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ABSTRACT: The area postrema (AP) is a circumventricular organ that lacks a blood-brain barrier. Previous studies have shown that the lesion of AP (APX) attenuated hyperphagic responses to glucoprivation. As the orexigenic neuropeptide Y (NPY) neurons have been implicated in the regulation of food intake, we examined whether the activation of NPY neurons by glucoprivation is mediated through the AP as well. In agreement with previous studies, hyperphagic responses to an injection of 2-deoxy-D-glucose that blocks glucose utilization were significantly attenuated in the APX group compared with the sham-operated (Sham) group. However, the expression levels of NPY heteronuclear RNA, a sensitive indicator for the gene transcription, were significantly increased in the arcuate nucleus by a 2-deoxy-D-glucose injection in both the APX and the Sham groups, and there were no significant differences in the values between groups. These data suggest that the hyperphagic response to glucoprivation, but not the activation of NPY gene transcription in the arcuate nucleus, was mediated through the AP in the hindbrain.
Neuroreport 05/2012; 23(11):673-5. · 1.66 Impact Factor
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ABSTRACT: The immunoglobulin heavy chain binding protein (BiP) is an endoplasmic reticulum (ER) chaperone that facilitates the proper folding of newly synthesized secretory and transmembrane proteins. Here we report that BiP mRNA was expressed in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus in wild-type mice under basal conditions. Dual in situ hybridization in the SON and PVN demonstrated that BiP mRNA was expressed in almost all the neurons of arginine vasopressin (AVP), an antidiuretic hormone. BiP mRNA expression levels were increased in proportion to AVP mRNA expression in the SON and PVN under dehydration. These data suggest that BiP is involved in the homeostasis of ER function in the AVP neurons in the SON and PVN.
Peptides 02/2012; 33(2):346-50. · 2.43 Impact Factor
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ABSTRACT: While the hypothalamus has been implicated in the regulation of energy balance, the central mechanisms and neural circuit that coordinate the feeding response to energy deficit have not been fully clarified. To better understand the role of the hypothalamus in mediating hyperphagic responses to food deprivation or glucoprivation, we examined the feeding responses in rats in which the medial hypothalamus (MH) was isolated from the rest of the brain. The isolation of the MH was performed with a Halasz's knife cut, and experiments were performed 7 days after the operation. Food consumption between 9:00 a.m. and 11:00 a.m. in rats which had been fasted overnight was significantly increased compared to that in rats which had access to food ad libitum before the measurement in both the sham and MH-isolated groups, and the absolute values of food consumption in fasted rats were not significantly different between the groups. On the other hand, while an injection of 2-deoxy-d-glucose, which blocks glucose utilization, significantly increased food consumption for 2h after injection compared to a saline injection in the sham group, it did not increase food intake compared to saline injection in the MH-isolated groups. Thus, it is demonstrated that glucoprivation is not an effective stimulus to induce feeding in MH-isolated rats.
Neuroscience Letters 09/2009; 464(1):6-9. · 2.11 Impact Factor
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ABSTRACT: The adipocyte-derived hormone adiponectin plays an important role in modulating energy homeostasis through peripheral tissues and the central nervous system. Several studies have reported that adiponectin exists in cerebrospinal fluid and that adiponectin receptors are expressed in the hypothalamus, including the paraventricular nucleus (PVN), which plays a key role in controlling pituitary hormone secretion. Furthermore, it has been reported that magnocellular arginine vasopressin (AVP) neurones within the PVN express adiponectin receptors. These findings suggest a central role of adiponectin in the modulation of neuroendocrinological functions. In the present study, we investigated the effect of centrally-administered adiponectin on AVP release in conscious rats. Intracerebroventricular (i.c.v.) administration of adiponectin significantly reduced the basal plasma AVP concentration in a dose-dependent manner, with a maximal effect being obtained 10 min after administration. The plasma AVP increase in response to either hyperosmolar or hypovolaemic stimulation was also significantly attenuated by an i.c.v. injection of adiponectin. Treatment with AMP-activated protein kinase (AMPK) inhibitor compound C (100 nmol, i.c.v.) partially reversed the inhibitory effects of adiponectin on AVP release. These findings suggest that central adiponectin plays an inhibitory role in the osmoregulation and baroregulation of AVP release, that the AMPK pathway is at least partly involved in the action of adiponectin, and further suggest a novel physiological or pathophysiological role for central adiponectin in water balance via inhibition of AVP release.
Journal of Neuroendocrinology 07/2009; 21(9):753-9. · 3.14 Impact Factor
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Minemori Watanabe,
Hiroshi Arima,
Kuriko Fukushima, Motomitsu Goto,
Hiroshi Shimizu,
Masayuki Hayashi,
Ryoichi Banno,
Ikuko Sato,
Nobuaki Ozaki,
Hiroshi Nagasaki,
Yutaka Oiso
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ABSTRACT: Expression of neuropeptide Y (Npy) heteronuclear (hn) RNA, an indicator of gene transcription, was significantly increased in the arcuate nucleus of rats 30min after insulin injection. Npy hnRNA levels were also increased significantly in response to hypoglycemia in rats in which the hypothalamus was deafferentated, although the absolute levels were significantly lower than in sham-operated rats. Direct effects of lowering glucose levels on Npy gene expression were also confirmed in hypothalamic organotypic cultures. Thus, Npy gene transcription in the arcuate nucleus increases rapidly in response to hypoglycemia, and both direct and indirect inputs are involved in the rapid upregulation.
FEBS Letters 11/2008; 582(25-26):3632-8. · 3.54 Impact Factor
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ABSTRACT: Recent studies suggest that the AMP-activated protein kinase (AMPK) signaling in the hypothalamus is the master regulator of energy balance. We reported in previous studies that glucocorticoids play a permissive role in the regulation of orexigenic neuropeptide Y (Npy) gene expression in the arcuate nucleus. In this study, we examined whether any cross talk occurs between glucocorticoids and AMPK signaling in the hypothalamus to regulate Npy as well as agouti-related peptide (Agrp) gene expression in the arcuate nucleus. In the hypothalamic organotypic cultures, the addition to the medium of the AMPK activator, 5-aminoimidazole-4-carboxamide-1-b-d-ribofuranoside, increased phosphorylated AMPK (p-AMPK) as well as phosphorylated acetyl-coenzyme A carboxylase (p-ACC) in the explants, accompanied by significant increases in Npy and Agrp gene expression in the arcuate nucleus. The incubation with dexamethasone (DEX) also activated AMPK signaling in the explants, accompanied by significant increases in Npy and Agrp gene expression in the arcuate nucleus. The addition of the AMPK inhibitor compound C to the medium, which blocked increases of p-AMPK and p-ACC by DEX, significantly attenuated Npy and Agrp gene expression stimulated by DEX. Furthermore, p-AMPK and p-ACC levels in the arcuate nucleus were significantly decreased in adrenalectomized rats compared with sham-operated rats, and a replacement of glucocorticoids reversed the AMPK signaling in adrenalectomized rats. Thus, our data demonstrated that glucocorticoids up-regulate the Npy and Agrp gene expression in the arcuate nucleus through AMPK signaling, suggesting that the activation of the hypothalamic APMK signaling by glucocorticoids might be essential to the energy homeostasis.
Endocrinology 07/2008; 149(9):4544-53. · 4.46 Impact Factor
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Ikuko Sato,
Hiroshi Arima,
Noriyuki Ozaki,
Nobuaki Ozaki,
Minemori Watanabe, Motomitsu Goto,
Hiroshi Shimizu,
Masayuki Hayashi,
Ryouichi Banno,
Hiroshi Nagasaki,
Yutaka Oiso
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ABSTRACT: Peripheral administration of baclofen significantly reduced food intake and body weight increase in both diabetic (db/db) and diet-induced obese mice for 5 weeks, whereas it had no significant effects on energy balance in their lean control mice. Despite the decreased body weight, neuropeptide Y expression in the arcuate nucleus was significantly decreased, whereas pro-opiomelanocortin expression was significantly increased by baclofen treatment. These data demonstrate that the inhibitory effects of baclofen on body weight in the obese mice were mediated via the arcuate nucleus at least partially, and suggest that GABA(B) agonists could be a new therapeutic reagent for obesity.
FEBS Letters 11/2007; 581(25):4857-64. · 3.54 Impact Factor
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Motomitsu Goto,
Hiroshi Arima,
Maiko Hiroi,
Hiroshi Shimizu,
Minemori Watanabe,
Masayuki Hayashi,
Ryouichi Banno,
Ikuko Sato,
Nobuaki Ozaki,
Hiroshi Nagasaki,
Yutaka Oiso
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ABSTRACT: Neuropeptide Y (NPY), synthesized in the arcuate nucleus of the hypothalamus, is one of the most potent orexigenic neuropeptides in the brain. The NPY neurons project to other hypothalamic nuclei, such as paraventricular nucleus (PVN), and it is reported that NPY contents in the PVN, but not NPY mRNA levels in the arcuate nucleus, decreased rapidly after food consumption. While many signals reflecting energy balance in the periphery are integrated at the NPY neurons, insulin has been implicated as one of the key regulators for NPY neurons. In the present study, we first examined whether there exist dynamic changes in NPY gene transcription in the arcuate nucleus in association with food intake in rats which had access to food only 4h a day. To detect possible changes in NPY gene transcription, we measured the expression levels of NPY heteronuclear (hn) RNA, a sensitive indicator of gene transcription, with intronic in situ hybridization. Our data showed that NPY hnRNA levels in the arcuate nucleus decreased rapidly after food consumption. We next examined whether postprandial increases in insulin release might contribute to the rapid downregulation of NPY gene transcription. To do so, insulin-deficient rats by streptozotocin injection were subjected to the same paradigm. Our data showed that NPY hnRNA levels also decreased rapidly after food consumption, suggesting that the postprandial increase in insulin release is not a prerequisite for the rapid downregulation of NPY gene transcription in the arcuate nucleus.
Neuroscience Letters 07/2007; 420(1):61-5. · 2.11 Impact Factor
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ABSTRACT: In this study, we examined the effects of intracerebroventricular administration of melanotan II (MTII), a melanocortin agonist, on insulin sensitivity in diet-induced obese (DIO) rats. Although MTII treatment significantly decreased food intake and body weight for 10 days, there was no significant difference in body weight between MTII and pair-fed groups. The insulin tolerance test showed that insulin sensitivity was significantly improved in the MTII group compared to the pair-fed group. Furthermore, MTII treatment increased the number of small-sized adipocytes in epididymal white adipose tissues, suggesting that MTII increased insulin sensitivity through action on the white adipose tissues in DIO rats.
FEBS Letters 04/2007; 581(6):1131-6. · 3.54 Impact Factor
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ABSTRACT: Ghrelin, which was identified from the rat stomach, is a potent stimulant for food intake. Several lines of evidence suggest that the orexigenic action of ghrelin is mediated via the neuropeptide Y (NPY) neurons in the arcuate nucleus, although the detailed mechanisms by which ghrelin stimulates NPY neurons are not clear. In this study, we examined the gene regulation of NPY and agouti-related peptide (AGRP), another orexigenic peptide synthesized in the NPY neurons, in the arcuate nucleus by ghrelin in hypothalamic organotypic cultures. Incubation of the hypothalamic explants with ghrelin significantly increased NPY and AGRP mRNA expression in the presence, but not absence, of dexamethasone. Glucocorticoids were also necessary for ghrelin action in vivo because an intracerebroventricular injection of ghrelin significantly increased NPY and AGRP mRNA expression in the arcuate nucleus only in sham-operated, but not in adrenalectomized rats. The stimulatory effects of ghrelin on gene expression were not blocked by a sodium channel blocker tetrodotoxin in the organotypic cultures. Ghrelin also increased NPY heteronuclear (hn) RNA expression, the first transcript that has been used as an indicator for gene transcription. The stimulatory effects of ghrelin on NPY gene expression were abolished in the presence of cycloheximide, which blocks translation, suggesting that de novo protein synthesis is required for ghrelin action. These data suggest that ghrelin stimulates NPY and AGRP gene expression independently of action potentials only in the presence of glucocorticoids. Furthermore, our data demonstrate stimulatory action of ghrelin on NPY gene transcription, which requires de novo protein synthesis.
Endocrinology 12/2006; 147(11):5102-9. · 4.46 Impact Factor
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ABSTRACT: The synthesis of arginine vasopressin (AVP) in the magnocellular neurons of the supraoptic (SON) and paraventricular nuclei (PVN) is physiologically regulated by plasma osmolality and volume. To clarify how the regulation of AVP gene transcription is affected by chronic dehydration, we examined changes in the transcriptional activities of AVP gene by plasma osmolality and volume in both euhydrated and dehydrated conditions. Euhydrated rats had free access to water, whereas dehydrated rats had been deprived of water for 3 days before experiments. Rats in both conditions were subjected to acute hypertonic stimuli or hypovolemia, and changes in AVP heteronuclear (hn)RNA levels, an indicator of gene transcription, in the SON and PVN were examined with in situ hybridization. The intraperitoneal (i.p.) injection (2% body wt) of hypertonic (1.5 M) saline increased plasma Na levels by approximately 40 meq/l in both euhydrated and dehydrated conditions. However, expression levels of AVP hnRNA in the SON and PVN were increased only in euhydrated, not dehydrated, rats. On the other hand, i.p. injection of polyethylene glycol decreased the plasma volume by approximately 16-20%, and AVP hnRNA levels in the SON and PVN were significantly increased in both conditions. Thus it is demonstrated that signaling pathways regulating AVP gene transcription in the magnocellular neurons were completely refractory to acute osmotic stimuli under the chronic dehydration and that AVP gene transcription could probably respond to acute hypovolemia through different intracellular signal transduction pathways from those for osmoregulation.
AJP Endocrinology and Metabolism 03/2006; 290(2):E213-7. · 4.75 Impact Factor
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ABSTRACT: Neuropeptide Y (NPY) in the arcuate nucleus is an orexigenic hormone of which levels are regulated by humoral as well as neural signals. In this study, we examined the regulation of NPY gene expression in the arcuate nucleus in hypothalamic organotypic cultures. Dexamethasone (DEX) (10(-9) to 10(-7) M) significantly increased NPY mRNA expression, and the effects were not influenced by coincubation with the sodium channel blocker tetrodotoxin (TTX), indicating that the action of DEX is independent of action potentials. Conversely, insulin (10(-11) to 10(-9) M) significantly inhibited NPY expression stimulated by DEX, and the inhibitory action of insulin was abolished in the presence of TTX. Because GABA and its receptors are expressed in the arcuate nucleus in vivo, we examined whether GABAergic systems were involved in the insulin action. The GABAB agonist baclofen significantly inhibited NPY expression stimulated by DEX, and the inhibitory action of insulin was completely abolished in the presence of either the GABAA antagonist bicuculline or the GABAB antagonist CGP35348 (p-3-aminopropyl-p-diethoxymethyl phosphoric acid). Furthermore, increases in the GABA-synthesizing enzyme glutamic acid decarboxylase 65 (GAD65) mRNA expression preceded decreases in NPY mRNA expression in the arcuate nucleus in the cultures. Experiments in vivo also demonstrated that increases in GAD65 mRNA expression in the arcuate nucleus preceded decreases in the NPY mRNA expression in a fasting-refeeding paradigm and that intracerebroventricular injection of insulin increased GAD65 mRNA expression in the arcuate nucleus in fasted rats. These data suggest that insulin inhibits NPY gene expression in the arcuate nucleus through GABAergic systems.
Journal of Neuroscience 10/2005; 25(38):8657-64. · 7.11 Impact Factor
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ABSTRACT: Effects of peripheral administration of melanotan II (MTII), a melanocortin agonist, on insulin sensitivity and glucose tolerance were examined in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Subcutaneous administration of MTII with osmotic mini-pumps decreased food intake and body weight in OLETF rats. MTII group showed more sensitivity to insulin compared with that allowed to eat ad libitum or pair-fed group in insulin tolerance tests on day 9. MTII group also showed significantly lower glucose values than ad libitum group in glucose tolerance tests on days 11 and 23. Thus, MTII increased insulin sensitivity and improved glucose tolerance in OLETF rats.
Peptides 09/2004; 25(8):1279-86. · 2.43 Impact Factor
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