had been induced by 2,4,6-trinitro-1-chlorobenzene (TNCB), were exposed to a 1-h period of electric foot-shock following intraperitoneal administration of CRA1000, a selective CRFR type 1 (CRFR1) antagonist, or vehicle everyday for 9 days. Histological examination of the skin showed that the epidermis significantly thickened and the number of mast cells in the dermis significantly increased by repeated exposure to stress, and that these changes were blocked by CRA1000. These results suggest that CRFR1 is involved in the stress-induced exacerbation of chronic contact dermatitis.

Animals↗
PubMed2003

Ghrelin mRNA and GH secretagogue receptor mRNA in human GH-producing pituitary adenomas is affected by mutations in the alpha subunit of G protein.

OBJECTIVE: Ghrelin and its receptor, growth hormone secretagogue (GHS) receptor (GHSR), are expressed in the normal pituitary gland and various types of pituitary adenoma. Somatic mutations in the subunit of Gs alpha protein (gsp), which led to a constitutive activation of adenylyl cyclase, are reported in GH-producing pituitary adenomas. We analysed the relationship between ghrelin mRNA and GHSR mRNA expression levels in gsp mutation-positive and -negative GH-producing pituitary adenomas. PATIENTS: Pituitary adenoma tissue was obtained at surgery from 20 patients with acromegaly. METHODS: The expression levels of human ghrelin mRNA and GHSR mRNA were quantified using a competitive RT-PCR method. To detect the gsp mutations, amplified Gs alpha subunit cDNA fragments were sequenced directly using RT-PCR method. RESULTS: There was no significant difference in the expression of ghrelin mRNA between mutation-positive and -negative adenomas. The expression of GHSR mRNA was significantly lower in gsp mutation-positive than -negative adenomas. There was a significant negative correlation between the levels of ghrelin mRNA and GHSR mRNA expression in mutation-negative adenomas; no such correlation was found in mutation-positive adenomas. CONCLUSION: These results suggest that GHSR mRNA expression is downregulated by ghrelin in gsp mutation-negative GH-producing pituitary adenomas, and that changes in intracellular signalling pathways in gsp mutation-positive GH-producing pituitary adenomas affect the expression of G protein-coupled receptors such as GHSR. The absence of negative correlation between ghrelin and GHSR expression might be induced by lowered GHSR expression in gsp mutation-positive GH-producing adenomas.

Adenoma↗
PubMed2003

A case of Sheehan's syndrome with panhypopituitarism due to the impairment of both the hypothalamus and the pituitary.

Sheehan's syndrome is thought to be caused by pituitary necrosis associated with massive hemorrhage at delivery. We report here on a patient with Sheehan's syndrome, showing a rare type of panhypopituitarism suggesting dysfunction of both the hypothalamus and the pituitary. Although the basal level of plasma ACTH was normal, that of plasma cortisol was low. ACTH showed a delayed high response to CRH and a low response to insulin-induced hypoglycemia, while plasma cortisol showed a low response to CRH and no response to insulin-induced hypoglycemia. In the standard ACTH test, a normal rise of plasma cortisol was found. These results indicate that the primary site responsible for hypothalamic-pituitary-adrenocortical hypofunction may be the hypothalamus. In addition, the dysfunction of the pituitary itself is suggested by the hyposecretion of other pituitary hormones with impaired responses in their provocative tests and partially empty sella.

Adrenocorticotropic Hormone↗
PubMed2002

Effect of chronic administration of a CRF(1) receptor antagonist, CRA1000, on locomotor activity and endocrine responses to stress.

Corticotropin-releasing factor (CRF) is involved in the regulation of stress responses. The actions of CRF in the brain are mediated through two distinct CRF receptor subtypes, CRF(1) and CRF(2) receptors. In the present study, we examined the effects in rat of chronic administration of a nonpeptidic CRF(1) receptor-selective antagonist, CRA1000, 2-[N-(2-methylthio-4-isopropylphenyl)-N-ethylamino]-4-[4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]-6-methylpyrimidine), on locomotor activity, feeding behavior and the hypothalamic-pituitary-adrenal axis. Chronic CRA1000 treatment significantly decreased locomotor activity in the dark phase of the diurnal cycle. However, chronic CRA1000 treatment showed no effect on food and water intake, or on body weight. After a 10-day period of CRA1000 treatment, plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone in basal conditions and under immobilization stress were no different from those in rats treated with vehicle. However, CRA1000 administered 2 h before immobilization stress significantly reduced ACTH and corticosterone responses to stress with no effect on basal ACTH and corticosterone concentrations. These results suggest that CRF(1) receptors are involved in the regulation of locomotor activity during the dark period, but are not involved in the regulation of feeding behavior under non-stressful conditions. Furthermore, the results suggest that a 10-day treatment with CRA1000 does not affect hypothalamic-pituitary-adrenal axis activity either under basal conditions or after acute stress.

Adrenocorticotropic Hormone↗
PubMed2002

Functional polymorphisms in the mineralocorticoid receptor and amirolide-sensitive sodium channel genes in a patient with sporadic pseudohypoaldosteronism.

Pseudohypoaldosteronism (PHA) is characterized by urinary salt-wasting in infancy resulting from a congenital resistance to aldosterone involving the genes for the mineralocorticoid receptor (MR) and the amiloride-sensitive sodium channel (ENaC). We identified, in a Japanese patient with sporadic PHA, three homozygous substitutions in the MR gene: G215-->C215, A754-->G754 (Ile180-->Val180), C938-->T938 (Ala241-->Val241), which had previously been reported to occur in healthy populations. Luciferase activities induced by MR with either G215-->C215, Ile180-->Val180, or Ala241-->Val241 substitution were significantly lower than those for wild-type MR with aldosterone at concentrations ranging from 10(-11) to 10(-9) M, 10(-8) M, or 10(-11) to 10(-6) M, respectively. A homozygous A-->G substitution of the donor splice site of alphaENaC intron 4 was found in the patient. The corresponding cDNA exhibited a normal structure, suggesting that this substitution does not alter the splice. The results suggest that each of three MR polymorphisms identified in our patient is functionally and structurally heterogeneous. We hypothesize that two or more "functional" polymorphisms, any of which exhibits only slight effects on MR or ENaC function and is alone incapable causing PHA, may in the right allelic combination induce the negative salt-conservation characteristic of PHA.

Aldosterone↗