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Central prostaglandins in food intake regulation
Nutrition 24 (2008) 798 – 801 www.elsevier.com/locate/nut
Central prostaglandins in food intake regulation Kousaku Ohinata, Ph.D.*, and Masaaki Yoshikawa, Ph.D. Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan Manuscript received June 3, 2008; accepted June 9, 2008.
Abstract
Prostaglandin (PG) E2 and PGD2, produced in the mammalian central nervous system, are known to have a variety of central actions on sleep, body temperature, and pain response via G-protein– coupled seven-transmembrane receptors. We found that centrally administered PGE2 suppressed food intake via the EP4 receptor, whereas PGD2 increased food intake via the DP1 receptor coupled to the neuropeptide Y Y1 receptor. In this review, we summarize roles of central PGs in food intake regulation and discuss the relation between PGs and neuropeptides controlling food intake. © 2008 Elsevier Inc. All rights reserved.
Keywords:
Food intake; Prostaglandin E2; EP4 receptor; Prostaglandin D2; DP1 receptor; Neuropeptide
Introduction Prostaglandins (PGs), bioactive lipids produced in the central nervous system (CNS) of animals and human, are known to have a variety of central actions on sleep, body temperature, and pain response [1,2]. Among them, PGE2 and PGD2 are positional isomers produced from the same precursor arachidonic acid via PGH2 and sometimes exhibit opposing biological activities in the CNS (Table 1). For example, centrally administered PGE2 promotes wakefulness, whereas PGD2 induces sleep [3]. PGE2 elevates body temperature, whereas PGD2 lowers it [4]. Recently, we found that centrally administered PGE2 suppressed food intake via the EP4 receptor [5], whereas PGD2 increased food intake via the DP1 receptor [6]. The aim of present report is to review roles of central PGs in food intake regulation and to discuss the relation between PGs and neuropeptide controlling food intake.
Anorexigenic effect of PGE2 PGE2 suppresses food intake via the EP4 receptor PGE2, a bioactive lipid produced in the CNS of mammals, including humans, has physiologically and patho* Corresponding author. Tel.: ⫹81-774-38-3733; fax: ⫹81-774-38-3774. E-mail address: [email protected] (K. Ohinata). 0899-9007/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2008.06.006
physiologically central actions on wakefulness, fever, pain response, and food intake [3,7–10]. PGE2 exerts its actions through four different types of G-protein-coupled seventransmembrane receptors, known as EP1–EP4 [1,2]. Recently, it has been revealed that EP3 and EP4 mediate the febrile response and wakefulness of PGE2, respectively [7,8]. We found that an EP4 agonist, ONO-AE1-329, decreased food intake after intracerebroventricular administration among four highly selective EP1–EP4 agonists [5]. The anorexigenic action of ONO-AE1-329 and PGE2 was blocked by an EP4 antagonist, ONO-AE3-208 [5]. These results suggest that EP4 activation in the CNS suppressed food intake (Fig. 1). Hypothalamic PGE synthase and the EP4 receptor It is known that the hypothalamus is an important site for food intake regulation in the CNS. PGE2 is produced from arachidonic acid by cyclo-oxygenase followed by PGE synthase and acts near its production site [1,11]. It has been reported that cyclo-oxygenase and microsomal PGE synthase are constitutively present in the paraventricular nucleus of the hypothalamus [11]. The EP4 receptor is widely distributed throughout the entire body and its mRNA is also expressed in almost all mouse tissue. In the hypothalamus, EP4 receptor mRNA was abundantly localized in the paraventricular nucleus and the supraoptic nucleus [12], suggesting that localization of the EP4 receptor is partly overlapped with that of microsomal PGE synthase in the hypothalamus.
K. Ohinata and M. Yoshikawa / Nutrition 24 (2008) 798 – 801 Table 1 Central actions of PGE2 and PD2 Action
Sleep Body temperature Food intake
PGE2
PGD2
2 1 2
1 2 1
PGD2, prostaglandin D2; PGE2, prostaglandin E2
Anorexigenic peptides activating the PGE2–EP4 receptor system We investigated the anorexigenic peptides activating the PGE2–EP4 system, and found that angiotensins (Angs) and complement C3a agonist peptides suppress food intake via a PGE2–EP4-dependent mechanism [13,14]. The renin–Ang system plays an important role in the regulation of blood pressure and fluid volume, and all the components of the renin–Ang system, including angiotensinogen, enzymes responsible for releasing Angs, and Ang receptors, are present in the CNS and the peripheral endocrine system. We found that centrally administered Ang II and III suppress food intake through the Ang AT2 receptor using an AT2-selective antagonist and AT2-knockout mice [13]. Furthermore, these anorexigenic activities of Ang II and III were completely blocked by an EP4-selective antagonist [13]. Taken together, Ang II and III may suppress food intake via PGE2 and EP4 activation downstream of the AT2 receptor. Complement C3a, a polypeptide enzymatically cleaved from C3 on activation of the complement system during host defense, has a number of physiologic effects such as degranulation of mast cells, smooth muscle contraction, and increase in capillary vascular permeability. The C3a receptor is present not only in the peripheral immune system but also in the CNS including glial cells and neurons. We found that centrally administered C3a decreases food intake [15]. The anorexigenic activity of the C3a agonist peptide (TrpPro-Leu-Pro-Arg) was blocked by the cyclo-oxygenase inhibitor and EP4 receptor antagonist [14]. These results suggest that the C3a agonist peptide decreases food intake through PGE2 production followed by EP4 activation.
799
We found for the first time that central administration of PGD2 stimulated food intake in non-fasted mice in a dosedependent manner [6]. Two receptor subtypes for PGD2, DP1 and DP2 receptors, are G-protein-coupled receptors and present in the CNS [1,19 –22]. The selective DP1 agonist BWA245C but not DP2 agonist 13,14-dihydro-15-ketoPGD2 stimulated food intake after central administration at the same level as that with PGD2 [6]. The orexigenic effect of PGD2 was completely blocked by the selective DP1 antagonist BWA868C [6]. Centrally administered PGD2 did not increase food intake in mice pretreated with the DP1antisense oligodeoxyribonucleotide (ODN) [6]. These results suggest that the exogenous PGD2-induced feeding is mediated by the DP1 receptor (Fig. 1). To investigate the role of endogenous PGD2 in food intake regulation, we tested the effects of intracerebroventricular administration of the DP1 antagonist or the DPantisense ODN on food intake, body weight, and fat mass. Bolus injection of BWA868C alone significantly decreased food intake in non-fasted mice [6]. The DP1-antisense ODN administration also markedly suppressed the daily food intake of mice in a dose-dependent manner [6]. Remarkable decreases in body weight and epididymal fat mass were also observed after administrations of the DP1-antisense ODN [6]. Taken together, DP1 stimulation with endogenous PGD2 may drive the orexigenic system in the CNS that regulates food intake, body weight, and fat deposition. Hypothalamic PGD synthase and the DP1 receptor The immunoreactivity of L-PGDS, responsible for the production of PGD2 in the CNS, was present in ependymal cells facing the third ventricle and oligodendroglial cells of the median eminence of the hypothalamus [6] as well as in the leptomeninges and the choroid plexus [18,20], where PGD2 was synthesized and secreted into cerebrospinal fluid. The DP1-like immunoreactivity was localized in the median eminence of the hypothalamus [6]. The mRNA expression of the DP1 was also observed in the median eminence and
Orexigenic effect of PGD2 PGD2 stimulates food intake via the DP1 receptor Prostaglandin D2 is the most abundant PG in the mammalian CNS [16], having central actions such as sleep induction, hypothermia, and attenuation of pain response (Table 1) [3,4,17]. PGD2 is produced by lipocalin-type PGD synthase (L-PGDS) from arachidonic acid, via PGH2 [18].
Fig. 1. Food intake regulation by central PGE2 and PGD2. NPY, neuropeptide Y; ODN, oligodeoxyribonucleotide; PGD2, prostaglandin D2; PGE2, prostaglandin E2.
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Fig. 2. The PGD2-DP1 receptor coupled to the NPY system in food intake regulation in the hypothalamus. 3V, third ventricle; L-PDGS, lipocalin-type prostaglandin D synthase; NPY, neuropeptide Y; PGD2, prostaglandin D2.
almost all cells of the arcuate nucleus (unpublished observation), where the neuropeptide Y (NPY)-positive neurons were present [23–25], suggesting that DP1 is localized in NPY neurons and other neurons in the arcuate nucleus. NPY-like immunoreactivity was also observed in the median eminence. Probably the DP1 neurons in median eminence or arcuate nucleus directly or indirectly innerve NPY neurons in energy homeostasis. Thus, PGD2 produced by L-PGDS in the median eminence in a paracrine manner may stimulate food intake via the DP-possessing NPY neurons of the hypothalamus (Fig. 2). It is known that the hypothalamus receives peripheral humoral inputs in response to energy condition. The PGD2 system in the hypothalamus may, at least in part, transfer peripheral signals in the regulation of food intake. Furthermore, hypothalamic mRNA expression of L-PGDS was upregulated after fasting [6], indicating that endogenous PGD2 plays an important role in energy homeostasis. NPY mediates orexigenic action of PGD2 NPY is a well-known orexigenic peptide that is abundant in the hypothalamus [23–25]. Among five receptor subtypes for NPY, the NPY Y1 receptor predominantly mediates orexigenic activity. The DP1 antagonist BWA868C did not inhibit the NPY-induced hyperphagia. However, the selective NPY Y1 receptor antagonist BIBO3304 blocked completely the orexigenic activity of PGD2 [6], suggesting that PGD2 activates the NPY Y1 system to increase food intake (Figs. 1 and 2).
Perspective We found that PGE2 decreases food intake via the EP4 receptor [5], whereas PGD2 increases food intake via the DP1 receptor [6]. The EP4 and DP1 receptors may be new therapeutic targets for the treatment of obesity and/or eating
disorders. Our findings will improve the understanding of the physiologic and pathophysiologic mechanisms involved in food intake regulation. Recently, it was reported that PGE2 induces wakefulness through the EP4 receptor, whereas PGD2 induces sleep through the DP1 receptor [8]. It is noteworthy that PGE2 and PGD2 have opposite effects on food intake regulation and sleep via activation of the EP4 and DP1 receptors, respectively. It has recently reported that inadequate sleep is a risk factor for obesity [26]. Sleep deprivation is known to stimulate food intake in animals [27]. It has been hypothesized that sleep-promoting and orexigenic substances might be increased after sleep deprivation. PGD2 induces sleep though DP1 in the leptomeninges of the basal forebrain [3,20,28]. Lack of sleep leads to an increased PGD2 concentration in the cerebrospinal fluid of rats [29]. We found that PGD2 stimulated feeding and that DP1 was also present in the hypothalamus. The central PGD2 system may play a key role in hyperphasia after sleep deprivation.
References [1] Narumiya S, Sugimoto Y, Ushikubi F. Prostanoid receptors: structures, properties, and functions. Physiol Rev 1999;79:1193–226. [2] Narumiya S, FitzGerald GA. Genetic and pharmacological analysis of prostanoid receptor function. J Clin Invest 2001;108:25–30. [3] Hayaishi O. Molecular mechanisms of sleep–wake regulation: roles of prostaglandins D2 and E2. FASEB J 1991;5:2575– 81. [4] Ueno R, Narumiya S, Ogorochi T, Nakayama T, Ishikawa Y, Hayaishi O. Role of prostaglandin D2 in the hypothermia of rats caused by bacterial lipopolysaccharide. Proc Natl Acad Sci U S A 1982;79:6093–7. [5] Ohinata K, Suetsugu K, Fujiwara Y, Yoshikawa M. Activation of prostaglandin E receptor EP4 subtype suppresses food intake in mice. Prostaglandins Other Lipid Mediat 2006;81:31– 6. [6] Ohinata K, Takagi K, Biyajima K, Fujiwara Y, Fukumoto S, Eguchi N, et al. Central prostaglandin D2 stimulates food intake via the neuropeptide Y system in mice. FEBS Lett 2008;582:679 – 84. [7] Ushikubi F, Segi E, Sugimoto Y, Murata T, Matsuoka T, Kobayashi T, et al. Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3. Nature 1998;395:281– 4. [8] Huang ZL, Sato Y, Mochizuki T, Okada T, Qu WM, Yamatodani A, et al. Prostaglandin E2 activates the histaminergic system via the EP4 receptor to induce wakefulness in rats. J Neurosci 2003;23:5975– 83. [9] Horton EW. Actions of prostaglandin E1, E2 and E3 on the central nervous system. Br J Pharmacol 1964;22:189 –92. [10] Levine AS, Morley JE. The effect of prostaglandins (PGE2 and PGF2␣) on food intake in rats. Pharmacol Biochem Behav 1981;15: 735– 8. [11] Matsuoka Y, Furuyashiki T, Bito H, Ushikubi F, Tanaka Y, Kobayashi T, et al. Impaired adrenocorticotropic hormone response to bacterial endotoxin in mice deficient in prostaglandin E receptor EP1 and EP3 subtypes. Proc Natl Acad Sci U S A 2003;100:4132–7. [12] Zhang J, Rivest S. Distribution, regulation and colocalization of the genes encoding the EP2- and EP4-PGE2 receptors in the rat brain and neuronal responses to systemic inflammation. Eur J Neurosci 1999; 11:2651– 68. [13] Ohinata K, Fujiwara Y, Fukumoto S, Iwai M, Horiuchi M, Yoshikawa M. Angiotensin II and III suppress food intake via angiotensin AT2 receptor and prostaglandin EP4 receptor in mice. FEBS Lett 2008;582:773–7.
K. Ohinata and M. Yoshikawa / Nutrition 24 (2008) 798 – 801 [14] Ohinata K, Suetsugu K, Fujiwara Y, Yoshikawa M. Suppression of food intake by a complement C3a agonist [Trp5]-oryzatensin(5-9). Peptides 2007;28:602– 6. [15] Ohinata K, Inui A, Asakawa A, Wada K, Wada E, Yoshikawa M. Albutensin A and complement C3a decrease food intake in mice. Peptides 2002;23:127–33. [16] Narumiya S, Ogorochi T, Nakao K, Hayaishi O. Prostaglandin D2 in rat brain, spinal cord and pituitary: basal level and regional distribution. Life Sci 1982;31:2093–103. [17] Eguchi N, Minami T, Shirafuji N, Kanaoka Y, Tanaka T, Nagata A, et al. Lack of tactile pain (allodynia) in lipocalin-type prostaglandin D synthase– deficient mice. Proc Natl Acad Sci U S A 1999;96: 726 –30. [18] Urade Y, Kitahama K, Ohishi H, Kaneko T, Mizuno N, Hayaishi O. Dominant expression of mRNA for prostaglandin D synthase in leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. Proc Natl Acad Sci U S A 1993;90:9070 – 4. [19] Hirata M, Kakizuka A, Aizawa M, Ushikubi F, Narumiya S. Molecular characterization of a mouse prostaglandin D receptor and functional expression of the cloned gene. Proc Natl Acad Sci U S A 1994;91;11192– 6. [20] Mizoguchi A, Eguchi N, Kimura K, Kiyohara Y, Qu WM, Huang ZL, et al. Dominant localization of prostaglandin D receptors on arachnoid trabecular cells in mouse basal forebrain and their involvement in the regulation of non-rapid eye movement sleep. Proc Natl Acad Sci U S A 2001;98:11674 –9.
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[21] Hirai H, Tanaka K, Yoshie O, Ogawa K, Kenmotsu K, Takamori Y, et al. Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2. J Exp Med 2001;193:255– 61. [22] Liang X, Wu L, Hand T, Andreasson K. Prostaglandin D2 mediates neuronal protection via the DP1 receptor. J Neurochem 2005;92(3): 447– 86. [23] Blomqvist AG, Herzog H. Y-receptor subtypes— how many more? Trends Neurosci 1997;20:294 – 8. [24] Inui A. Neuropeptide Y feeding receptors—are multiple subtypes involved? Trends Pharmacol Sci 1999;20:43– 6. [25] Inui A. Feeding and body weight regulation by hypothalamic neuropeptides—mediation of the actions of leptin. Trends Neurosci 1999; 22:62–7. [26] Gangwisch JE, Malaspina D, Boden-Albala B, Heymsfield SB. Inadequate sleep as a risk factor for obesity: analyses of the NHANES I. Sleep 2005;28:1289 –96. [27] Everson CA, Bergmann BM, Rechtschaffen A. Sleep deprivation in the rat: III. Total sleep deprivation. Sleep 1989;12:13–21. [28] Oida H, Hirata M, Sugimoto Y, Ushikubi F, Ohishi H, Mizuno N, et al. Expression of messenger RNA for the prostaglandin D receptor in the leptomeninges of the mouse brain. FEBS Lett 1997;417:53– 6. [29] Ram A, Pandey HP, Matsumura H, Kasahara-Orita K, Nakajima T, Takahata R, et al. cerebrospinal fluid levels of prostaglandins, especially the level of prostaglandin D2, are correlated with increasing propensity towards sleep in rats. Brain Res 1997;751:81–9.
Central prostaglandins in food intake regulation Kousaku Ohinata, Ph.D.*, and Masaaki Yoshikawa, Ph.D. Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan Manuscript received June 3, 2008; accepted June 9, 2008.
Abstract
Prostaglandin (PG) E2 and PGD2, produced in the mammalian central nervous system, are known to have a variety of central actions on sleep, body temperature, and pain response via G-protein– coupled seven-transmembrane receptors. We found that centrally administered PGE2 suppressed food intake via the EP4 receptor, whereas PGD2 increased food intake via the DP1 receptor coupled to the neuropeptide Y Y1 receptor. In this review, we summarize roles of central PGs in food intake regulation and discuss the relation between PGs and neuropeptides controlling food intake. © 2008 Elsevier Inc. All rights reserved.
Keywords:
Food intake; Prostaglandin E2; EP4 receptor; Prostaglandin D2; DP1 receptor; Neuropeptide
Introduction Prostaglandins (PGs), bioactive lipids produced in the central nervous system (CNS) of animals and human, are known to have a variety of central actions on sleep, body temperature, and pain response [1,2]. Among them, PGE2 and PGD2 are positional isomers produced from the same precursor arachidonic acid via PGH2 and sometimes exhibit opposing biological activities in the CNS (Table 1). For example, centrally administered PGE2 promotes wakefulness, whereas PGD2 induces sleep [3]. PGE2 elevates body temperature, whereas PGD2 lowers it [4]. Recently, we found that centrally administered PGE2 suppressed food intake via the EP4 receptor [5], whereas PGD2 increased food intake via the DP1 receptor [6]. The aim of present report is to review roles of central PGs in food intake regulation and to discuss the relation between PGs and neuropeptide controlling food intake.
Anorexigenic effect of PGE2 PGE2 suppresses food intake via the EP4 receptor PGE2, a bioactive lipid produced in the CNS of mammals, including humans, has physiologically and patho* Corresponding author. Tel.: ⫹81-774-38-3733; fax: ⫹81-774-38-3774. E-mail address: [email protected] (K. Ohinata). 0899-9007/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2008.06.006
physiologically central actions on wakefulness, fever, pain response, and food intake [3,7–10]. PGE2 exerts its actions through four different types of G-protein-coupled seventransmembrane receptors, known as EP1–EP4 [1,2]. Recently, it has been revealed that EP3 and EP4 mediate the febrile response and wakefulness of PGE2, respectively [7,8]. We found that an EP4 agonist, ONO-AE1-329, decreased food intake after intracerebroventricular administration among four highly selective EP1–EP4 agonists [5]. The anorexigenic action of ONO-AE1-329 and PGE2 was blocked by an EP4 antagonist, ONO-AE3-208 [5]. These results suggest that EP4 activation in the CNS suppressed food intake (Fig. 1). Hypothalamic PGE synthase and the EP4 receptor It is known that the hypothalamus is an important site for food intake regulation in the CNS. PGE2 is produced from arachidonic acid by cyclo-oxygenase followed by PGE synthase and acts near its production site [1,11]. It has been reported that cyclo-oxygenase and microsomal PGE synthase are constitutively present in the paraventricular nucleus of the hypothalamus [11]. The EP4 receptor is widely distributed throughout the entire body and its mRNA is also expressed in almost all mouse tissue. In the hypothalamus, EP4 receptor mRNA was abundantly localized in the paraventricular nucleus and the supraoptic nucleus [12], suggesting that localization of the EP4 receptor is partly overlapped with that of microsomal PGE synthase in the hypothalamus.
K. Ohinata and M. Yoshikawa / Nutrition 24 (2008) 798 – 801 Table 1 Central actions of PGE2 and PD2 Action
Sleep Body temperature Food intake
PGE2
PGD2
2 1 2
1 2 1
PGD2, prostaglandin D2; PGE2, prostaglandin E2
Anorexigenic peptides activating the PGE2–EP4 receptor system We investigated the anorexigenic peptides activating the PGE2–EP4 system, and found that angiotensins (Angs) and complement C3a agonist peptides suppress food intake via a PGE2–EP4-dependent mechanism [13,14]. The renin–Ang system plays an important role in the regulation of blood pressure and fluid volume, and all the components of the renin–Ang system, including angiotensinogen, enzymes responsible for releasing Angs, and Ang receptors, are present in the CNS and the peripheral endocrine system. We found that centrally administered Ang II and III suppress food intake through the Ang AT2 receptor using an AT2-selective antagonist and AT2-knockout mice [13]. Furthermore, these anorexigenic activities of Ang II and III were completely blocked by an EP4-selective antagonist [13]. Taken together, Ang II and III may suppress food intake via PGE2 and EP4 activation downstream of the AT2 receptor. Complement C3a, a polypeptide enzymatically cleaved from C3 on activation of the complement system during host defense, has a number of physiologic effects such as degranulation of mast cells, smooth muscle contraction, and increase in capillary vascular permeability. The C3a receptor is present not only in the peripheral immune system but also in the CNS including glial cells and neurons. We found that centrally administered C3a decreases food intake [15]. The anorexigenic activity of the C3a agonist peptide (TrpPro-Leu-Pro-Arg) was blocked by the cyclo-oxygenase inhibitor and EP4 receptor antagonist [14]. These results suggest that the C3a agonist peptide decreases food intake through PGE2 production followed by EP4 activation.
799
We found for the first time that central administration of PGD2 stimulated food intake in non-fasted mice in a dosedependent manner [6]. Two receptor subtypes for PGD2, DP1 and DP2 receptors, are G-protein-coupled receptors and present in the CNS [1,19 –22]. The selective DP1 agonist BWA245C but not DP2 agonist 13,14-dihydro-15-ketoPGD2 stimulated food intake after central administration at the same level as that with PGD2 [6]. The orexigenic effect of PGD2 was completely blocked by the selective DP1 antagonist BWA868C [6]. Centrally administered PGD2 did not increase food intake in mice pretreated with the DP1antisense oligodeoxyribonucleotide (ODN) [6]. These results suggest that the exogenous PGD2-induced feeding is mediated by the DP1 receptor (Fig. 1). To investigate the role of endogenous PGD2 in food intake regulation, we tested the effects of intracerebroventricular administration of the DP1 antagonist or the DPantisense ODN on food intake, body weight, and fat mass. Bolus injection of BWA868C alone significantly decreased food intake in non-fasted mice [6]. The DP1-antisense ODN administration also markedly suppressed the daily food intake of mice in a dose-dependent manner [6]. Remarkable decreases in body weight and epididymal fat mass were also observed after administrations of the DP1-antisense ODN [6]. Taken together, DP1 stimulation with endogenous PGD2 may drive the orexigenic system in the CNS that regulates food intake, body weight, and fat deposition. Hypothalamic PGD synthase and the DP1 receptor The immunoreactivity of L-PGDS, responsible for the production of PGD2 in the CNS, was present in ependymal cells facing the third ventricle and oligodendroglial cells of the median eminence of the hypothalamus [6] as well as in the leptomeninges and the choroid plexus [18,20], where PGD2 was synthesized and secreted into cerebrospinal fluid. The DP1-like immunoreactivity was localized in the median eminence of the hypothalamus [6]. The mRNA expression of the DP1 was also observed in the median eminence and
Orexigenic effect of PGD2 PGD2 stimulates food intake via the DP1 receptor Prostaglandin D2 is the most abundant PG in the mammalian CNS [16], having central actions such as sleep induction, hypothermia, and attenuation of pain response (Table 1) [3,4,17]. PGD2 is produced by lipocalin-type PGD synthase (L-PGDS) from arachidonic acid, via PGH2 [18].
Fig. 1. Food intake regulation by central PGE2 and PGD2. NPY, neuropeptide Y; ODN, oligodeoxyribonucleotide; PGD2, prostaglandin D2; PGE2, prostaglandin E2.
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K. Ohinata and M. Yoshikawa / Nutrition 24 (2008) 798 – 801
Fig. 2. The PGD2-DP1 receptor coupled to the NPY system in food intake regulation in the hypothalamus. 3V, third ventricle; L-PDGS, lipocalin-type prostaglandin D synthase; NPY, neuropeptide Y; PGD2, prostaglandin D2.
almost all cells of the arcuate nucleus (unpublished observation), where the neuropeptide Y (NPY)-positive neurons were present [23–25], suggesting that DP1 is localized in NPY neurons and other neurons in the arcuate nucleus. NPY-like immunoreactivity was also observed in the median eminence. Probably the DP1 neurons in median eminence or arcuate nucleus directly or indirectly innerve NPY neurons in energy homeostasis. Thus, PGD2 produced by L-PGDS in the median eminence in a paracrine manner may stimulate food intake via the DP-possessing NPY neurons of the hypothalamus (Fig. 2). It is known that the hypothalamus receives peripheral humoral inputs in response to energy condition. The PGD2 system in the hypothalamus may, at least in part, transfer peripheral signals in the regulation of food intake. Furthermore, hypothalamic mRNA expression of L-PGDS was upregulated after fasting [6], indicating that endogenous PGD2 plays an important role in energy homeostasis. NPY mediates orexigenic action of PGD2 NPY is a well-known orexigenic peptide that is abundant in the hypothalamus [23–25]. Among five receptor subtypes for NPY, the NPY Y1 receptor predominantly mediates orexigenic activity. The DP1 antagonist BWA868C did not inhibit the NPY-induced hyperphagia. However, the selective NPY Y1 receptor antagonist BIBO3304 blocked completely the orexigenic activity of PGD2 [6], suggesting that PGD2 activates the NPY Y1 system to increase food intake (Figs. 1 and 2).
Perspective We found that PGE2 decreases food intake via the EP4 receptor [5], whereas PGD2 increases food intake via the DP1 receptor [6]. The EP4 and DP1 receptors may be new therapeutic targets for the treatment of obesity and/or eating
disorders. Our findings will improve the understanding of the physiologic and pathophysiologic mechanisms involved in food intake regulation. Recently, it was reported that PGE2 induces wakefulness through the EP4 receptor, whereas PGD2 induces sleep through the DP1 receptor [8]. It is noteworthy that PGE2 and PGD2 have opposite effects on food intake regulation and sleep via activation of the EP4 and DP1 receptors, respectively. It has recently reported that inadequate sleep is a risk factor for obesity [26]. Sleep deprivation is known to stimulate food intake in animals [27]. It has been hypothesized that sleep-promoting and orexigenic substances might be increased after sleep deprivation. PGD2 induces sleep though DP1 in the leptomeninges of the basal forebrain [3,20,28]. Lack of sleep leads to an increased PGD2 concentration in the cerebrospinal fluid of rats [29]. We found that PGD2 stimulated feeding and that DP1 was also present in the hypothalamus. The central PGD2 system may play a key role in hyperphasia after sleep deprivation.
References [1] Narumiya S, Sugimoto Y, Ushikubi F. Prostanoid receptors: structures, properties, and functions. Physiol Rev 1999;79:1193–226. [2] Narumiya S, FitzGerald GA. Genetic and pharmacological analysis of prostanoid receptor function. J Clin Invest 2001;108:25–30. [3] Hayaishi O. Molecular mechanisms of sleep–wake regulation: roles of prostaglandins D2 and E2. FASEB J 1991;5:2575– 81. [4] Ueno R, Narumiya S, Ogorochi T, Nakayama T, Ishikawa Y, Hayaishi O. Role of prostaglandin D2 in the hypothermia of rats caused by bacterial lipopolysaccharide. Proc Natl Acad Sci U S A 1982;79:6093–7. [5] Ohinata K, Suetsugu K, Fujiwara Y, Yoshikawa M. Activation of prostaglandin E receptor EP4 subtype suppresses food intake in mice. Prostaglandins Other Lipid Mediat 2006;81:31– 6. [6] Ohinata K, Takagi K, Biyajima K, Fujiwara Y, Fukumoto S, Eguchi N, et al. Central prostaglandin D2 stimulates food intake via the neuropeptide Y system in mice. FEBS Lett 2008;582:679 – 84. [7] Ushikubi F, Segi E, Sugimoto Y, Murata T, Matsuoka T, Kobayashi T, et al. Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3. Nature 1998;395:281– 4. [8] Huang ZL, Sato Y, Mochizuki T, Okada T, Qu WM, Yamatodani A, et al. Prostaglandin E2 activates the histaminergic system via the EP4 receptor to induce wakefulness in rats. J Neurosci 2003;23:5975– 83. [9] Horton EW. Actions of prostaglandin E1, E2 and E3 on the central nervous system. Br J Pharmacol 1964;22:189 –92. [10] Levine AS, Morley JE. The effect of prostaglandins (PGE2 and PGF2␣) on food intake in rats. Pharmacol Biochem Behav 1981;15: 735– 8. [11] Matsuoka Y, Furuyashiki T, Bito H, Ushikubi F, Tanaka Y, Kobayashi T, et al. Impaired adrenocorticotropic hormone response to bacterial endotoxin in mice deficient in prostaglandin E receptor EP1 and EP3 subtypes. Proc Natl Acad Sci U S A 2003;100:4132–7. [12] Zhang J, Rivest S. Distribution, regulation and colocalization of the genes encoding the EP2- and EP4-PGE2 receptors in the rat brain and neuronal responses to systemic inflammation. Eur J Neurosci 1999; 11:2651– 68. [13] Ohinata K, Fujiwara Y, Fukumoto S, Iwai M, Horiuchi M, Yoshikawa M. Angiotensin II and III suppress food intake via angiotensin AT2 receptor and prostaglandin EP4 receptor in mice. FEBS Lett 2008;582:773–7.
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