Papers - IDA Takanori
-
Ghrelin is essential for lowering blood pressure during torpor Reviewed
Matsui K., Ida T., Oishi K., Kojima M., Sato T.
Frontiers in Endocrinology 15 1487028 2024.10
Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers in Endocrinology
Introduction: Daily torpor is an active hypothermic phenomenon that is observed in some mammals and birds during fasting. A decrease in blood pressure has also been observed in torpor; however, there remains a lack of knowledge of the underlying mechanism. We have previously reported that ghrelin, an orexigenic hormone, has a hypothermic effect and is essential for the induction and maintenance of torpor. It is also known that the ghrelin secretion is enhanced during fasting and that ghrelin receptors are distributed in the cardiovascular system. Therefore, this study was conducted to test the hypothesis that ghrelin is actively involved in the regulation of blood pressure during torpor induction. Methods: Male wild-type and ghrelin gene-deficient mice were generated by homologous recombination as previously reported. Mice, 10 weeks old, were included in this study and housed five per cage. The mice were maintained on a 12-h light/dark cycle (lights on from 7:00 to 19:00) with access to food and water ad libitum. Results: The continuous measurement of blood pressure using a telemetry system showed that induction of torpor by fasting did not decrease blood pressure in ghrelin gene-deficient mice. The analysis of heart rate variability revealed that sympathetic nerve activity was predominant in ghrelin-deficient mice during fasting. Furthermore, these features were cancelled by administration of a ghrelin receptor agonist and were comparable to those in wild-type mice. Discussion: In this study, we showed that blood pressure was elevated in ghrl-/- mice and that the blood pressure rhythm was abnormal. Furthermore, we showed that the ghrelin gene deficiency does not cause sufficient blood pressure reduction upon entry into the torpor, and that the administration of the ghrelin receptor agonist, GHRP-6, causes blood pressure reduction associated with torpor. Thus, we have shown for the first time that the active role of ghrelin is essential for active blood pressure reduction associated with torpor, and that this action is mediated by the inhibition of sympathetic nerve activity by ghrelin.
-
Yazawa T., Watanabe Y., Yokohama Y., Imamichi Y., Hasegawa K., Nakajima K.I., Kitano T., Ida T., Sato T., Islam M.S., Umezawa A., Takahashi S., Kato Y., Jahan S., Kawabe J.I.
Frontiers in Endocrinology 15 1480722 2024.10
Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers in Endocrinology
3β-Hydroxysteroid dehydrogenases (3β-HSDs) catalyze the oxidative conversion of delta (5)-ene-3-beta-hydroxy steroids and ketosteroids. Human 3β-HSD type 2 (HSD3B2) is predominantly expressed in gonadal and adrenal steroidogenic cells for producing all classes of active steroid hormones. Mutations in HSD3B2 gene cause a rare form of congenital adrenal hyperplasia with varying degree of salt wasting and incomplete masculinization, resulting from reduced production of corticoids and androgens. Therefore, evaluation of the HSD3B2 enzymatic activity in both pathways for each steroid hormone production is important for accurately understanding and diagnosing this disorder. Using progesterone receptor (PR)- and androgen receptor (AR)-mediated transactivation, we adapted a method that easily evaluates enzymatic activity of HSD3B2 by quantifying the conversion from substrates [pregnenolone (P5) and dehydroepiandrosterone (DHEA)] to (progesterone and androstenedione). HEK293 cells were transduced to express human HSD3B2, and incubated medium containing P5 or DHEA. Depending on the incubation time with HSD3B2-expressing cells, the culture media progressively increased luciferase activities in CV-1 cells, transfected with the PR/AR expression vector and progesterone-/androgen-responsive reporter. Culture media from human and other mammalian HSD3B1-expressing cells also increased the luciferase activities. HEK293 cells expressing various missense mutations in the HSD3B2 gene revealed the potential of this system to evaluate the relationship between the enzymatic activities of mutant proteins and patient phenotype.
-
Acyl modifications in bovine, porcine, and equine ghrelins Reviewed
Ida T., Tominaga H., Iwamoto E., Kurogi A., Okura A., Shimada K., Kato J., Kuwano A., Ode H., Nagata S., Kitamura K., Yazawa T., Sato-Hashimoto M., Yasuda M., Miyazato M., Shiimura Y., Sato T., Kojima M.
Frontiers in Endocrinology 15 1411483 2024.5
Authorship：Lead author, Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers in Endocrinology
Ghrelin is a peptide hormone with various important physiological functions. The unique feature of ghrelin is its serine 3 acyl-modification, which is essential for ghrelin activity. The major form of ghrelin is modified with n-octanoic acid (C8:0) by ghrelin O-acyltransferase. Various acyl modifications have been reported in different species. However, the underlying mechanism by which ghrelin is modified with various fatty acids remains to be elucidated. Herein, we report the purification of bovine, porcine, and equine ghrelins. The major active form of bovine ghrelin was a 27-amino acid peptide with an n-octanoyl (C8:0) modification at Ser3. The major active form of porcine and equine ghrelin was a 28-amino acid peptide. However, porcine ghrelin was modified with n-octanol (C8:0), whereas equine ghrelin was modified with n-butanol (C4:0) at Ser3. This study indicates the existence of structural divergence in ghrelin and suggests that it is necessary to measure the minor and major forms of ghrelin to fully understand its physiology.
-
Jiang D, Matsuzaki M, Ida T, Kitamura K, Kato J
Hypertension research : official journal of the Japanese Society of Hypertension 47 ( 4 ) 1017 - 1023 2024.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Nature
Increased blood pressure variability (BPV) was shown to be associated with cardiovascular morbidities and/or mortalities. There are various types of BPV depending on time intervals of BP measurements, ranging from beat-to-beat to visit-to-visit or year-to-year. We previously found that continuous infusion of noradrenaline (NA) for 14 days increased short-term BPV every 15 min in rats. The aims of this study were to examine (1) whether NA infusion increases very short-term beat-to-beat BPV, (2) the effects of azelnidipine and hydralazine on NA-induced BPV, and (3) whether baroreceptor reflex sensitivity (BRS) is affected by NA or NA plus those vasodilators. Nine-week-old Wistar rats infused subcutaneously with 30 μg/h NA were orally treated with or without 9.7 mg/day azelnidipine or 5.9 mg/day hydralazine over 14 days. BP levels were continuously monitored via abdominal aortic catheter with a telemetry system in an unrestrained condition. Standard deviations (SDs) were used to evaluate beat-to-beat BPV and BPV every 15 min which was obtained by averaging BP levels for 10-s segment at each time point. BRS was determined by a sequence analysis. Continuous NA infusion over 14 days increased average BP, beat-to-beat BPV, and BPV every 15 min, lowering BRS. Comparing the two vasodilators, hydralazine reduced BP elevation by NA; meanwhile, azelnidipine alleviated BPV augmentation, preserving BRS, despite a smaller BP reduction. Thus, NA infusion increased both very short- and short-term BPV concomitantly with impaired BRS, while azelnidipine had an inhibitory effect, possibly independent of BP-lowering, on those types of BPV and impairment of BRS.
-
Diversity of Androgens; Comparison of Their Significance and Characteristics in Vertebrate Species Reviewed
Yazawa T., Imamichi Y., Sato T., Ida T., Umezawa A., Kitano T.
Zoological Science 41 ( 1 ) 77 - 86 2024.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Zoological Science
Androgen(s) is one of the sex steroids that are involved in many physiological phenomena of vertebrate species. Although androgens were originally identified as male sex hormones, it is well known now that they are also essential in females. As in the case of other steroid hormones, androgen is produced from cholesterol through serial enzymatic reactions. Although testis is a major tissue to produce androgens in all species, androgens are also produced in ovary and adrenal (interrenal tissue). Testosterone is the most common and famous androgen. It represents a major androgen both in males and females of almost vertebrate species. In addition, testosterone is a precursorforproducingsignificantandrogenssuchas11-ketotestosterone,5α-dihydrotestosterone, 11-ketodihydrotestosterones and 15α-hydroxytestosterone in a species- or sex-dependent manner for their homeostasis. In this article, we will review the significance and characteristics of these androgens, following a description of the history of testosterone discovery and its synthetic pathways.
DOI： 10.2108/zs230064
-
Izumi T., Saito A., Ida T., Mukuda T., Katayama Y., Wong M.K.S., Tsukada T.
Cell and Tissue Research 396 ( 2 ) 197 - 212 2024
Language：English Publishing type：Research paper (scientific journal) Publisher：Cell and Tissue Research
The natriuretic peptide (NP) family consists of cardiac NPs (ANP, BNP, and VNP) and brain NPs (CNPs) in teleosts. In addition to CNP1-4, a paralogue of CNP4 (named CNP4b) was recently discovered in basal teleosts including Japanese eel. Mammals have lost most Cnps during the evolution, but teleost cnps were conserved and diversified, suggesting that CNPs are important hormones for maintaining brain functions in teleost. The present study evaluated the potency of each Japanese eel CNP to their NP receptors (NPR-A, NPR-B, NPR-C, and NPR-D) overexpressed in CHO cells. A comprehensive brain map of cnps- and nprs-expressing neurons in Japanese eel was constructed by integrating the localization results obtained by in situ hybridization. The result showed that CHO cells expressing NPR-A and NPR-B induced strong cGMP productions after stimulation by cardiac and brain NPs, respectively. Regarding brain distribution of cnps, cnp1 is engaged in the ventral telencephalic area and periventricular area including the parvocellular preoptic nucleus (Pp), anterior/posterior tuberal nuclei, and periventricular gray zone of the optic tectum. cnp3 is found in the habenular nucleus and prolactin cells in the pituitary. cnp4 is expressed in the ventral telencephalic area, while cnp4b is expressed in the motoneurons in the medullary area. Such CNP isoform-specific localizations suggest that function of each CNP has diverged in the eel brain. Furthermore, the Pp lacking the blood-brain barrier expressed both npra and nprb, suggesting that endocrine and paracrine NPs interplay for regulating the Pp functions in Japanese eels.
-
Natriuretic peptides potentiate cardiac hypertrophic response to noradrenaline in rats Reviewed
Jiang D., Matsuzaki M., Ida T., Kitamura K., Tsuruda T., Kaikita K., Kato J.
Peptides 166 171035 2023.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Peptides
Excessive activation of the sympathetic nervous system is involved in cardiovascular damage including cardiac hypertrophy. Natriuretic peptides are assumed to exert protective actions for the heart, alleviating hypertrophy and/or fibrosis of the myocardium. In contrast to this assumption, we show in the present study that both atrial and C-type natriuretic peptides (ANP and CNP) potentiate cardiac hypertrophic response to noradrenaline (NA) in rats. Nine-week-old male Wistar rats were continuously infused with subcutaneous 30 micro-g/h NA without or with persistent intravenous administration of either 1.0 micro-g/h ANP or CNP for 14 days. Blood pressure (BP) was recorded under an unrestrained condition by a radiotelemetry system. Cardiac hypertrophic response to NA was evaluated by heart weight/body weight (HW/BW) ratio and microscopic measurement of myocyte size of the left ventricle. Mean BP levels at the light and dark cycles rose by about 20 mmHg following NA infusion for 14 days, with slight increases in HW/BW ratio and ventricular myocyte size. Infusions of ANP and CNP had no significant effects on mean BP in NA-infused rats, while two natriuretic peptides potentiated cardiac hypertrophic response to NA. Cardiac hypertrophy induced by co-administration of NA and ANP was attenuated by treatment with prazosin or atenolol. In summary, both ANP and CNP potentiated cardiac hypertrophic effect of continuously infused NA in rats, suggesting a possible pro-hypertrophic action of natriuretic peptides on the heart.
-
Nakagami S., Notaguchi M., Kondo T., Okamoto S., Ida T., Sato Y., Higashiyama T., Tsai A.Y.L., Ishida T., Sawa S.
Science advances 9 ( 22 ) eadf4803 2023.6
Language：English Publishing type：Research paper (scientific journal) Publisher：Science advances
Plants use many long-distance and systemic signals to modulate growth and development, as well as respond to biotic and abiotic stresses. Parasitic nematodes infect host plant roots and cause severe damage to crop plants. However, the molecular mechanisms that regulate parasitic nematode infections are still unknown. Here, we show that plant parasitic root-knot nematodes (RKNs), Meloidogyne incognita, modulate the host CLAVATA3 (CLV3)/EMBRYO SURROUNDING REGION (CLE)-CLV1 signaling module to promote the infection progression. Plants deficient in the CLE signaling pathway show enhanced RKN resistance, whereas CLE overexpression leads to increased susceptibility toward RKN. Grafting analysis shows that CLV1 expression in the shoot alone is sufficient to positively regulate RKN infection. Together with results from the split-root culture system, infection assays, and CLE3-CLV1 binding assays, we conclude that mobile root-derived CLE signals are perceived by CLV1 in the shoot, which subsequently produce systemic signals to promote gall formation and RKN reproduction.
-
Comparison of Placental HSD17B1 Expression and Its Regulation in Various Mammalian Species. Reviewed
Yazawa T, Islam MS, Imamichi Y, Watanabe H, Yaegashi K, Ida T, Sato T, Kitano T, Matsuzaki S, Umezawa A, Muranishi Y
Animals : an open access journal from MDPI 13 ( 4 ) 2023.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Animals
During mammalian gestation, large amounts of progesterone are produced by the placenta and circulate for the maintenance of pregnancy. In contrast, primary plasma estrogens are different between species. To account for this difference, we compared the expression of ovarian and placental steroidogenic genes in various mammalian species (mouse, guinea pig, porcine, ovine, bovine, and human). Consistent with the ability to synthesize progesterone, CYP11A1/Cyp11a1, and bi-functional HSD3B/Hsd3b genes were expressed in all species. CYP17A1/Cyp17a1 was expressed in the placenta of all species, excluding humans. CYP19A/Cyp19a1 was expressed in all placental estrogen-producing species, whereas estradiol-producing HSD17B1 was only strongly expressed in the human placenta. The promoter region of HSD17B1 in various species possesses a well-conserved SP1 site that was activated in human placental cell line JEG-3 cells. However, DNA methylation analyses in the ovine placenta showed that the SP1-site in the promoter region of HSD17B1 was completely methylated. These results indicate that epigenetic regulation of HSD17B1 expression is important for species-specific placental sex steroid production. Because human HSD17B1 showed strong activity for the conversion of androstenedione into testosterone, similar to HSD17B1/Hsd17b1 in other species, we also discuss the biological significance of human placental HSD17B1 based on the symptoms of aromatase-deficient patients.
DOI： 10.3390/ani13040622
-
Kobayashi M, Maruyama N, Yamamoto Y, Togawa T, Ida T, Yoshida M, Miyazato M, Kitada M, Hayashi Y, Kashiwagi A, Kitamura T
Journal of diabetes investigation 14 ( 5 ) 648 - 658 2023.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Diabetes Investigation
Aims/Introduction: Glucagon, a peptide hormone produced from proglucagon, is involved in the pathophysiology of diabetes. Plasma glucagon levels are currently measured by sandwich enzyme-linked immunosorbent assay (ELISA), but the currently used sandwich ELISA cross-reacts with proglucagon-derived peptides, thereby providing incorrect results in subjects with elevated plasma proglucagon-derived peptide levels. We aimed to develop a more broadly reliable ELISA for measuring plasma glucagon levels. Materials and Methods: A new sandwich ELISA was developed using newly generated monoclonal antibodies against glucagon. After its validation, plasma glucagon levels were measured with the new ELISA and the currently used ELISA in subjects who underwent laparoscopic sleeve gastrectomy (LSG) and in outpatients with suspected glucose intolerance. The ELISA results were compared with those from liquid chromatography-high resolution mass (LC-HRMS) analysis, which we previously established as the most accurate measuring system. Results: The new ELISA has high specificity (<1% cross-reactivities) and high sensitivity (a lower range of 0.31 pmol/L). Plasma glucagon values in the subjects who underwent laparoscopic sleeve gastrectomy and some outpatients with suspected glucose intolerance differed between the new ELISA and the currently used ELISA. These subjects also showed markedly high plasma glicentin levels. Despite the elevated plasma glicentin levels, the new ELISA showed better positive correlation with LC-HRMS than did the currently used ELISA. Conclusions: The new ELISA enables more accurate measurement of plasma glucagon than the currently used ELISA, even in subjects with elevated proglucagon-derived peptide levels. It should be clinically useful in elucidating the pathophysiology of individual diabetic patients.
DOI： 10.1111/jdi.13986
-
Insights into the Regulation of Offspring Growth by Maternally Derived Ghrelin Reviewed
Sato T, Ida T, Shimura Y, IMatsui K, Oishi K, Kojima M
Frontiers in Endocrinology 13 852636 2022
Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers in Endocrinology
The regulation of fetal development by bioactive substances such as hormones and neuropeptides derived from the gestational mother is considered to be essential for the development of the fetus. On the other hand, it has been suggested that changes in the physiological state of the pregnant mother due to various factors may alter the secretion of these bioactive substances and induce metabolic changes in the offspring, such as obesity, overeating, and inflammation, thereby affecting postnatal growth and health. However, our knowledge of how gestational maternal bioactive substances modulate offspring physiology remains fragmented and lacks a systematic understanding. In this mini-review, we focus on ghrelin, which regulates growth and energy metabolism, to advance our understanding of the mechanisms by which maternally derived ghrelin regulates the growth and health of the offspring. Understanding the regulation of offspring growth by maternally-derived ghrelin is expected to clarify the fetal onset of metabolic abnormalities and lead to a better understanding of lifelong health in the next generation of offspring.
-
Thermoregulatory role of ghrelin in the induction of torpor under a restricted feeding condition Reviewed
Sato T., Oishi K., Koga D., Ida T., Sakai Y., Kangawa K., Kojima M.
Scientific Reports 11 ( 1 ) 17954 2021.12
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Scientific Reports
Ghrelin, a circulating orexigenic hormone secreted from the stomach, stimulates appetite and food intake by activating the hypothalamic arcuate nucleus. Administration of exogenous ghrelin exerts anabolic effects, causing weight gain, increased adiposity, and decreased metabolism. Body temperature (BT), which is determined by the balance of heat production and heat loss, must be strictly regulated to maintain proper cellular function and metabolism. However, the role of ghrelin in thermoregulation remains unclear. In this study, we found that ghrelin was essential for decreasing BT when mice are placed under calorie restriction. Elevated ghrelin concentrations induced by fasting correlated with significant decreases in BT, a hibernation-like state called torpor. Ghrelin-deficient (Ghrl−/−) animals could not enter torpor. The BT of Ghrl−/− mice also remained high under restricted feeding, but the animals gradually entered precipitous hypothermia, indicating thermoregulatory impairment. These effects of ghrelin on thermoregulation were the result of suppression of sympathetic nervous system activity input to brown adipose tissue; in the absence of ghrelin, it was not possible to suppress uncoupling protein 1 (ucp1) expression and decrease BT in low-energy states. Together, these findings demonstrate that ghrelin is an essential circulating hormone involved in lowering BT.
-
Analyses of molecular characteristics and enzymatic activities of ovine hsd17b3 Reviewed
Islam M.S., Uwada J., Hayashi J., Kikuya K.I., Muranishi Y., Watanabe H., Yaegashi K., Hasegawa K., Ida T., Sato T., Imamichi Y., Kitano T., Miyashiro Y., Khan R.I., Takahashi S., Umezawa A., Suzuki N., Sekiguchi T., Yazawa T.
Animals 11 ( 10 ) 2021.10
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Animals
17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) converts androstenedione (A4) into testosterone (T), which regulates sex steroid production. Because various mutations of the HSD17B3 gene cause disorder of sex differentiation (DSD) in multiple mammalian species, it is very important to reveal the molecular characteristics of this gene in various species. Here, we revealed the open reading frame of the ovine HSD17B3 gene. Enzymatic activities of ovine HSD17B3 and HSD17B1 for converting A4 to T were detected using ovine androgen receptor-mediated transactivation in reporter assays. Although HSD17B3 also converted estrone to estradiol, this activity was much weaker than those of HSD17B1. Although ovine HSD17B3 has an amino acid sequence that is conserved compared with other mammalian species, it possesses two amino acid substitutions that are consistent with the reported variants of human HSD17B3. Substitutions of these amino acids in ovine HSD17B3 for those in human did not affect the enzymatic activities. However, enzymatic activities declined upon missense mutations of the HSD17B3 gene associated with 46,XY DSD, affecting amino acids that are conserved between these two species. The present study provides basic information and tools to investigate the molecular mechanisms behind DSD not only in ovine, but also in various mammalian species.
DOI： 10.3390/ani11102876
-
Kato J., Kawagoe Y., Jiang D., Ida T., Shimamoto S., Igarashi K., Kitamura K.
Peptides 142 2021.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Peptides
Plasma levels of the hypotensive peptides of adrenomedullin and atrial and B-type natriuretic peptides (AM, ANP, BNP) are possible biomarkers for cardiovascular diseases. Increased variability of body mass index (BMI) over a certain period of time has been reported to be associated with cardiovascular morbidity or mortality. The aim of this study is to examine clinical significance of those hypotensive peptides as biomarkers by analyzing the relationship between plasma levels of the peptides and year-by-year variability of BMI in the general population without overt cardiovascular diseases. The subjects were 427 local residents (141 males and 286 females) attending their annual health check-up, who had been examined at least 5 times over the preceding period of 10 years. They were divided into two groups of low or high variability by the median of coefficient of variation (CV) of BMI values for each gender. Plasma AM levels of those with high year-by-year variability of BMI were significantly increased, as compared to the group with low variability, in both genders; meanwhile, such a difference was not noted in plasma levels of the natriuretic peptides. No significant differences were found in the basal parameters, which could affect plasma AM level, such as age, BMI, blood pressure or serum creatinine, between two groups. In conclusion, increase in plasma AM was associated with high year-by-year variability of BMI in the general population without overt heart disease. This relationship between the two suggests that increased plasma AM level is a cardiovascular risk marker.
-
Characterization of putative tachykinin peptides in Caenorhabditis elegans Reviewed
Sakai N., Ohno H., Yoshida M., Iwamoto E., Kurogi A., Jiang D., Sato T., Miyazato M., Kojima M., Kato J., Ida T.
Biochemical and Biophysical Research Communications 559 197 - 202 2021.6
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Biochemical and Biophysical Research Communications
Tachykinin-like peptides, such as substance P, neurokinin A, and neurokinin B, are among the earliest discovered and best-studied neuropeptide families, and research on them has contributed greatly to our understanding of the endocrine control of many physiological processes. However, there are still many orphan tachykinin receptor homologs for which cognate ligands have not yet been identified, especially in small invertebrates, such as the nematode Caenorhabditis elegans (C. elegans). We here show that the C. elegans nlp-58 gene encodes putative ligands for the orphan G protein-coupled receptor (GPCR) TKR-1, which is a worm ortholog of tachykinin receptors. We first determine, through an unbiased biochemical screen, that a peptide derived from the NLP-58 preprotein stimulates TKR-1. Three mature peptides that are predicted to be generated from NLP-58 show potent agonist activity against TKR-1. We designate these peptides as C. elegans tachykinin (CeTK)-1, −2, and −3. The CeTK peptides contain the C-terminal sequence GLR-amide, which is shared by tachykinin-like peptides in other invertebrate species. nlp-58 exhibits a strongly restricted expression pattern in several neurons, implying that CeTKs behave as neuropeptides. The discovery of CeTKs provides important information to aid our understanding of tachykinin-like peptides and their functional interaction with GPCRs.
-
Yazawa T., Inaba H., Imamichi Y., Sekiguchi T., Uwada J., Islam M.S., Orisaka M., Mikami D., Ida T., Sato T., Miyashiro Y., Takahashi S., Khan M.R.I., Suzuki N., Umezawa A., Kitano T.
Frontiers in Endocrinology 12 657360 2021.3
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Frontiers in Endocrinology
Although 11-ketotestosterone (11KT) and testosterone (T) are major androgens in both teleosts and humans, their 5α-reduced derivatives produced by steroid 5α-reductase (SRD5A/srd5a), i.e., 11-ketodihydrotestosterone (11KDHT) and 5α-dihydrotestosterone (DHT), remains poorly characterized, especially in teleosts. In this study, we compared the presence and production of DHT and 11KDHT in Japanese eels and humans. Plasma 11KT concentrations were similar in both male and female eels, whereas T levels were much higher in females. In accordance with the levels of their precursors, 11KDHT levels did not show sexual dimorphism, whereas DHT levels were much higher in females. It is noteworthy that plasma DHT levels in female eels were higher than those in men. In addition, plasma 11KDHT was undetectable in both sexes in humans, despite the presence of 11KT. Three srd5a genes (srd5a1, srd5a2a and srd5a2b) were cloned from eel gonads. All three srd5a genes were expressed in the ovary, whereas only both srd5a2 genes were expressed in the testis. Human SRD5A1 was expressed in testis, ovary and adrenal, whereas SRD5A2 was expressed only in testis. Human SRD5A1, SRD5A2 and both eel srd5a2 isoforms catalyzed the conversion of T and 11KT into DHT and 11KDHT, respectively, whereas only eel srd5a1 converted T into DHT. DHT and 11KDHT activated eel androgen receptor (ar)α-mediated transactivation as similar fashion to T and 11KT. In contrast, human AR and eel arβ were activated by DHT and11KDHT more strongly than T and 11KT. These results indicate that in teleosts, DHT and 11KDHT may be important 5α-reduced androgens produced in the gonads. In contrast, DHT is the only major 5α-reduced androgens in healthy humans.
-
11-Ketotestosterone is a Major Androgen Produced in Porcine Adrenal Glands and Testes. Reviewed
Yazawa T, Sato T, Nemoto T, Nagata S, Imamichi Y, Kitano T, Sekiguchi T, Uwada J, Islam MS, Mikami D, Nakajima I, Takahashi S, Khan MRI, Suzuki N, Umezawa A, Ida T
The Journal of steroid biochemistry and molecular biology 210 105847 2021.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Steroid Biochemistry and Molecular Biology
Porcine steroid hormone profiles have some unique characteristics. We previously studied human and murine steroidogenesis using steroidogenic cells-derived from mesenchymal stem cells (MSCs). To investigate porcine steroidogenesis, we induced steroidogenic cells from porcine subcutaneous preadipocytes (PSPA cells), which originate from MSCs. Using cAMP, adenovirus-mediated introduction of steroidogenic factor-1 (SF-1)/adrenal 4-binding protein (Ad4BP) induced the differentiation of PSPA cells into sex steroid-producing cells. Introducing SF-1/Ad4BP also induced the aldo-keto reductase 1C1 (AKR1C1) gene. Porcine AKR1C1 had 17β-hydroxysteroid dehydrogenase activity, which converts androstenedione and 11-ketoandrostenedione into testosterone (T) and 11-ketotestosteorne (11KT). Furthermore, differentiated cells expressed hydroxysteroid 11β-dehydrogenase 2 (HSD11B2) and produced 11KT. HSD11B2 was expressed in testicular Leydig cells and the adrenal cortex. 11KT was present in the plasma of both immature male and female pigs, with slightly higher levels in the male pigs. T levels were much higher in the male pigs. It is noteworthy that in the female pigs, the 11KT levels were >10-fold higher than the T levels. However, castration altered the 11KT and T plasma profiles in the male pigs to near those of the females. 11KT induced endothelial nitric oxide synthase (eNOS) in porcine vascular endothelial cells. These results indicate that 11KT is produced in porcine adrenal glands and testes, and may regulate cardiovascular functions through eNOS expression.
-
Evaluation of 17β-hydroxysteroid dehydrogenase activity using androgen receptor-mediated transactivation. Reviewed
Yazawa T, Imamichi Y, Uwada J, Sekiguchi T, Mikami D, Kitano T, Ida T, Sato T, Nemoto T, Nagata S, Islam Khan MR, Takahashi S, Ushikubi F, Suzuki N, Umezawa A, Taniguchi T
The Journal of steroid biochemistry and molecular biology 196 105493 2020.2
Language：Japanese Publishing type：Research paper (scientific journal)
-
Suppressive effect of ghrelin on nicotine-induced clock gene expression in the mouse pancreas. Reviewed
Sato T, Oishi K, Ida T, Kojima M
Endocrine journal 67 ( 1 ) 73 - 80 2020.1
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：一般社団法人 日本内分泌学会
Those who smoke nicotine-based cigarettes have elevated plasma levels of ghrelin, a hormone secreted from the stomach. Ghrelin has various physiological functions and has recently been shown to be involved in regulating biological rhythms. Therefore, in this study, in order to clarify the significance of the plasma ghrelin increase in smokers, we sought to clarify how nicotine and ghrelin affect the expression dynamics of clock genes using a mouse model. A single dose of nicotine administered intraperitoneally increased plasma ghrelin concentrations transiently, whereas continuous administration of nicotine with an osmotic minipump did not induce any change in the plasma ghrelin concentration. Single administration of nicotine resulted in a transient increase in ghrelin gene expression in the pancreas but not in the stomach, which is the major producer of ghrelin. In addition, in the pancreas, the expression of clock genes was also increased temporarily. Therefore, in order to clarify the interaction between nicotine-induced ghrelin gene expression and clock gene expression in the pancreas, nicotine was administered to ghrelin gene-deficient mice. Administration of nicotine to ghrelin-gene deficient mice increased clock gene expression in the pancreas. However, upon nicotine administration to mice pretreated with octanoate to upregulate ghrelin activity, expression levels of nicotine-inducible clock genes in the pancreas were virtually the same as those in mice not administered nicotine. Thus, our findings indicate that pancreatic ghrelin may suppress nicotine-induced clock gene expression in the pancreas.
-
A new action of peptide hormones for survival in a low-nutrient environment. Reviewed
Sato T, Nemoto T, Hasegawa K, Ida T, Kojima M
Endocrine journal 66 ( 11 ) 943 - 952 2019.11
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：一般社団法人 日本内分泌学会
Malnutrition occurs when nutrient intake is too low for any reason and occurs regardless of gender or age. Therefore, besides loss of eating or digestive functionality due to illness, malnutrition can occur when a healthy individual undergoes an extreme diet and biases their nutrition, or when athletes exerts more energy than they can replenish through food. It has recently been reported that in Japan, the mortality rate of leaner individuals is equal to or higher than that of obese people. It is important to understand what homeostatic maintenance mechanism is behind this when the body is under hypotrophic conditions. Such mechanisms are generally endocranially controlled. We address this fundamental concern in this paper by focusing on peptide hormones. We introduce a mechanism for survival in a malnourished state <i>via</i> the regulation of food intake and temperature. Additionally, we will discuss the latest findings and future prospects for research on changes in the endocrine environment associated with malnutrition associated with exercise. We also review changes in next-generation endocrine environments when caused by malnutrition brought on by dieting.
-
Searching for peptide hormones
Ida T
Abstracts for Annual Meeting of Japanese Proteomics Society 2019 ( 0 ) 148 - 148 2019
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Proteomics Society (Japan Human Proteome Organisation)
-
Fujiwara Y., Hermann-Luibl C., Katsura M., Sekiguchi M., Ida T., Helfrich-Förster C., Yoshii T.
Frontiers in Physiology 9 ( SEP ) 1276 2018.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers in Physiology
© 2018 Fujiwara, Hermann-Luibl, Katsura, Sekiguchi, Ida, Helfrich-Förster and Yoshii. The fruit fly Drosophila melanogaster possesses approximately 150 brain clock neurons that control circadian behavioral rhythms. Even though individual clock neurons have self-sustaining oscillators, they interact and synchronize with each other through a network. However, little is known regarding the factors responsible for these network interactions. In this study, we investigated the role of CCHamide1 (CCHa1), a neuropeptide expressed in the anterior dorsal neuron 1 (DN1a), in intercellular communication of the clock neurons. We observed that CCHa1 connects the DN1a clock neurons to the ventral lateral clock neurons (LNv) via the CCHa1 receptor, which is a homolog of the gastrin-releasing peptide receptor playing a role in circadian intercellular communications in mammals. CCHa1 knockout or knockdown flies have a generally low activity level with a special reduction of morning activity. In addition, they exhibit advanced morning activity under light-dark cycles and delayed activity under constant dark conditions, which correlates with an advance/delay of PAR domain Protein 1 (PDP1) oscillations in the small-LNv (s-LNv) neurons that control morning activity. The terminals of the s-LNv neurons show rather high levels of Pigment-dispersing factor (PDF) in the evening, when PDF is low in control flies, suggesting that the knockdown of CCHa1 leads to increased PDF release; PDF signals the other clock neurons and evidently increases the amplitude of their PDP1 cycling. A previous study showed that high-amplitude PDP1 cycling increases the siesta of the flies, and indeed, CCHa1 knockout or knockdown flies exhibit a longer siesta than control flies. The DN1a neurons are known to be receptive to PDF signaling from the s-LNv neurons; thus, our results suggest that the DN1a and s-LNv clock neurons are reciprocally coupled via the neuropeptides CCHa1 and PDF, and this interaction fine-tunes the timing of activity and sleep.
-
Interleukin-15 derived from Guanylin-GC-C-expressing macrophages inhibits fatty acid synthase in adipocytes. Reviewed
Akieda-Asai S, Ida T, Miyazato M, Kangawa K, Date Y
Peptides 99 14 - 19 2017.10
Language：English Publishing type：Research paper (scientific journal)
-
Role of neuromedin U in accelerating of non-alcoholic steatohepatitis in mice. Reviewed
Teranishi H, Hayashi M, Higa R, Mori K, Miyazawa T, Hino J, Amano Y, Tozawa R, Ida T, Hanada T, Miyazato M, Hanada R, Kangawa K, Nakao K
Peptides 2017.10
Language：English Publishing type：Research paper (scientific journal)
-
Identification of neuromedin U precursor-related peptide and its possible role in the regulation of prolactin release. Reviewed
Mori K, Ida T, Fudetani M, Mori M, Kaiya H, Hino J, Nakahara K, Murakami N, Miyazato M, Kangawa K
Scientific reports 7 ( 1 ) 10468 2017.9
Language：English Publishing type：Research paper (scientific journal)
-
Luqin-like RYamide peptides regulate food-evoked responses in C. elegans. Reviewed
Ohno H, Yoshida M, Sato T, Kato J, Miyazato M, Kojima M, Ida T, Iino Y
eLife 6 2017.8
Language：English Publishing type：Research paper (scientific journal)
DOI： 10.7554/eLife.28877
-
Kono T., Ida T., Kawahara N., Watanabe F., Biswas G., Sato T., Mori K., Miyazato M.
Developmental and Comparative Immunology 73 246 - 256 2017.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Developmental and Comparative Immunology
© 2017 Elsevier Ltd In this study, immunoregulatory function of neuromedin U (Nmu) in the teleost fish Fugu (Takifugu rubripes) was characterized. Three splicing variants of nmu mRNA encoding preproNMUs consisting of 164 (Nmu1), 139 (Nmu2), and 129 (Nmu3) amino acid residues were found in Fugu.The biologically active C-terminal region of Fugu Nmu showed high homology among fish and other vertebrate NMUs. The genomic organization of Fugu nmu differed from those of zebrafish and mammals. However, in phylogenetic analysis, Fugu Nmu formed a cluster with NMUs of other vertebrates, in addition to neuromedin S. The splicing variants of mRNA were identified in various tissues. Nmu-21 and Nmu-9 were purified as endogenous peptides from Fugu intestine. The synthetic Nmu-21 peptide activated phagocytic cells, and elevated the expression of cytokine mRNA in peripheral blood leukocytes.
-
Mekata T., Kono T., Satoh J., Yoshida M., Mori K., Sato T., Miyazato M., Ida T.
General and Comparative Endocrinology 246 321 - 330 2017.5
Language：English Publishing type：Research paper (scientific journal) Publisher：General and Comparative Endocrinology
© 2017 To understand the regulation systems of appetite, bioactive peptides from the kuruma shrimp Marsupenaeus japonicus (Mj) were isolated and purified by reverse pharmacological assays using CHO cel ls expressing the Drosophila melanogaster G-protein-coupled receptors (GPCRs) CG5811 (a RYamide receptor) or CG14593 (a CCHamide-2 receptor). Four peptides having binding activity to GPCRs were obtained and named Mj RYamide-1, Mj RYamide-2, Mj RYamide-3, and Mj CCHamide. Genes encoding the prepropeptides of these peptides were identified using kuruma shrimp transcriptome databases. The Mj prepro-RYamide gene encodes a 130-amino acid polypeptide containing Mj RYamide-1, Mj RYamide-2, and Mj RYamide-3, whereas the Mj prepro-CCHamide gene encodes a 119-amino acid polypeptide containing a single Mj CCHamide peptide. The expression of these genes was confirmed in various neuronal organs including the brain and ventral nerve cord. In addition, prepro-RYamide gene expression is significantly reduced in the brain after starvation. RYamides may thus be associated with regulation of feeding or digestion. Changes in kayak (the c-fos ortholog in invertebrates) gene expression after administration of synthetic peptides were also investigated. Mj kayak expression levels are upregulated in hepatopancreas after treatment with Mj RYamide-3 or CCHamide. Thus, the peptides isolated in this study may have some regulatory effect on cellular metabolism in aquacultured invertebrates.
-
Role of biological rhythms in the performance of physical activity Reviewed
Sato Takahiro, Ida Takanori, Kojima Masayasu
The Journal of Physical Fitness and Sports Medicine 6 ( 3 ) 125 - 134 2017
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：一般社団法人日本体力医学会
Most organisms display various periodicities. Periodicity has been observed in humans in association with sleep, body temperature and hormone secretion. The molecular mechanisms involved are being elucidated by the investigation of clock genes in mammals. The relationship between biological rhythms and disease is also being studied. For example, myocardial infarction occurs more frequently in the morning, and disruption of biological rhythm is associated with obesity and diabetes. Some drugs have different medicinal effects depending on the time of dosing. Drug therapy known as chronotherapy, that takes into account the diurnal rhythm found in a given target disease, is being administered in some cases. Moreover, physiological responses and metabolism differ with time. Therefore, understanding the mechanisms underlying biological rhythms could enable the safe and effective performance of physical activity, in addition to potential medical applications. This review article outlines current understandings of biological rhythmicity and explores the relationship between biological rhythms and exercise, training, and sports.
DOI： 10.7600/jpfsm.6.125
-
Suppressive effects of dRYamides on feeding behavior of the blowfly, Phormia regina Reviewed
Maeda T, Nakamura Y, Shiotani H, Hojo M, Yoshii T, Ida T, Sato T, Yoshida M, Miyazato M, Kojima M, Ozaki M
Zoological Letters 2015.9
Language：English Publishing type：Research paper (scientific journal)
-
Physiological functions and pathology of ghrelin Reviewed
Sato T, Oishi K, Ida T, Kojima M
American Journal of Life Sciences 2015.5
Language：English Publishing type：Research paper (scientific journal)
-
Sano H., Nakamura A., Texada M., Truman J., Ishimoto H., Kamikouchi A., Nibu Y., Kume K., Ida T., Kojima M.
PLoS Genetics 11 ( 5 ) e1005209 2015.5
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：PLoS Genetics
© 2015 Sano et al. The coordination of growth with nutritional status is essential for proper development and physiology. Nutritional information is mostly perceived by peripheral organs before being relayed to the brain, which modulates physiological responses. Hormonal signaling ensures this organ-to-organ communication, and the failure of endocrine regulation in humans can cause diseases including obesity and diabetes. In Drosophila melanogaster, the fat body (adipose tissue) has been suggested to play an important role in coupling growth with nutritional status. Here, we show that the peripheral tissue-derived peptide hormone CCHamide-2 (CCHa2) acts as a nutrient-dependent regulator of Drosophila insulin-like peptides (Dilps). A BAC-based transgenic reporter revealed strong expression of CCHa2 receptor (CCHa2-R) in insulin-producing cells (IPCs) in the brain. Calcium imaging of brain explants and IPC-specific CCHa2-R knockdown demonstrated that peripheral-tissue derived CCHa2 directly activates IPCs. Interestingly, genetic disruption of either CCHa2 or CCHa2-R caused almost identical defects in larval growth and developmental timing. Consistent with these phenotypes, the expression of dilp5, and the release of both Dilp2 and Dilp5, were severely reduced. Furthermore, transcription of CCHa2 is altered in response to nutritional levels, particularly of glucose. These findings demonstrate that CCHa2 and CCHa2-R form a direct link between peripheral tissues and the brain, and that this pathway is essential for the coordination of systemic growth with nutritional availability. A mammalian homologue of CCHa2-R, Bombesin receptor subtype-3 (Brs3), is an orphan receptor that is expressed in the islet β-cells; however, the role of Brs3 in insulin regulation remains elusive. Our genetic approach in Drosophila melanogaster provides the first evidence, to our knowledge, that bombesin receptor signaling with its endogenous ligand promotes insulin production.
-
Identification and application of Drosophila novel bioactive peptides dRYamides Reviewed
Ida T, Iwamoto E, Sato T, Kojima M
American Journal of Life Sciences 2015.4
Language：English Publishing type：Research paper (scientific journal)
-
Suppressive effects of dRYamides on feeding behavior of the blowfly, Phormia regina. Reviewed
Maeda T, Nakamura Y, Shiotani H, Hojo MK, Yoshii T, Ida T, Sato T, Yoshida M, Miyazato M, Kojima M, Ozaki M
Zoological letters 1 35 2015
Language：Japanese Publishing type：Research paper (scientific journal)
-
Physiological roles of ghrelin on obesity Reviewed
Sato T., Ida T., Nakamura Y., Shiimura Y., Kangawa K., Kojima M.
Obesity Research and Clinical Practice 8 ( 5 ) e405 - e413 2014.9
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Obesity Research and Clinical Practice
© 2013 Asian Oceanian Association for the Study of Obesity. Ghrelin is a stomach hormone that acts as an endogenous ligand of orphan G-protein coupled receptor. Ghrelin has various physiological functions, such as the stimulation of growth hormone release and of appetite, and fat accumulation. Ghrelin is the only peripheral hormone to transmit satiety signal. Mature ghrelin peptide is consisted of 28 amino acid residues, and is unusual among peptide hormones in that Ser3 is n-octanoylated to obtain. Furthermore, this modification is essential for ghrelin's activity. In order to add this side chain to acyl ghrelin, it is necessary for the recently discovered enzyme, ghrelin-O-acyl transferase (GOAT). Therefore, to understand of ghrelin's functions, it is useful to obtain the knowledge on structures and functions of ghrelin, ghrelin receptor and GOAT. Here, we review our current understanding of the structures and functions of ghrelin, and the relation between obesity and ghrelin. Finally, we referred to the ghrelin and related substances as a drug design target for obesity.
-
More Drosophila enteroendocrine peptides: Orcokinin B and the CCHamides 1 and 2 Reviewed
Veenstra JA, Ida T
Cell Tisuue Res 357 ( 3 ) 607 - 621 2014.5
Language：English Publishing type：Research paper (scientific journal)
-
Mori M., Mori K., Ida T., Sato T., Kojima M., Miyazato M., Kangawa K.
Frontiers in Endocrinology 3 ( DEC ) 2012.12
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Frontiers in Endocrinology
Neuromedin S (NMS) is a neuropeptide identified as another endogenous ligand for two orphan G protein-coupled receptors, FM-3/GPR66 and FM-4/TGR-1, which have also been identifiedastypes1and2receptorsforneuromedinUstructurallyrelatedtoNMS.Although expressionofNMSmRNAisfoundmainlyinthebrain, spleen, andtestis, thedistributionof itspeptidehasnotyetbeeninvestigated. Usinganewlypreparedantiserum, wedeveloped a highly sensitive radioimmunoassay for rat NMS. NMS peptide was clearly detected in the ratbrainataconcentrationof68.3±3.4fmol/gwetweight, butitwashardlydetectedinthe spleenandtestis.AhighcontentofNMSpeptidewasfoundinthehypothalamus, midbrain, and pons-medulla oblongata, whereas abundant expression of NMS mRNA was detected only in the hypothalamus.These differing distributions of the mRNA and peptide suggest that nerve fibers originating from hypothalamic NMS neurons project into the midbrain, pons, or medulla oblongata. In addition, abundant expression of type 2 receptor mRNA was detected not only in the hypothalamus, but also in the midbrain and pons-medulla oblongata. These results suggest novel, unknown physiological roles of NMS within the brainstem. © 2012 Mori, Mori, Ida, Sato, Kojima, MiyazatoandKangawa.
-
Ida T., Takahashi T., Tominaga H., Sato T., Sano H., Kume K., Ozaki M., Hiraguchi T., Shiotani H., Terajima S., Nakamura Y., Mori K., Yoshida M., Kato J., Murakami N., Miyazato M., Kangawa K., Kojima M.
Frontiers in Endocrinology 3 ( DEC ) 177 2012.12
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Frontiers in Endocrinology
There are many orphan G protein-coupled receptors (GPCRs) for which ligands have not yet been identified. One such GPCR is the bombesin receptor subtype 3 (BRS-3). BRS-3 plays a role in the onset of diabetes and obesity. GPCRs in invertebrates are similar to those in vertebrates. Two Drosophila GPCRs (CG30106 and CG14593) belong to the BRS-3 phylogenetic subgroup. Here, we succeeded to biochemically purify the endogenous ligands of Drosophila CG30106 and CG14593 from whole Drosophila homogenates using functional assays with the reverse pharmacological technique, and identified their primary amino acid sequences.The purified ligands had been termed CCHamide-1 and CCHamide-2, although structurally identical to the peptides recently predicted from the genomic sequence searching. In addition, our biochemical characterization demonstrated two N-terminal extended forms of CCHamide-2.When administered to blowflies, CCHamide-2 increased their feeding motivation. Our results demonstrated these peptides actually present as the major components to activate these receptors in living Drosophila. Studies on the effects of CCHamides will facilitate the search for BRS-3 ligands. © 2012 Ida, Takahashi, Tom-inaga, Sato, Sano, Kume, Ozaki, Hiraguchi, Shiotani, Terajima, Naka-mura, Mori, Yoshida, Kato, Murakami, Miyazato, Kangawa and Kojima.
-
Variety of acyl modifications in mammalian ghrelins. Reviewed
Ida T.
Methods in enzymology 514 63 - 73 2012.12
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Methods in enzymology
Ghrelin, a 28-amino acid-long peptide with an n-octanoyl modification at Ser(3), has been isolated from rat and human stomachs as an endogenous ligand for the growth hormone secretagogue receptor. It is very important to study the ghrelin from mammals (especially, domestic animals) that serve as human companions, food resources, and model organisms. We purified feline and caprine ghrelin and observed that the administration of synthetic ghrelin increased plasma growth hormone (GH) levels in cats and goats. Therefore, we believe that ghrelin may play important roles in GH release in mammals. Copyright © 2012 Elsevier Inc. All rights reserved.
-
Different distribution of neuromedin S (NMS) and its mRNA in the rat brain: NMS peptide is present not only in the hypothalamus as the mRNA, but also in the brainstem Reviewed
Mori M, Mori K, Ida T, Sato T, Kojima M, Miyazato M, Kangawa K
Frontiers in Endocrinol 3 ( 152 ) 2012.1
Language：English Publishing type：Research paper (scientific journal)
-
The role of neuromedin U during inflammatory response in the common carp Reviewed
Kono T., Hamasuna S., Korenaga H., Iizasa T., Nagamine R., Ida T., Sakai M.
Fish and Shellfish Immunology 32 ( 1 ) 151 - 160 2012.1
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Fish and Shellfish Immunology
In the current study, we cloned and characterized the neuromedin U (NMU) gene from the common carp Cyprinus carpio L., and identified its participation in immune responses in the teleost. Five isoforms of the preproNMU genes were generated by alternative splicing and isolated from carp. The longest form of the carp preproNMU1 (isoform 1) cDNA was composed of 803 bp, and contained an 18 bp 5'-UTR, a 212 bp 3'-UTR and a 573 bp open reading frame, which translates into a peptide comprising 190 amino acid (aa) residues. The remaining carp preproNMU isoforms were composed of 175 (preproNMU2), 158 (preproNMU3), 150 (preproNMU4) and 133 (preproNMU5) aa residues. Isoforms 1-3 contained four processing signals (KR or RR), while isoforms 4 and 5 contained only two processing signals. High homology was demonstrated among fish and other vertebral NMU at the biologically active C-terminal region (aa position 175-182). Carp preproNMU transcript variants were identified in various tissues, and the expression pattern has been shown to change depending on feeding status. Moreover, it was shown that the expression of preproNMU3 and preproNMU5 was increased following treatment with bacterial or viral mimics. Finally, we investigated the functional aspect of carp NMU using a synthetic NMU peptide. The peptide was found to increase the expression of inflammation-related cytokine genes in intestinal cells within 1 h of treatment. In addition, the activation of phagocytic cells was also stimulated by the NMU peptide. The discovery of NMU in carp allows for a further understanding of immune regulation by biologically active substances. © 2011 Elsevier Ltd.
-
2. 年少児・障がい者に対するアニマル・セラピーの試み(シンポジウム「各ライフステージでの特色ある心理・心身医学的手法の実践と成果」,第49回日本心身医学会九州地方会演題抄録(1))
久富 一郎, 津輪元 修一, 井田 隆徳, 秋坂 真史
心身医学 52 ( 8 ) 2012
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：一般社団法人 日本心身医学会
-
Variety of acyl modifications in mammalian ghrelins. Reviewed
Ida T
Methods in enzymology 514 63 - 73 2012
Language：Japanese Publishing type：Research paper (scientific journal)
-
HIRAGUCHI Tetsutaro, MAEDA Toru, SHIOTANI Hajime, IDA Takanori, KOJIMA Masayasu, OZAKI Mamiko
The Japanese journal of taste and smell research 18 ( 3 ) 295 - 298 2011.12
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Association for the Study of Taste and Smell
-
Ida T., Takahashi T., Tominaga H., Sato T., Kume K., Yoshizawa-Kumagaye K., Nishio H., Kato J., Murakami N., Miyazato M., Kangawa K., Kojima M.
Biochemical and Biophysical Research Communications 414 ( 1 ) 44 - 48 2011.10
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Biochemical and Biophysical Research Communications
There are many orphan G protein-coupled receptors (GPCRs), for which ligands have not yet been identified, in both vertebrates and invertebrates, such as Drosophila melanogaster. Identification of their cognate ligands is critical for understanding the function and regulation of such GPCRs. Indeed, the discovery of bioactive peptides that bind GPCRs has enhanced our understanding of mechanisms underlying many physiological processes. Here, we identified an endogenous ligand of the Drosophila orphan GPCR, CG34381. The purified ligand is a peptide comprised of 28 amino acids with three intrachain disulfide bonds. The preprotein is coded for by gene CG14871. We designated the cysteine-rich peptide " trissin" (it means for triple S-S bonds) and characterized the structure of intrachain disulfide bonds formation in a synthetic trissin peptide. Because the expression of trissin and its receptor is reported to predominantly localize to the brain and thoracicoabdominal ganglion, trissin is expected to behave as a neuropeptide. The discovery of trissin provides an important lead to aid our understanding of cysteine-rich peptides and their functional interaction with GPCRs. © 2011 Elsevier Inc.
-
Ida T., Takahashi T., Tominaga H., Sato T., Kume K., Ozaki M., Hiraguchi T., Maeda T., Shiotani H., Terajima S., Sano H., Mori K., Yoshida M., Miyazato M., Kato J., Murakami N., Kangawa K., Kojima M.
Biochemical and Biophysical Research Communications 410 ( 4 ) 872 - 877 2011.7
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Biochemical and Biophysical Research Communications
A number of bioactive peptides are involved in regulating a wide range of animal behaviors, including food consumption. Vertebrate neuropeptide Y (NPY) is a potent stimulator of appetitive behavior. Recently, Drosophila neuropeptide F (dNPF) and short NPF (sNPF), the Drosophila homologs of the vertebrate NPY, were identified to characterize the functions of NPFs in the feeding behaviors of this insect. Dm-NPFR1 and NPFR76F are the receptors for dNPF and sNPF, respectively; both receptors are G protein-coupled receptors (GPCRs). Another GPCR (CG5811; NepYR) was indentified in Drosophila as a neuropeptide Y-like receptor. Here, we identified 2 ligands of CG5811, dRYamide-1 and dRYamide-2. Both peptides are derived from the same precursor (CG40733) and have no significant structural similarities to known bioactive peptides. The C-terminal sequence RYamide of dRYamides is identical to that of NPY family peptides; on the other hand, dNPF and sNPF have C-terminal RFamide. When administered to blowflies, dRYamide-1 suppressed feeding motivation. We propose that dRYamides are related to the NPY family in vertebrates, similar to dNPF and sNPF. © 2011 Elsevier Inc.
-
Sato T., Nakashima Y., Nakamura Y., Ida T., Kojima M.
Journal of Molecular Neuroscience 43 ( 2 ) 193 - 199 2011.2
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Journal of Molecular Neuroscience
Ghrelin is a hormone that mediates a variety of physiological roles, such as stimulating appetite, initiating food intake, and modulating energy metabolism. Although it has been reported that a bolus injection of ghrelin decreases blood pressure, the effect of continuous ghrelin administration on vasoregulation has yet to be determined. We examined the longitudinal effect of ghrelin on vasoregulation using Dahl-Iwai salt-sensitive rats. In this model, a high-salt diet induced high blood pressure and increased ghrelin levels but reduced food intake. In salt-sensitive hypertension, cumulative food intake decreased, while both ghrelin messenger RNA levels and plasma ghrelin content increased. Continuous administration of a ghrelin receptor agonist, growth hormone releasing peptide-6 (GHRP-6), for 2 weeks by mini-osmotic pump did not change blood pressure values although the cumulative food intake recovered. In contrast, continuous administration of a ghrelin receptor antagonist, [D-Lys 3 ]-GHRP-6, induced early elevations in blood pressure without changes in heart rate. Quantitative RT-PCR revealed high expression levels of genes involved in the catecholamine biosynthetic pathway, tyrosine hydroxylase and dopamine-β-hydroxylase, after continuous [D-Lys 3 ]-GHRP-6 administration. These results indicate that continuous antagonism of the ghrelin receptor results in early induction of salt-sensitive hypertension in this animal model and suggests that increases in autonomic nervous activity induced by ghrelin receptor antagonism are responsible, as indicated by the high expression levels of genes in the catecholamine biosynthetic pathway. © 2010 Springer Science+Business Media, LLC.
-
Comparison of feeding suppression by the anorexigenic hormones neuromedin U and neuromedin S in rats Reviewed
Nakahara K., Katayama T., Maruyama K., Ida T., Mori K., Miyazato M., Kangawa K., Murakami N.
Journal of Endocrinology 207 ( 2 ) 185 - 193 2010.11
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Journal of Endocrinology
We compared the central mechanisms of feeding suppression by the anorexigenic hormones neuromedin U (NMU) and neuromedin S (NMS) in rats. I.c.v. injection of either NMU or NMS dose dependently decreased 3-h food intake during the first quarter of a dark period. Pretreatment involving i.c.v. injection of a specific anti-NMS IgG blocked the suppression of food intake induced by i.c.v.- and i.p.-injected leptin, but anti-NMU IgG elicited no blockade. Quantitative PCR analysis revealed that i.c.v. injection of NMU or NMS caused a dose-dependent increase in CRH and proopiomelanocortin mRNA expression in the paraventricular nucleus (PVN) and arcuate nucleus (Arc) respectively. In tissue cultures of the Arc, secretion of α-melanocyte-stimulating hormone was stimulated by NMU and NMS, with more potent stimulation by NMS. The time-course curves of the increase in neuronal firing rate in Arc slices in response to NMU and NMS showed almost the same pattern, with a peak 10-15 min after treatment, whereas the time-course curves for the PVN slices differed between NMU and NMS. These results suggest that NMS and NMU may share anorexigenic effects, depending on physiological conditions. © 2010 Society for Endocrinology.
DOI： 10.1677/JOE-10-0081
-
Purification and characterization of caprine ghrelin and its effect on growth hormone release Reviewed
Ida T., Miyazato M., Lin X., Kaiya H., Sato T., Nakahara K., Murakami N., Kangawa K., Kojima M.
Journal of Molecular Neuroscience 42 ( 1 ) 99 - 105 2010.9
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Journal of Molecular Neuroscience
Ghrelin, a novel peptide modified by n-octanoic acid at the third serine residue (Ser 3 ), serves as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R) 1a. The octanoyl modification at Ser 3 is essential for receptor binding or growth hormone release. Here, we report the purification of caprine ghrelin and its physiological role in goats. The major form of caprine ghrelin is a 27 amino acid peptide that is octanoylated (C8:0) at Ser 3 and lacks Gln 14 , which is present in rat and human ghrelin. Additionally, we identified various acyl modifications in caprine ghrelin: nonanoic (C9:0), decanoic (10:0), unsaturated octanoic acids (C8:1), and an unidentified fatty acid modification. We observed that differences in acyl modifications affected GHS-R1a activation. In addition, administration of synthetic bovine ghrelin increased plasma growth hormone (GH) levels in goats. Thus, the present study indicates a structural divergence in caprine ghrelin and suggests that ghrelin is involved in GH release in ruminants. © 2010 Springer Science+Business Media, LLC.
-
Neuromedin U is necessary for normal gastrointestinal motility and is regulated by serotonin Reviewed
Nakashima Y., Ida T., Sato T., Nakamura Y., Takahashi T., Mori K., Miyazato M., Kangawa K., Kusukawa J., Kojima M.
Annals of the New York Academy of Sciences 1200 104 - 111 2010.7
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Annals of the New York Academy of Sciences
Neuromedin U (NMU) was originally isolated from porcine spinal cord and shown to be distributed in numerous tissues, including the gastrointestinal tract. However, little is known about the role of NMU in the regulation of gastrointestinal functions. We established a radioimmunoassay system that is exceptionally specific for mouse NMU and found high NMU content in the gastrointestinal tract, particularly in the Auerbach's and Meissner's plexi, suggesting a possible role of NMU in gastrointestinal motility. NMU promoted small intestinal transit, and NMU deficiency resulted in lowered intestinal motility rate and diminished the effect of serotonin-induced defecation and diarrhea. These results indicate that NMU promotes intestinal transit and maintains intestinal homeostasis. © 2010 New York Academy of Sciences.
-
Takahashi T., Ida T., Sato T., Nakashima Y., Nakamura Y., Tsuji A., Kojima M.
Journal of Biochemistry 146 ( 5 ) 675 - 682 2009.11
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Journal of Biochemistry
Ghrelin was originally isolated from rat stomach as an endogenous ligand for the GH secretagogue receptor. The major active form of ghrelin is a 28-amino acid peptide modified by an n-octanoic acid on the serine 3 residue, and this lipid modification is essential for the biological activity of ghrelin. However, it is not clear whether prohormone convertase (PC) and ghrelin O-acyltransferase (GOAT) are the minimal requirements for synthesis of acyl-modified ghrelin in cultured cells. By using three cultured cell lines, TT, AtT20 and COS-7, in which the expression levels of processing proteases and GOAT vary, we examined the processing patterns of ghrelin precursor. We found that not only PC1/3 but also both PC2 and furin could process proghrelin to the 28-amino acid ghrelin. Moreover, the presence of PC and GOAT in the cells, as well as n-octanoic acid in the culture medium, was necessary to produce n-octanoyl ghrelin.
DOI： 10.1093/jb/mvp112
-
Ohgusu H., Shirouzu K., Nakamura Y., Nakashima Y., Ida T., Sato T., Kojima M.
Biochemical and Biophysical Research Communications 386 ( 1 ) 153 - 158 2009.8
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Biochemical and Biophysical Research Communications
Ghrelin is a peptide hormone in which serine 3 is modified by n-octanoic acid through GOAT (ghrelin O-acyltransferase). However, the enzymological properties of GOAT remain to be elucidated. We analyzed the in vitro activity of GOAT using the recombinant enzyme. Unexpectedly, although the main active form of ghrelin is modified by n-octanoic acid, GOAT had a strong preference for n-hexanoyl-CoA over n-octanoyl-CoA as an acyl donor. Moreover, a four-amino acid peptide derived from the N-terminal sequence of ghrelin can be modified by GOAT, indicating that these four amino acids constitute the core motif for substrate recognition by the enzyme. © 2009 Elsevier Inc. All rights reserved.
-
Miyazato M., Mori K., Ida T., Kojima M., Murakami N., Kangawa K.
Regulatory Peptides 145 ( 1-3 ) 37 - 41 2008.1
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Regulatory Peptides
We identified a novel 36-amino acid neuropeptide in rat brain as an endogenous ligand for the G protein-coupled receptors FM-3/GPR66 and FM-4/TGR-1, which were identified to date as the neuromedin U (NMU) receptors, and designated this peptide neuromedin S (NMS) because it was specifically expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus. NMS shared a C-terminal core structure with NMU. NMS mRNA was highly expressed in the central nervous system, spleen and testis. In rat brain, NMS expression was restricted to the ventrolateral portion of the SCN and has a diurnal peak under light/dark cycling, but remains stable under constant darkness. Intracerebroventricular (ICV) administration of NMS in rats induced nonphotic type phase shifts in the circadian rhythm of locomotor activity. ICV injection of NMS also decreased 12-h food intake during the dark period in rats. This anorexigenic effect was more potent than that observed with the same dose of NMU. ICV administration of NMS increased proopiomelanocortin (POMC) mRNA expression in the arcuate nucleus (Arc) and corticotropin-releasing hormone mRNA in the paraventricular nucleus, and induced c-Fos expression in the POMC neurons in the Arc. These findings suggest that NMS is implicated in the regulation of circadian rhythm and feeding behavior. © 2007 Elsevier B.V. All rights reserved.
-
Ghrelin deficiency does not influence feeding performance Reviewed
Sato T., Kurokawa M., Nakashima Y., Ida T., Takahashi T., Fukue Y., Ikawa M., Okabe M., Kangawa K., Kojima M.
Regulatory Peptides 145 ( 1-3 ) 7 - 11 2008.1
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Regulatory Peptides
Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor that is synthesized predominantly in the stomach. Previous studies demonstrated that ghrelin stimulates growth hormone release and food intake. These data suggested that antagonism of ghrelin could serve as a useful treatment for eating disorders and obesity. To study the role of endogenous ghrelin in feeding performance further, we generated ghrelin-deficient (ghrl -/- ) mice. Unexpectedly, ghrl -/- mice exhibited normal growth, cumulative food intake, reproduction, histological characters, and serum parameters. There were no differences in feeding patterns between ghrl +/+ and ghrl -/- mice. Ghrl -/- mice displayed normal responses to scheduled feedings as seen for ghrl +/+ mice. Memory-related feeding performances of ghrl -/- mice were indistinguishable from ghrl +/+ littermates. These data indicate that ghrelin is not critical for feeding performance. © 2007 Elsevier B.V. All rights reserved.
-
Identification and functional analysis of a novel ligand for G protein-coupled receptor, Neuromedin S Reviewed
Miyazato M, et al.
Regul Pept 145 ( 1-3 ) 37 - 41 2008.1
Language：English Publishing type：Research paper (scientific journal)
-
Structure of Mammalian and Nonmammalian Ghrelins Reviewed
Kojima M., Ida T., Sato T.
Vitamins and Hormones 77 31 - 46 2007.11
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Vitamins and Hormones
The discovery of ghrelin has elucidated the role of the stomach as an important organ in the regulation of growth hormone (GH) release and energy homeostasis. Ghrelin is a peptide hormone in which Ser3 Thr3 in frogs) is modified by an n-octanoic acid; this modification is essential for ghrelin's activity. Ghrelin and motilin, another gastric peptide, structurally and functionally define a peptide superfamily; these two factors may have evolved from a common ancestral peptide. Ghrelin is found in both mammalian species as well as nonmammalian species, such as frogs, birds, and fish. Moreover, ghrelin structure, particularly that of the acyl-modification regions, is highly conserved throughout vertebrate species. All of the ghrelin peptides that have been identified are modified by a fatty acid, primarily n-octanoic acid. These discoveries implicate ghrelin as an essential hormone in the maintenance of GH release and energy homeostasis in vertebrates. © 2007 Elsevier Inc. All rights reserved.
-
Central control of bone remodeling by neuromedin U Reviewed
Sato S., Hanada R., Kimura A., Abe T., Matsumoto T., Iwasaki M., Inose H., Ida T., Mieda M., Takeuchi Y., Fukumoto S., Fujita T., Kato S., Kangawa K., Kojima M., Shinomiya K., Takeda S.
Nature Medicine 13 ( 10 ) 1234 - 1240 2007.10
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Nature Medicine
Bone remodeling, the function affected in osteoporosis, the most common of bone diseases, comprises two phases: bone formation by matrix-producing osteoblasts and bone resorption by osteoclasts. The demonstration that the anorexigenic hormone leptin inhibits bone formation through a hypothalamic relay suggests that other molecules that affect energy metabolism in the hypothalamus could also modulate bone mass. Neuromedin U (NMU) is an anorexigenic neuropeptide that acts independently of leptin through poorly defined mechanisms. Here we show that Nmu-deficient (Nmu -/- ) mice have high bone mass owing to an increase in bone formation; this is more prominent in male mice than female mice. Physiological and cell-based assays indicate that NMU acts in the central nervous system, rather than directly on bone cells, to regulate bone remodeling. Notably, leptin- or sympathetic nervous system-mediated inhibition of bone formation was abolished in Nmu -/- mice, which show an altered bone expression of molecular clock genes (mediators of the inhibition of bone formation by leptin). Moreover, treatment of wild-type mice with a natural agonist for the NMU receptor decreased bone mass. Collectively, these results suggest that NMU may be the first central mediator of leptin-dependent regulation of bone mass identified to date. Given the existence of inhibitors and activators of NMU action, our results may influence the treatment of diseases involving low bone mass, such as osteoporosis. © 2007 Nature Publishing Group.
DOI： 10.1038/nm1640
-
Purification and characterization of feline ghrelin and its possible role Reviewed
Ida T., Miyazato M., Naganobu K., Nakahara K., Sato M., Lin X., Kaiya H., Doi K., Noda S., Kubo A., Murakami N., Kangawa K.
Domestic Animal Endocrinology 32 ( 2 ) 93 - 105 2007.2
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Domestic Animal Endocrinology
Ghrelin, a novel 28-amino acid peptide with an n-octanoyl modification at Ser 3 , has been isolated from rat and human stomach as an endogenous ligand for the growth hormone secretagogue receptor. Here, we purified feline ghrelin and examined its possible physiological role in cats. The major active form of feline ghrelin is a 28-amino acid peptide octanoylated (C8:0) at Ser 3 ; except for one amino acid residue replacement, this structure is identical to those of rat and human ghrelins. However, much structural divergence in peptide length and fatty acid modification was observed in feline ghrelin: peptides consisting of 27 or 26 amino acids lacking Gln 14 and/or Arg 28 were found, and the third serine residue was modified by octanoic acid (C8:0), decanoic acid (10:0), or unsaturated fatty acids (C8:1, C10:1 and C10:2). In agreement with the structural divergence, two kinds of cDNA with different lengths were isolated. Administration of synthetic rat ghrelin increased plasma growth hormone levels in cats, with a potency similar to that in rat or human. Plasma levels of ghrelin in cats increased approximately 2.5-fold after fasting. The present s tudy indicates the existence of structural divergence in feline ghrelin and suggests that, as in other animals, ghrelin may play important roles in GH release and feeding in cats. © 2006 Elsevier Inc. All rights reserved.
-
Date Y., Shimbara T., Koda S., Toshinai K., Ida T., Murakami N., Miyazato M., Kokame K., Ishizuka Y., Ishida Y., Kageyama H., Shioda S., Kangawa K., Nakazato M.
Cell Metabolism 4 ( 4 ) 323 - 331 2006.10
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Cell Metabolism
Ghrelin, a gastrointestinal peptide, stimulates feeding when administered peripherally. Blockade of the vagal afferent pathway abolishes ghrelin-induced feeding, indicating that the vagal afferent pathway may be a route conveying orexigenic ghrelin signals to the brain. Here, we demonstrate that peripheral ghrelin signaling, which travels to the nucleus tractus solitarius (NTS) at least in part via the vagus nerve, increases noradrenaline (NA) in the arcuate nucleus of the hypothalamus, thereby stimulating feeding at least partially through α- 1 and β- 2 noradrenergic receptors. In addition, bilateral midbrain transections rostral to the NTS, or toxin-induced loss of neurons in the hindbrain that express dopamine β hydroxylase (an NA synthetic enzyme), abolished ghrelin-induced feeding. These findings provide new evidence that the noradrenergic system is necessary in the central control of feeding behavior by peripherally administered ghrelin. © 2006 Elsevier Inc. All rights reserved.
-
Neuromedin S is a novel anorexigenic hormone Reviewed
Ida T., Mori K., Miyazato M., Egi Y., Abe S., Nakahara K., Nishihara M., Kangawa K., Murakami N.
Endocrinology 146 ( 10 ) 4217 - 4223 2005.10
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Endocrinology
A novel 36-amino acid neuropeptide, neuromedin S (NMS), has recently been identified in rat brain and has been shown to be an endogenous ligand for two orphan G protein-coupled receptors, FM-3/GPR66 and FM-4/TGR-1. These receptors have been identified as neuromedin U (NMU) receptor type 1 and type 2, respectively. In this study, the physiological role of the novel peptide, NMS, on feeding regulation was investigated. Intracerebroventricular (icv) injection of NMS decreased 12-h food intake during the dark period in rats. This anorexigenic effect was more potent and persistent than that observed with the same dose of NMU. Neuropeptide Y, ghrelin, and agouti-related protein-induced food intake was counteracted by co-administration of NMS. Icv administration of NMS increased proopiomelanocortin mRNA expression in the arcuate nucleus (Arc) and CRH mRNA in the paraventricular nucleus (PVN). Pretreatment with SHU9119 (antagonist for α-MSH) and α-helical corticotropin-releasing factor-(9-41) (antagonist for CRH) attenuated NMS-induced suppression of 24-h food intake. After icv injection of NMS, Fos-immunoreactive cells were detected in both the PVN and Arc. When neuronal multiple unit activity was recorded in the PVN before and after icv injection of NMS, a significant increase in firing rate was observed 5 min after administration, and this increase continued for 100 min. These results suggest that the novel peptide, NMS, may be a potent anorexigenic hormone in the hypothalamus, and that expression of proopiomelanocortin mRNA in the Arc and CRH mRNA in the PVN may be involved in NMS action on feeding. Copyright © 2005 by The Endocrine Society.
DOI： 10.1210/en.2005-0107
-
Identification of neuromedin S and its possible role in the mammalian circadian oscillator system Reviewed
Mori K., Miyazato M., Ida T., Murakami N., Serino R., Ueta Y., Kojima M., Kangawa K.
EMBO Journal 24 ( 2 ) 325 - 335 2005.1
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：EMBO Journal
The discovery of neuropeptides has resulted in an increased understanding of novel regulatory mechanisms of certain physiological phenomena. Here we identify a novel neuropeptide of 36 amino-acid residues in rat brain as an endogenous ligand for the orphan G protein-coupled receptor FM-4/TGR-1, which was identified to date as the neuromedin U (NMU) receptor, and designate this peptide 'neuromedin S (NMS)' because it is specifically expressed in the suprachiasmatic nuclei (SCN) of the hypothalamus. NMS shares a C-terminal core structure with NMU. The NMS precursor contains another novel peptide. NMS mRNA is highly expressed in the central nervous system, spleen and testis. In rat brain, NMS expression is restricted to the core of the SCN and has a diurnal peak under light/dark cycling, but remains stable under constant dar kness. Intracerebroventricular administration of NMS in rats activates SCN neurons and induces nonphotic type phase shifts in the circadian rhythm of locomotor activity. These findings suggest that NMS in the SCN is implicated in the regulation of circadian rhythms through autocrine and/or paracrine actions.
-
Neuromedin U is involved in nociceptive reflexes and adaptation to environmental stimuli in mice Reviewed
Nakahara K., Kojima M., Hanada R., Egi Y., Ida T., Miyazato M., Kangawa K., Murakami N.
Biochemical and Biophysical Research Communications 323 ( 2 ) 615 - 620 2004.10
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Biochemical and Biophysical Research Communications
Following our recent observations of inactivity and slowed movement in neuromedin U knockout (NMU KO) mice, we compared nociceptive reflexes and environmental adaptation in NMU KO and wild-type mice. Hot plate and formalin tests revealed that reflexes to heat and pain were significantly decreased in NMU KO mice. Conversely, intracerebroventricular injection of NMU into wild-type mice stimulated nociceptive reflexes in a dose-dependent manner. After NMU injection, increased c-Fos expression was observed in a wide range of locations in hypothalamus, brainstem, and spinal cord. NMU mRNA expression increased in the spinal cord, but not in the hypothalamus, 2 and 4 h after formalin injection. When their light-dark cycle was advanced or retarded by 5 h, NMU KO mice required a longer time to re-entrain into the new light-dark cycle than did wild-type mice. Wild-type mice displayed increased blood pressure after their environmental temperature was changed from 23 to 37°C, whereas no such increase was observed in NMU KO mice. Blood corticosterone levels were significantly increased after 10 min of immobilization stress in wild-type mice, but not in NMU KO mice. These results suggest that endogenous NMU may be involved in reflexes and adaptation to environmental stimuli. © 2004 Elsevier Inc. All rights reserved.
-
The gut-brain peptide neuromedin U is involved in the mammalian circadian oscillator system Reviewed
Nakahara K., Hanada R., Murakami N., Teranishi H., Ohgusu H., Fukushima N., Moriyama M., Ida T., Kangawa K., Kojima M.
Biochemical and Biophysical Research Communications 318 ( 1 ) 156 - 161 2004.5
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Biochemical and Biophysical Research Communications
Immunohistochemical analysis revealed the presence of a gut-brain peptide, neuromedin U (NMU), in the suprachiasmatic nucleus (SCN), which is the site of the master circadian oscillator. The expression of NMU mRNA exhibited a circadian rhythm, with the peak expression in the SCN occurring at CT4-8h. The two NMU-binding receptors (NMU-R1 and NMU-R2) were also expressed in the SCN, but their phase angles were different. Intracerebroventricular injection (ICV) of NMU induced the expression of Fos protein in the SCN cells and caused a phase-dependent phase shift of the circadian locomotor activity rhythm. The magnitude of th e phase shift was dose dependent. This NMU-induced phase shift was of the nonphotic type. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed increases in the expression in the SCN of immediate early genes, such as c-fos, NGFI-A, NGFI-B, and JunB. Furthermore, ICV injection of NMU increased the expression of Per1, but not Per2, in the SCN. These results indicate that NMU may play some important role in the circadian oscillator by exerting an autocrine or paracrine action in the SCN. © 2004 Elsevier Inc. All rights reserved.
-
Role for central ghrelin in food intake and secretion profile of stomach ghrelin in rats Reviewed
Murakami N., Hayashida T., Kuroiwa T., Nakahara K., Ida T., Mondal M., Nakazato M., Kojima M., Kangawa K.
Journal of Endocrinology 174 ( 2 ) 283 - 288 2002.8
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Journal of Endocrinology
Ghrelin, a 28-amino-acid peptide, has recently been isolated from the rat stomach as an endogenous ligand for the GH secretagogue receptor. We have reported previously that central or peripheral administration of ghrelin stimulates food intake, and the secretion of GH and gastric acid in rats. In the present study, we investigated how much endogenous centrally released ghrelin is involved in the control of food intake and body weight gain. We also examined the profile of ghrelin secretion from the stomach by RIA using two kinds of anti-ghrelin antiserum, one raised against the N-terminal ([Cys 12 ]-ghrelin[1-11] ) region and one raised against the C-terminal ([Cys 0 ]-ghrelin [13-28] ) region of the peptide. The former antibody recognizes specifically ghrelin with n-octanoylated Ser 3 (acyl ghrelin), and does not recognize des-acyl ghrelin. The latter also recognizes des-acyl ghrelin (i.e. total ghrelin). Intracerebroventricular treatment with the anti-ghrelin antiserum against the N-terminal region twice a day for 5 days decreased significantly both daily food intake and body weight. Des-acyl ghrelin levels were significantly higher in the gastric vein than in the trunk. Either fasting for 12 h, administration of gastrin or cholecystokinin resulted in increase of both acyl and des-acyl ghrelin levels. The ghrelin levels exhibited a diurnal pattern, with the bimodal peaks occurring before dark and light periods. These two peaks were consistent with maximum and minimum volumes of gastric content respectively. These results suggest that (1) endogenous centrally released ghrelin participates in the regulation of food intake and body weight, (2) acyl ghrelin is secreted from the stomach, (3) intestinal hormones stimulate ghrelin release from the stomach, and (4) regulation of the diurnal rhythm of ghrelin is complex, since ghrelin secretion is augmented under conditions of both gastric emptying and filling.
-
Ida T., Nakahara K., Kuroiwa T., Fukui K., Nakazato M., Murakami T., Murakami N.
Neuroscience Letters 293 ( 2 ) 119 - 122 2000.10
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Neuroscience Letters
Orexin (hypocretin) is a peptide that has been found to stimulate food intake in rats. However, we have recently demonstrated that orexin stimulates the release of corticotropin releasing hormone (CRF) which has been known to decrease the food intake. Therefore, we examined the mechanism of effect of orexin on food intake. Although the other appetite stimulating peptides; neuropeptide Y (NPY), agouti-related peptide (AGRP) and one of the growth hormone releasing secretagogue (GHRP-6) stimulated dose-dependently the food intake during 2 h in the early light period, orexin did not increase significantly the food intake. No significant increase was also observed during 2 h in the early dark period. However, pretreatment with α-helical CRF, an antagonist of CRF, or anti-CRF antiserum resulted in significant increase of food intake by orexin. Orexin-stimulated feeding under these conditions was blocked by NPY Y1 receptor antagonist (1229U91). In an 8 h- fasting rat, anti-orexin serum decreased slightly the food intake. These results suggest that effect of orexin on the food intake may be complex because of orexin-CRF and orexin-NPY linkage. (C) 2000 Elsevier Science Ireland Ltd.
-
シマリス(T.asiaticus)における季節外冬眠誘起およびセロトニンの冬眠誘起と維持への関与(短報)
村上 昇, 幸野 亮太, 中原 桂子, 井田 隆徳, 黒田 治門
The journal of veterinary medical science 62 ( 7 ) S・viii, 763 - 766 2000.7
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：社団法人日本獣医学会
一年以上の間, 室温22度, 14時間明:10時間暗の照明条件下で飼育されたシマリスを短日照明(10時間明:14時間暗)と低温条件に暴露することにより季節外冬眠を誘起した.我々は一年のどの時期でもこの季節外冬眠を誘起できた.この季節外冬眠は季節間において, 冬眠一党醒インターバルや, それぞれの冬眠や覚醒時間には有意な差を認めなかったが, 冬眠に入るまでの期間の長さにおいて夏のみ約60日を要し, 他の季節の平均30日より長かった.さらに, 覚醒インターバルでの覚醒時刻は冬では明期に起こるのに対し, 春では明期と暗期でほぼ等しい割合で起こった.これらの結果はシマリスの冬眠がサーカディアンリズム(概日リズム)とサーカニュアルリズム(概年リズム)の両者にリンクしていることを示唆している.夏の季節外冬眠において, セロトニン枯渇剤であるパラクロロフェニルアラニン(PCPA)の冬眠中での慢性投与は冬眠を阻止し, 非冬眠動物への投与は逆に冬眠を誘発した.一方, オピオイドのアンタゴニストであるナロキソンの投与は覚醒時間の延長を起こした.これらの結果は, セロトニンによる冬眠誘超や維持機構がサーカニュアル(概年リズム)システムと独立したものであることを示唆している.
DOI： 10.1292/jvms.62.763
-
Induction of unseasonable hibernation and involvement of serotonin in entrance into and maintenance of its hibernation of chipmunks T. asiaticus Reviewed
Murakami N, et al.
J Vet Med Sci 62 ( 7 ) 763 - 766 2000.7
Language：English Publishing type：Research paper (scientific journal)
-
Murakami N., Kono R., Nakahara K., Ida T., Kuroda H.
Journal of Veterinary Medical Science 62 ( 7 ) 763 - 766 2000.7
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Journal of Veterinary Medical Science
Chipmunks that had been housed at 22°C under a light-dark cycle of 14L:10D for at least one year were exposed to a short photoperiod (10L:14D) and low temperature to induce unseasonable hibernation. We were able to induce hibernation at any time of year and there was no significant difference in the duration of the hibernation bout, the duration of interbout euthermia and duration of bouts of torpor throughout the year; however entrance into hibernation took about 60 days in summer but only about 30 days in any other seasons. In addition, interbout euthermia predominantly occurred during the light phase in winter, whereas in spring interbout euthermia occurred equally in the light and dark phases. These results suggest that both the circadian and circannual systems are linked to hibernation in chipmunks. Subcutaneous infusion of a serotonin antagonist, para-chlorophenylalanine (PCPA), facilitated entrance into and interrupted hibernation in aroused and hibernating chipmunks in summer, respectively. On the other hand, opioid antagonist, naloxone, did not affect hibernation, but extended the period of interbout euthermia. These results suggest that the role of serotonin in entrance into and maintenance of hibernation in chipmunks is independent of the circannual system, and that opioid system may not be involved in hibernation in chipmunks.
-
Possible involvement of orexin in the stress reaction in rats Reviewed
Ida T., Nakahara K., Murakami T., Hanada R., Nakazato M., Murakami N.
Biochemical and Biophysical Research Communications 270 ( 1 ) 318 - 323 2000.4
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Biochemical and Biophysical Research Communications
We examined whether corticotropin-releasing factor (CRF) was involved in orexin-induced grooming and face-washing behaviors, and whether orexin was involved in the stress reaction. Administration of α-helical CRF, CRF antagonist, alone had no behavioral effect, but it blocked the orexin-induced grooming and face-washing behaviors in rats. The level of corticosterone increased in a dose-dependent manner 15 min after icy injection of orexin, and it remained high for at least 60 min. In 2-month-old rats, 1 h of immobilization stress increased orexin mRNA levels, but not the melanin-concentrating hormone (MCH) mRNA, in the lateral hypothalamic area (LHA). In 6-month-old rats, 30 min of cold stress increased the expression of orexin mRNA in the LHA. Unlike in the 2-month-old rats, immobilization stress did not change orexin mRNA expression in 6-month-old rats. These results suggest that CRF is involved in orexin-induced behaviors, and that orexin may play an important role in some stress reactions. (C) 2000 Academic Press.
-
Ida T., Nakahara K., Katayama T., Murakami N., Nakazato M.
Brain Research 821 ( 2 ) 526 - 529 1999.3
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Brain Research
The effect of lateral cerebroventricular injection of the appetite- stimulating neuropeptide, orexin and neuropeptide Y (NPY), on the behavior of rats was investigated. An immediate increase in face washing activity was observed after injection of orexin A or orexin B, but not NPY. Orexin A had a more potent effect on face washing behavior than orexin B. Grooming and burrowing activities also increased significantly after injection of orexin A, whereas, orexin B significantly increased burrowing and searching behavior. Feeding behavior and food consumption increased dramatically within 10 min of injection of NPY. Although the significant increase in feeding behavior was also observed after injection of orexin A, total food intake did not change significantly. These results suggest that orexin may be involved in the regulation of several other behavioral activities in rats, besides feeding.