Akio Kanatani - Academia.edu (original) (raw)
Papers by Akio Kanatani
The Journal of Biochemistry, 1991
ABSTRACT The prolyl endopeptidase [EC 3.4.21.26] gene of Flavobacterium meningosepticum was clone... more ABSTRACT The prolyl endopeptidase [EC 3.4.21.26] gene of Flavobacterium meningosepticum was cloned in Escherichia coli with the aid of an oligonucleotide probe which was prepared based on the amino acid sequence. The hybrid plasmid, pFPEP1, with a 3.5 kbp insert at the HincII site of pUC19 containing the enzyme gene, was subcloned into pUC19 to construct plasmid pFPEP3. The whole nucleotide sequence of an inserted HincII-BamHI fragment of plasmid pFPEP3 was determined by the dideoxy chain-terminating method. The purified prolyl endopeptidase was labeled with tritium DFP, and the sequence surrounding the reactive serine residue was found to be Ala (551)-Leu-Ser-Gly-Arg-*Ser-Asn(557). Ser-556 was identified as a reactive serine residue. The enzyme consists of 705 amino acid residues as deduced from the nucleotide sequence and has a molecular weight of 78,705, which coincides well with the value estimated by ultra centrifugal analysis. The amino acid sequence was 38.2% homologous to that of the porcine brain prolyl endopeptidase [Rennex et al. (1991) Biochemistry 30, 2195-2203] and 24.5% homologous to E. coli protease II, which has substrate specificity for basic amino acids [Kanatani et al. (1991) J. Biochem. 110, 315-320].
Journal of Endocrinology, 2006
G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) is a novel G protein-coupled receptor for b... more G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) is a novel G protein-coupled receptor for bile acid. Tissue distribution and cell-type specificity of Gpbar1 mRNA suggest a potential role for the receptor in the endocrine system; however, the precise physiological role of Gpbar1 still remains to be elucidated. To investigate the role of Gpbar1 in vivo, the Gpbar1 gene was disrupted in mice. In homozygous mice, total bile acid pool size was significantly decreased by 21-25% compared with that of the wild-type mice, suggesting that Gpbar1 contributes to bile acid homeostasis. In order to assess the impact of Gpbar1 deficiency in bile acid homeostasis more precisely, Gpbar1 homozygous mice were fed a high-fat diet for 2 months. As a result, female Gpbar1 homozygous mice showed significant fat accumulation with body weight gain compared with that of the wild-type mice. These findings were also observed in heterozygous mice to the same extent. Although the precise mechanism for fat accumulation in female Gpbar1 homozygous mice remains to be addressed, these data indicate that Gpbar1 is a potential new player in energy homeostasis. Thus, Gpbar1-deficient mice are useful in elucidating new physiological roles for Gpbar1.
European Journal of Pharmacology, Sep 1, 2009
Neuropeptide Y plays a key role in the physiological control of energy homeostasis. Five neuropep... more Neuropeptide Y plays a key role in the physiological control of energy homeostasis. Five neuropeptide Y receptor subtypes have been cloned, and multiple neuropeptide Y receptor subtypes are thought to mediate neuropeptide Y activity. However, interactions among neuropeptide Y receptor subtypes have not been elucidated to date. Herein, we examined the interaction between neuropeptide Y 1 and Y 5 receptors in feeding regulation by employing selective neuropeptide Y 1 and Y 5 receptor antagonists in C57BL/6 and neuropeptide Y 1 receptor knockout mice fed a high-fat diet. A single-dose of a neuropeptide Y 1 receptor antagonist (10-30 mg/kg) suppressed spontaneous food intake and reduced body weight in high-fat diet-fed C57BL/6 mice, while treatment with a neuropeptide Y 5 receptor antagonist did not significantly reduce food intake or body weight. Coadministration of a neuropeptide Y 1 receptor antagonist with a neuropeptide Y 5 receptor antagonist further suppressed food intake and reduced body weight. Next, we evaluated the chronic efficacy of a neuropeptide Y 5 receptor antagonist in high-fat diet-fed neuropeptide Y 1 receptor knockout mice in order to mimic chronic combination treatment with neuropeptide Y 1 and Y 5 receptor antagonists. The neuropeptide Y 5 receptor antagonist produced greater body weight reductions in high-fat diet-fed neuropeptide Y 1 receptor knockout mice than in wild-type C57BL/6 mice. These findings confirm an interaction between neuropeptide Y 1 and Y 5 receptors in the regulation of energy homeostasis, as blockade of both the neuropeptide Y 1 and Y 5 receptors produced a greater anti-obesity effect than blocking either receptor alone.
Biochem Biophys Res Commun, 1999
Neuropeptide Y (NPY) is known to induce robust feeding through the action of NPY receptors in the... more Neuropeptide Y (NPY) is known to induce robust feeding through the action of NPY receptors in the hypothalamus. Among the subtypes of NPY receptors, Y 1 receptors may play a key role in feeding regulation. In the present study, we demonstrated that a novel Y 1 antagonist, J-104870, shows high selectivity and potency for the Y 1 receptor with an anorexigenic effect on NPYmediated feeding. J-104870 displaced [ 125 I]peptide YY (PYY) binding to cloned human and rat Y 1 receptors with K i values of 0.29 and 0.54 nM, respectively, and inhibited the NPY (10 nM)-induced increase in intracellular calcium levels (IC 50 ؍ 3.2 nM) in cells expressing human Y 1 receptors. In contrast, J-104870 showed low affinities for human Y 2 (K i > 10 M), Y 4 (K i > 10 M), and Y 5 receptors (K i ؍ 6 M). In rat hypothalamic membranes, J-104870 also completely displaced the binding of [ 125 I]1229U91, which is known to bind to the typical Y 1 receptor, with a high affinity (K i ؍ 2.0 nM). Intracerebroventricular (ICV) injection of J-104870 (200 g) significantly suppressed NPY (5 g)-induced feeding in satiated Sprague-Dawley rats by 74%. Furthermore, ICV and oral administration of J-104870 (200 g and 100 mg/ kg, respectively) significantly suppressed spontaneous food intake in Zucker fatty rats. These findings suggested that J-104870 is a selective and potent nonpeptide Y 1 antagonist with oral bioavailability and brain penetrability. In addition, the anorexigenic effect of J-104870 clearly revealed the participation of the Y 1 receptor in NPY-mediated feeding regulation. The potent and orally active Y 1 antagonist J-104970 is a useful tool for elucidating the physiological roles of NPY in obesity.
American Journal of Physiology Regulatory Integrative and Comparative Physiology, May 1, 1998
Neuropeptide Y (NPY) is one of the most potent orexigenic substances known. 1229U91 was found to ... more Neuropeptide Y (NPY) is one of the most potent orexigenic substances known. 1229U91 was found to be a potent and selective NPY antagonist. To elucidate a physiological role of NPY in hyperphagia in obese animals, we studied the effect of 1229U91 on spontaneous food intake in obese and lean Zucker rats. The food intake of Zucker rats was suppressed by intracerebroventricular administration of 1229U91 more potently in obese than in lean animals without abnormal behavior (31.7 and 67.3% inhibition at doses of 10 and 30 micrograms, respectively, in Zucker fatty rats and 22.2% inhibition at 30 micrograms in lean rats). This compound markedly suppressed NPY-induced food intake at 30 micrograms but did not affect galanin-induced food intake, suggesting that the feeding suppression seen in Zucker fatty and lean rats is pharmacologically and behaviorally specific. These results suggest that NPY is involved in feeding behavior in Zucker fatty rats and that NPY contributes to feeding to a greater degree in Zucker fatty than in lean rats. The hyperphagia in Zucker fatty rats may be due to the abnormal overactivation of the NPYergic system.
Bioorganic Medicinal Chemistry Letters, Mar 1, 2009
A series of spiroindoline-3,4 0 -piperidine derivatives were synthesized and evaluated for their ... more A series of spiroindoline-3,4 0 -piperidine derivatives were synthesized and evaluated for their binding affinities and antagonistic activities at Y5 receptors. Potent Y5 antagonists were tested for their oral bioavailabilities and brain penetration in rats. Some of the antagonists showed good oral bioavailability and/ or good brain penetration. In particular, compound 6e was orally bioavailable and brain penetrant, and oral administration of 6e inhibited bPP-induced food intake in rats with a minimum effective dose of 10 mg/kg. Ó 2009 Published by Elsevier Ltd.
![Research paper thumbnail of [Development of anorectic NPY antagonists: possible roles of Y1 and Y5 receptors in feeding regulation]](https://attachments.academia-assets.com/52549939/thumbnails/1.jpg)
](Folia Pharmacologica Japonica, Mar 1, 2006
Endocrinology, May 1, 2003
To clarify the role of the neuropeptide Y (NPY) Y5 receptor subtype in energy homeostasis, the ef... more To clarify the role of the neuropeptide Y (NPY) Y5 receptor subtype in energy homeostasis, the effect of the intracerebroventricular infusion of a selective Y5 agonist, D-Trp(34)NPY, was investigated in C57BL/6J mice. Intracerebroventricular infusion of D-Trp(34)NPY (5 and 10 microg/d) produced hyperphagia and body weight gain, accompanied by increased adipose tissue weight, hypercholesterolemia, hyperinsulinemia, and hyperleptinemia. Oral administration of a selective Y5 antagonist at a dose of 100 mg/kg twice a day completely suppressed all of these D-Trp(34)NPY-induced changes, indicating that chronic activation of the Y5 receptor produces hyperphagia and obesity. In addition, D-Trp(34)NPY still resulted in an increase in adipose tissue weight accompanied by hyperleptinemia and hypercholesterolemia, although D-Trp(34)NPY-induced food intake was restricted by pair-feeding. Under the pair-fed condition, D-Trp(34)NPY decreased hormone-sensitive lipase activity in white adipose tissue and uncoupling protein-1 mRNA expression in brown adipose tissue. These findings indicate that Y5-mediated obesity may involve metabolic changes, such as decreased lipolysis and thermogenesis, as well as hyperphagia. Therefore, the Y5 receptor can play a key role in regulating energy homeostasis.
Regulatory Peptides, 1998
We have reported that the potent peptidic Y1 antagonist, 1229U91, significantly suppressed NPY-in... more We have reported that the potent peptidic Y1 antagonist, 1229U91, significantly suppressed NPY-induced and spontaneous feeding [32,. However, information on the precise selectivity of 1229U91 for NPY receptors is lacking. The Y5 receptor has been considered a key receptor for feeding regulation. In the present study we showed that 1229U91 has high affinities for the human and rat Y1 receptors (K 5 0.041 nM and 0.16 nM, respectively) and also a high affinity for the human Y4 receptor (K 5 0.33 nM), whereas it shows moderate i i affinities for the human Y2, Y5 and rat Y5 receptors (K values of 20-170 nM). Moreover, 1229U91 potently inhibits NPY-induced i 21
Regulatory Peptides, 2000
Five NPY receptors, Yl, Y2, Y4, Y5 and y6 have been cloned from a variety of species, including h... more Five NPY receptors, Yl, Y2, Y4, Y5 and y6 have been cloned from a variety of species, including human, rat, and mouse. Since a growing collection of mice is available with alterations in the NPY pathway (NPY -I-, Yl -I-, Y2 -I-, Y5 -/-and tg NPY over expressor), it would be useful to identify ligands selective for each mouse NPY receptor. Thus we performed a pharmacological analysis of agonists and antagonists with the five cloned murine receptors in artificial cerebral spinal (aCSF) buffer. Of the agonists tested, none were highly selective for the Yl or y6 receptors. Two moderately selective Y2 agonists, C2-NPY and [Leu28,3l]NPY(24-36) are >25 fold selective for Y2 over the other mouse receptors. A previously described rat Y4 agonist, rPP, is >400-fold selective for the mouse Y4 receptor. Among several Y5 agonists tested, D-Trp34NPY and two truncated analogs, D-Trp34NPY(2-36) and D-Trp34NPY(3-36) are >30-fold selective for Y5 over the Yl, Y2, Y4, and y6 receptors. The orally bioavailable Y5 antagonist compound 1 is >86 fold selective for Y5 over the other four murine receptors. The selective Y5 ligands were used to develop a model of YS-mediated obesity. A one week ICV infusion with the Y5 agonist D-Trp34NPY induces hyperphagia and obesity in mice. Oral administration of the selective Y5 antagonist, compound 1, completely inhibited the D-Trp34NPY-induced increases in food intake and body weight.
Proceedings of the National Academy of Sciences, 2006
Histamine H3 receptors (H3Rs) are located on the presynaptic membranes and cell soma of histamine... more Histamine H3 receptors (H3Rs) are located on the presynaptic membranes and cell soma of histamine neurons, where they negatively regulate the synthesis and release of histamine. In addition, H3Rs are also located on nonhistaminergic neurons, acting as heteroreceptors to regulate the releases of other amines such as dopamine, serotonin, and norepinephrine. The present study investigated the effects of H3R ligands on appetite and body-weight regulation by using WT and H3R-deficient mice (H3RKO), because brain histamine plays a pivotal role in energy homeostasis. The results showed that thioperamide, an H3R inverse agonist, increases, whereas imetit, an H3R agonist, decreases appetite and body weight in diet-induced obese (DiO) WT mice. Moreover, in DiO WT mice, but not in DiO H3RKO mice, imetit reduced fat mass, plasma concentrations of leptin and insulin, and hepatic triglyceride content. The anorexigenic effects of imetit were associated with a reduction in histamine release, but a comparable reduction in histamine release with ␣-fluoromethylhistidine, an inhibitor of histamine synthesis, increased appetite. Moreover, the anorexigenic effects of imetit were independent of the melanocortin system, because imetit comparably reduced appetite in melanocortin 3 and 4 receptor-deficient mice. The results provide roles of H3Rs in energy homeostasis and suggest a therapeutic potential for H3R agonists in the treatment of obesity and diabetes mellitus.
Pharmacology Biochemistry and Behavior, 2006
Histamine H3 receptors (H3Rs) are presynaptic receptors that negatively regulate the release of h... more Histamine H3 receptors (H3Rs) are presynaptic receptors that negatively regulate the release of histamine. The present study examined the physiological role of H3Rs in drinking behavior. In water-replete rats, intracerebroventricular (i.c.v.) administration of R-alpha-methylhistamine (RalphaMeHA), an H3R agonist, elicited drinking behavior. In contrast, i.c.v. administration of thioperamide, an H3R inverse agonist, significantly attenuated the drinking behavior elicited by either overnight dehydration or i.c.v. administration of angiotensin-II (AT-II). Inhibition of histamine release with alpha-fluoromethylhistidine, an inhibitor of histidine decarboxylase, did not elicit drinking behavior. Moreover, the inhibitory effects of thioperamide on drinking behavior in water-depleted rats were not mimicked by i.c.v. administration of histamine. These results suggest that the predominant effects of H3Rs on drinking behavior are not mediated by the modulation of histamine release. In H3R-deficient (H3RKO) mice, drinking behavior induced by overnight dehydration or i.c.v. administration of AT-II was significantly impaired compared to wild type mice. Collectively, these observations suggest that brain H3Rs play a pivotal role in drinking behavior in response to dehydration and AT-II, and these effects may be largely independent of the modulation of histaminergic tone.
The Journal of Biochemistry, 1991
ABSTRACT The prolyl endopeptidase [EC 3.4.21.26] gene of Flavobacterium meningosepticum was clone... more ABSTRACT The prolyl endopeptidase [EC 3.4.21.26] gene of Flavobacterium meningosepticum was cloned in Escherichia coli with the aid of an oligonucleotide probe which was prepared based on the amino acid sequence. The hybrid plasmid, pFPEP1, with a 3.5 kbp insert at the HincII site of pUC19 containing the enzyme gene, was subcloned into pUC19 to construct plasmid pFPEP3. The whole nucleotide sequence of an inserted HincII-BamHI fragment of plasmid pFPEP3 was determined by the dideoxy chain-terminating method. The purified prolyl endopeptidase was labeled with tritium DFP, and the sequence surrounding the reactive serine residue was found to be Ala (551)-Leu-Ser-Gly-Arg-*Ser-Asn(557). Ser-556 was identified as a reactive serine residue. The enzyme consists of 705 amino acid residues as deduced from the nucleotide sequence and has a molecular weight of 78,705, which coincides well with the value estimated by ultra centrifugal analysis. The amino acid sequence was 38.2% homologous to that of the porcine brain prolyl endopeptidase [Rennex et al. (1991) Biochemistry 30, 2195-2203] and 24.5% homologous to E. coli protease II, which has substrate specificity for basic amino acids [Kanatani et al. (1991) J. Biochem. 110, 315-320].
Journal of Endocrinology, 2006
G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) is a novel G protein-coupled receptor for b... more G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) is a novel G protein-coupled receptor for bile acid. Tissue distribution and cell-type specificity of Gpbar1 mRNA suggest a potential role for the receptor in the endocrine system; however, the precise physiological role of Gpbar1 still remains to be elucidated. To investigate the role of Gpbar1 in vivo, the Gpbar1 gene was disrupted in mice. In homozygous mice, total bile acid pool size was significantly decreased by 21-25% compared with that of the wild-type mice, suggesting that Gpbar1 contributes to bile acid homeostasis. In order to assess the impact of Gpbar1 deficiency in bile acid homeostasis more precisely, Gpbar1 homozygous mice were fed a high-fat diet for 2 months. As a result, female Gpbar1 homozygous mice showed significant fat accumulation with body weight gain compared with that of the wild-type mice. These findings were also observed in heterozygous mice to the same extent. Although the precise mechanism for fat accumulation in female Gpbar1 homozygous mice remains to be addressed, these data indicate that Gpbar1 is a potential new player in energy homeostasis. Thus, Gpbar1-deficient mice are useful in elucidating new physiological roles for Gpbar1.
European Journal of Pharmacology, Sep 1, 2009
Neuropeptide Y plays a key role in the physiological control of energy homeostasis. Five neuropep... more Neuropeptide Y plays a key role in the physiological control of energy homeostasis. Five neuropeptide Y receptor subtypes have been cloned, and multiple neuropeptide Y receptor subtypes are thought to mediate neuropeptide Y activity. However, interactions among neuropeptide Y receptor subtypes have not been elucidated to date. Herein, we examined the interaction between neuropeptide Y 1 and Y 5 receptors in feeding regulation by employing selective neuropeptide Y 1 and Y 5 receptor antagonists in C57BL/6 and neuropeptide Y 1 receptor knockout mice fed a high-fat diet. A single-dose of a neuropeptide Y 1 receptor antagonist (10-30 mg/kg) suppressed spontaneous food intake and reduced body weight in high-fat diet-fed C57BL/6 mice, while treatment with a neuropeptide Y 5 receptor antagonist did not significantly reduce food intake or body weight. Coadministration of a neuropeptide Y 1 receptor antagonist with a neuropeptide Y 5 receptor antagonist further suppressed food intake and reduced body weight. Next, we evaluated the chronic efficacy of a neuropeptide Y 5 receptor antagonist in high-fat diet-fed neuropeptide Y 1 receptor knockout mice in order to mimic chronic combination treatment with neuropeptide Y 1 and Y 5 receptor antagonists. The neuropeptide Y 5 receptor antagonist produced greater body weight reductions in high-fat diet-fed neuropeptide Y 1 receptor knockout mice than in wild-type C57BL/6 mice. These findings confirm an interaction between neuropeptide Y 1 and Y 5 receptors in the regulation of energy homeostasis, as blockade of both the neuropeptide Y 1 and Y 5 receptors produced a greater anti-obesity effect than blocking either receptor alone.
Biochem Biophys Res Commun, 1999
Neuropeptide Y (NPY) is known to induce robust feeding through the action of NPY receptors in the... more Neuropeptide Y (NPY) is known to induce robust feeding through the action of NPY receptors in the hypothalamus. Among the subtypes of NPY receptors, Y 1 receptors may play a key role in feeding regulation. In the present study, we demonstrated that a novel Y 1 antagonist, J-104870, shows high selectivity and potency for the Y 1 receptor with an anorexigenic effect on NPYmediated feeding. J-104870 displaced [ 125 I]peptide YY (PYY) binding to cloned human and rat Y 1 receptors with K i values of 0.29 and 0.54 nM, respectively, and inhibited the NPY (10 nM)-induced increase in intracellular calcium levels (IC 50 ؍ 3.2 nM) in cells expressing human Y 1 receptors. In contrast, J-104870 showed low affinities for human Y 2 (K i > 10 M), Y 4 (K i > 10 M), and Y 5 receptors (K i ؍ 6 M). In rat hypothalamic membranes, J-104870 also completely displaced the binding of [ 125 I]1229U91, which is known to bind to the typical Y 1 receptor, with a high affinity (K i ؍ 2.0 nM). Intracerebroventricular (ICV) injection of J-104870 (200 g) significantly suppressed NPY (5 g)-induced feeding in satiated Sprague-Dawley rats by 74%. Furthermore, ICV and oral administration of J-104870 (200 g and 100 mg/ kg, respectively) significantly suppressed spontaneous food intake in Zucker fatty rats. These findings suggested that J-104870 is a selective and potent nonpeptide Y 1 antagonist with oral bioavailability and brain penetrability. In addition, the anorexigenic effect of J-104870 clearly revealed the participation of the Y 1 receptor in NPY-mediated feeding regulation. The potent and orally active Y 1 antagonist J-104970 is a useful tool for elucidating the physiological roles of NPY in obesity.
American Journal of Physiology Regulatory Integrative and Comparative Physiology, May 1, 1998
Neuropeptide Y (NPY) is one of the most potent orexigenic substances known. 1229U91 was found to ... more Neuropeptide Y (NPY) is one of the most potent orexigenic substances known. 1229U91 was found to be a potent and selective NPY antagonist. To elucidate a physiological role of NPY in hyperphagia in obese animals, we studied the effect of 1229U91 on spontaneous food intake in obese and lean Zucker rats. The food intake of Zucker rats was suppressed by intracerebroventricular administration of 1229U91 more potently in obese than in lean animals without abnormal behavior (31.7 and 67.3% inhibition at doses of 10 and 30 micrograms, respectively, in Zucker fatty rats and 22.2% inhibition at 30 micrograms in lean rats). This compound markedly suppressed NPY-induced food intake at 30 micrograms but did not affect galanin-induced food intake, suggesting that the feeding suppression seen in Zucker fatty and lean rats is pharmacologically and behaviorally specific. These results suggest that NPY is involved in feeding behavior in Zucker fatty rats and that NPY contributes to feeding to a greater degree in Zucker fatty than in lean rats. The hyperphagia in Zucker fatty rats may be due to the abnormal overactivation of the NPYergic system.
Bioorganic Medicinal Chemistry Letters, Mar 1, 2009
A series of spiroindoline-3,4 0 -piperidine derivatives were synthesized and evaluated for their ... more A series of spiroindoline-3,4 0 -piperidine derivatives were synthesized and evaluated for their binding affinities and antagonistic activities at Y5 receptors. Potent Y5 antagonists were tested for their oral bioavailabilities and brain penetration in rats. Some of the antagonists showed good oral bioavailability and/ or good brain penetration. In particular, compound 6e was orally bioavailable and brain penetrant, and oral administration of 6e inhibited bPP-induced food intake in rats with a minimum effective dose of 10 mg/kg. Ó 2009 Published by Elsevier Ltd.
Folia Pharmacologica Japonica, Mar 1, 2006
Endocrinology, May 1, 2003
To clarify the role of the neuropeptide Y (NPY) Y5 receptor subtype in energy homeostasis, the ef... more To clarify the role of the neuropeptide Y (NPY) Y5 receptor subtype in energy homeostasis, the effect of the intracerebroventricular infusion of a selective Y5 agonist, D-Trp(34)NPY, was investigated in C57BL/6J mice. Intracerebroventricular infusion of D-Trp(34)NPY (5 and 10 microg/d) produced hyperphagia and body weight gain, accompanied by increased adipose tissue weight, hypercholesterolemia, hyperinsulinemia, and hyperleptinemia. Oral administration of a selective Y5 antagonist at a dose of 100 mg/kg twice a day completely suppressed all of these D-Trp(34)NPY-induced changes, indicating that chronic activation of the Y5 receptor produces hyperphagia and obesity. In addition, D-Trp(34)NPY still resulted in an increase in adipose tissue weight accompanied by hyperleptinemia and hypercholesterolemia, although D-Trp(34)NPY-induced food intake was restricted by pair-feeding. Under the pair-fed condition, D-Trp(34)NPY decreased hormone-sensitive lipase activity in white adipose tissue and uncoupling protein-1 mRNA expression in brown adipose tissue. These findings indicate that Y5-mediated obesity may involve metabolic changes, such as decreased lipolysis and thermogenesis, as well as hyperphagia. Therefore, the Y5 receptor can play a key role in regulating energy homeostasis.
Regulatory Peptides, 1998
We have reported that the potent peptidic Y1 antagonist, 1229U91, significantly suppressed NPY-in... more We have reported that the potent peptidic Y1 antagonist, 1229U91, significantly suppressed NPY-induced and spontaneous feeding [32,. However, information on the precise selectivity of 1229U91 for NPY receptors is lacking. The Y5 receptor has been considered a key receptor for feeding regulation. In the present study we showed that 1229U91 has high affinities for the human and rat Y1 receptors (K 5 0.041 nM and 0.16 nM, respectively) and also a high affinity for the human Y4 receptor (K 5 0.33 nM), whereas it shows moderate i i affinities for the human Y2, Y5 and rat Y5 receptors (K values of 20-170 nM). Moreover, 1229U91 potently inhibits NPY-induced i 21
Regulatory Peptides, 2000
Five NPY receptors, Yl, Y2, Y4, Y5 and y6 have been cloned from a variety of species, including h... more Five NPY receptors, Yl, Y2, Y4, Y5 and y6 have been cloned from a variety of species, including human, rat, and mouse. Since a growing collection of mice is available with alterations in the NPY pathway (NPY -I-, Yl -I-, Y2 -I-, Y5 -/-and tg NPY over expressor), it would be useful to identify ligands selective for each mouse NPY receptor. Thus we performed a pharmacological analysis of agonists and antagonists with the five cloned murine receptors in artificial cerebral spinal (aCSF) buffer. Of the agonists tested, none were highly selective for the Yl or y6 receptors. Two moderately selective Y2 agonists, C2-NPY and [Leu28,3l]NPY(24-36) are >25 fold selective for Y2 over the other mouse receptors. A previously described rat Y4 agonist, rPP, is >400-fold selective for the mouse Y4 receptor. Among several Y5 agonists tested, D-Trp34NPY and two truncated analogs, D-Trp34NPY(2-36) and D-Trp34NPY(3-36) are >30-fold selective for Y5 over the Yl, Y2, Y4, and y6 receptors. The orally bioavailable Y5 antagonist compound 1 is >86 fold selective for Y5 over the other four murine receptors. The selective Y5 ligands were used to develop a model of YS-mediated obesity. A one week ICV infusion with the Y5 agonist D-Trp34NPY induces hyperphagia and obesity in mice. Oral administration of the selective Y5 antagonist, compound 1, completely inhibited the D-Trp34NPY-induced increases in food intake and body weight.
Proceedings of the National Academy of Sciences, 2006
Histamine H3 receptors (H3Rs) are located on the presynaptic membranes and cell soma of histamine... more Histamine H3 receptors (H3Rs) are located on the presynaptic membranes and cell soma of histamine neurons, where they negatively regulate the synthesis and release of histamine. In addition, H3Rs are also located on nonhistaminergic neurons, acting as heteroreceptors to regulate the releases of other amines such as dopamine, serotonin, and norepinephrine. The present study investigated the effects of H3R ligands on appetite and body-weight regulation by using WT and H3R-deficient mice (H3RKO), because brain histamine plays a pivotal role in energy homeostasis. The results showed that thioperamide, an H3R inverse agonist, increases, whereas imetit, an H3R agonist, decreases appetite and body weight in diet-induced obese (DiO) WT mice. Moreover, in DiO WT mice, but not in DiO H3RKO mice, imetit reduced fat mass, plasma concentrations of leptin and insulin, and hepatic triglyceride content. The anorexigenic effects of imetit were associated with a reduction in histamine release, but a comparable reduction in histamine release with ␣-fluoromethylhistidine, an inhibitor of histamine synthesis, increased appetite. Moreover, the anorexigenic effects of imetit were independent of the melanocortin system, because imetit comparably reduced appetite in melanocortin 3 and 4 receptor-deficient mice. The results provide roles of H3Rs in energy homeostasis and suggest a therapeutic potential for H3R agonists in the treatment of obesity and diabetes mellitus.
Pharmacology Biochemistry and Behavior, 2006
Histamine H3 receptors (H3Rs) are presynaptic receptors that negatively regulate the release of h... more Histamine H3 receptors (H3Rs) are presynaptic receptors that negatively regulate the release of histamine. The present study examined the physiological role of H3Rs in drinking behavior. In water-replete rats, intracerebroventricular (i.c.v.) administration of R-alpha-methylhistamine (RalphaMeHA), an H3R agonist, elicited drinking behavior. In contrast, i.c.v. administration of thioperamide, an H3R inverse agonist, significantly attenuated the drinking behavior elicited by either overnight dehydration or i.c.v. administration of angiotensin-II (AT-II). Inhibition of histamine release with alpha-fluoromethylhistidine, an inhibitor of histidine decarboxylase, did not elicit drinking behavior. Moreover, the inhibitory effects of thioperamide on drinking behavior in water-depleted rats were not mimicked by i.c.v. administration of histamine. These results suggest that the predominant effects of H3Rs on drinking behavior are not mediated by the modulation of histamine release. In H3R-deficient (H3RKO) mice, drinking behavior induced by overnight dehydration or i.c.v. administration of AT-II was significantly impaired compared to wild type mice. Collectively, these observations suggest that brain H3Rs play a pivotal role in drinking behavior in response to dehydration and AT-II, and these effects may be largely independent of the modulation of histaminergic tone.