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Third Department of Internal Medicine (S.K., Y.D., T.S., T.H., K.T., M.N.), Miyazaki Medical College, University of Miyazaki, Miyazaki 889-1692; Daiichi Suntory Biomedical Research Co., Ltd. (S.K., M.F., N.I.), Osaka 681-8513 Japan; Department of Veterinary Physiology (N.M.), Faculty of Agriculture, Miyazaki University, Miyazaki 889-2192; Department of Physiology, Niigata University School of Medicine (A.N.), Niigata 951-8510; and Daiichi Suntory Pharma Co., Ltd. (T.H., K.O.), Gunma 370-0503, Japan
Address all correspondence and requests for reprints to: Masamitsu Nakazato, M.D., Ph.D., Third Department of Internal Medicine, Miyazaki Medical College, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan. E-mail: nakazato{at}med.miyazaki-u.ac.jp.
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Introduction |
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Peptide YY (PYY) is a 36-amino acid peptide secreted from endocrine L cells of the ileum (2, 3, 4). This peptide, belonging to the neuropeptide Y (NPY) peptide family, reduces food intake in rodents and humans through binding to the NPY Y2 receptor (Y2-R) within the hypothalamus (5). PYY secretion is accelerated by both neural and humoral factors and luminal nutrient content (6). Plasma PYY levels peak in normal subjects 60 min after eating (6), suggesting that PYY functions as a peripheral satiety signal. Circulating PYY is thought to enter the brain by crossing the blood-brain barrier (7). However, considering that the vagal afferent fibers are the major neuroanatomical structure linking the alimentary tract and the brain, it is likely that PYY signaling may be conveyed to the brain via the vagal afferent pathway.
Sensory information from viscera travels directly to the NTS by the vagal afferent pathway, a veritable express route. Efferent projection of the NTS includes: (1) descending fibers to autonomic centers such as the dorsal motor vagal nucleus and the nucleus ambiguous; (2) ascending fibers via the ventrolateral and dorsolateral tegmental area to the hypothalamus, amygdala, preoptic area, olfactory tubercles, and olfactory bulbs including the dorsal and ventral bundle of catecholaminergic pathways; and (3) ascending fibers to forebrain structures in the dorsal pons-medulla that more rostrally form the dorsal periventricular system. Therefore, bilateral midbrain transections, as well as vagotomy, are useful to determine whether the vagal afferent fibers and/or ascending efferent fibers of the NTS are necessary elements in the feedback pathway mediating the behavioral effects of substances produced in the peripheral tissues. Subdiaphragmatic vagotomy or midbrain transections to cut ascending efferent fibers of the NTS have been known to block cholecystokinin (CCK)-induced feeding reduction, indicating that CCK, an anorectic gut peptide, transmits its satiety signals to the brain via the afferent limb of the vagus nerve (8, 9).
Here we investigated the effect of peripherally administered PYY3–36 on food intake in rats with subdiaphragmatic vagotomy or bilateral midbrain transections. We examined the effect of vagotomy on PYY3–36-induced c-fos expression in the arcuate nucleus. We also demonstrated that PYY3–36 stimulated afferent discharge of the vagus nerve. Finally, we investigated the localization of Y2-R in vagal afferent neurons and the transport of this protein to afferent terminals. Peripheral PYY3–36 signals for satiety are thus relayed to the brain in part via the vagus nerve.
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Materials and Methods |
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Rats were sufficiently habituated to handling and ip injection before experiments. They were handled at least for a week and ip injected with saline (500 µl) once a day for 2 d before experiments. We also used rats for feeding experiments whose 4-h food intake from the beginning of the dark phase was constant. All animals had free access to food and water. Until these rats were used in experiments, we monitored their body weight gain and dark-phase food intake to confirm that their behavior patterns in daily life were normal. There were no rats that had behavioral abnormalities. All procedures were performed in accordance with the Japanese Physiological Society’s guidelines for animal care.
Food intake
Experiments were performed 2 wk after vagotomy or 1 wk after midbrain transection. Only rats that demonstrated progressive weight gain and food intake (body weight after vagotomy: treated rats, 382.2 ± 8.5 g; sham, 385.4 ± 7.8 g; P > 0.7, n = 10 per group; dark-phase food intake after vagotomy: treated rats, 20.8 ± 0.8 g; sham, 21.9 ± 0.8 g; P > 0.3, n = 10 per group; body weight after transection: treated rats, 343.7 ± 8.0 g; sham, 340.4 ± 5.5 g; P > 0.7, n = 8–9 per group; dark-phase food intake after transection: treated rats, 25.2 ± 1.3 g; sham, 21.9 ± 0.7 g; P = 0.048, n = 8–9 per group) were used in subsequent feeding experiments. Because midbrain transection in rats induces significantly greater food intake in the basal state (11), larger food intake of midbrain transectioned rats as compared with sham-operated rats is thought to support that the location of the lesions was effectual. Human PYY3–36 (Peptide Institute, Inc., Osaka, Japan), dissolved in 0.9% saline at 0.3, 3.0, and 10 nmol/rat per 500 µl or saline (500 µl) was administered ip at 1930–2000 h to rats that had undergone bilateral subdiaphragmatic vagotomy or sham operation (n = 7–12 per group). The PYY3–36 solution (10 nmol/rat per 500 µl) or saline (500 µl) was also administered ip at 1930–2000 h to rats that had undergone bilateral midbrain transections or sham operation (n = 10 per group). After injection, rats were immediately returned to their cages. At 2 and 4 h, food intake of vagotomized rats and midbrain transectioned rats was measured after injection.
Fos expression
PYY3–36 (5 nmol/rat per 500 µl) or saline (500 µl) was injected ip into rats that had received bilateral subdiaphragmatic vagotomy or sham operation (n = 5 per group) 90 min before transcardial perfusion with fixative containing 4% paraformaldehyde. The brain was then sectioned into 30-µm-thick samples. Immunohistochemistry against Fos was performed as described (12) to determine the number of Fos-positive neurons in the arcuate nucleus of each animal. We subjected a portion of the arcuate nucleus sections from PYY3–36-injected sham-operated rats to double staining with an anti-
MSH antibody (Chemicon International, Inc., Temecula, CA; final dilution 1:4000). We counted the Fos-positive neurons in five sections of the hypothalamic arcuate nucleus from each animal.
Y2-R expression
Three rats were perfused transcardially with fixative containing 4% paraformaldehyde. The nodose ganglia were sectioned at –20 C into 12-µm-thick samples using a cryostat and stored at –80 C until immunostaining. Primary neurons were obtained from the nodose ganglia of five rats, ranging from 5 to 6 wk of age. After collagenase and papain digestion as described (13, 14), isolated neurons were seeded and cultured for 4 d at 37 C in 5% CO2 on polyethylenimine-coated Lab-Tek chamber slides in complete DMEM (25 mM glucose) supplemented with 10 mM HEPES buffer (Gibco, Grand Island, NY), 5% newborn calf serum (Gibco), 5% horse serum (Gibco), 100 U/ml penicillin, 100 µg/ml streptomycin (Sigma Chemical Co., St. Louis, MO), 4 mM L-glutamine, 0.6 mM L-ascorbic acid (Nacalai Tesque, Inc., Kyoto, Japan), 1.2 mM pyruvic acid (Nacalai Tesque), and 30 ng/ml nerve growth factor 2.5S (Sigma). Medium was replaced every 2 d. Slides were washed in 0.01 M PBS (pH 7.4) and then fixed in 10% formaldehyde. Slides of both the primary cultures and sectioned nodose ganglia were incubated with goat anti-Y2-R (Santa Cruz Biotechnology, Inc., Santa Cruz, CA; final dilution 1:100) and then with Alexa Fluor 488 donkey antigoat IgG (Molecular Probes, Inc., Eugene, OR). Slides were visualized by fluorescence microscopy (BH2-RFC; Olympus, Tokyo, Japan).
Vagal ligation and autoradiography
A crushing ligation of the vagus nerve of rats (n = 4) with suture thread was made 20 mm caudal to the nodose ganglion. Sixteen hours later, the vagus nerve was excised, embedded in Tissue-Tek O.C.T. compound (Sakura Finetechnical Co., Ltd., Tokyo, Japan), and frozen. Serial sections (10 µm) were cut using a cryostat along the longitudinal axis of the nerve and mounted onto gelatin-coated glass slides. After incubating the sections at 37 C with binding buffer [20 mM HEPES, 150 mM NaCl, 5 mM MgCl2, 1 mM ethylene glycol-bis (ß-aminoethyl ether)-N, N, N', N'-tetraacetic acid, and 0.1% BSA] for 60 min, nerves were incubated in 3 nM 125I-human PYY3–36 for 30 min. Nonspecific binding was determined in the presence of excess (3 µM) unlabeled human PYY3–36. Sections were exposed to an imaging plate (Fuji Film, Tokyo, Japan) for 24 h and analyzed using a BAS-2000 (Fuji Film).
Electrophysiologic study
Multiunit neural discharge in gastric vagal afferent fibers was recorded extracellularly. In brief, rats were anesthetized by an ip injection of urethan (1 g/kg; Sigma). The electrophysiological study was performed under anesthetization throughout. The rat trachea was intubated, and the electrocardiogram was recorded. Body temperature was maintained at 37 C. Standard methods of extracellular recording from vagal nerve filaments were used, as described in detail elsewhere (15). After laparotomy, a small catheter (Intramedic PE-10; Clay Adams, Parsippany, NJ) was inserted into the inferior vena cava and fixed. The catheter tip was located at the rostral position 2 cm from the inserted site. After gastric branches of the vagus nerve were visualized, we placed filaments isolated from the peripheral cut end of the ventral branch for recording of afferent nerve activity on a pair of silver wire electrodes. Silver wire electrodes connected through an AC-coupled differential amplifier (DAP-10E, Dia Medical Systems Co., Tokyo, Japan) to an oscilloscope and magnetic tape recorder were used for display and storage of the neural activity. A window discriminator (DSE-325A) converted spikes to constant amplitude pulses for analysis of spike frequency with a rate meter that reset at 5-sec intervals. Output from the rate meter was recorded on a chart paper (8K20 recorder; NEC-SAN E1 Co., Tokyo, Japan). Either PYY3–36 (0.3 nmol/rat) or saline was administered iv within 30 sec at 1000–1100 h through the catheter inserted into the inferior vena cava (n = 12 per group). Multiunit afferent nerve discharges were recorded for 90 min after administration and analyzed (15).
Statistical analysis
We analyzed groups of data (means ± SEM) using ANOVA and post hoc Fisher tests. P < 0.05 was considered to be significant (two tailed).
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, A and B).
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).
Fos expression in the arcuate nucleus induced by peripherally administered PYY3–36
To examine the neuronal populations activated by PYY3–36 stimulation, we investigated Fos expression after ip administration. Treatment with PYY3–36 induced Fos expression in the hypothalamic arcuate nucleus of sham-operated rats. The number of PYY3–36-induced Fos-immunoreactive neurons was significantly increased from the levels observed in rats treated with saline (arcuate nucleus: PYY3–36, 59 ± 3; saline, 34 ± 2; P < 0.01) (Fig. 2, A, B, and F). There were no significant differences between vagotomized rats with PYY3–36 and with saline in the number of Fos-expressed neurons (arcuate nucleus: PYY3–36, 33 ± 3; saline, 27 ± 3; P > 0.2) (Fig. 2, C, D, and F).
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MSH, PYY3–36 induced Fos expression in 21.7 ± 1.6% of the MSH-positive neurons (Fig. 2E). This result is consistent with previous findings that peripheral administration of PYY3–36 activated approximately 20% of neurons containing proopiomelanocortin (POMC), an MSH precursor (5).
Expression of Y2-R in the vagal nodose ganglion
Approximately 40% of the neuronal cell bodies in the vagal nodose ganglion expressed Y2-R (Fig. 3A). Y2-R-immunoreactive neurons were also observed in the cultures of rat neurons from the nodose ganglion (Fig. 3B). Specific immunoreactivity was not detected in either sections or cultured neurons of the nodose ganglion using normal goat serum controls (Fig. 3C).
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). Specific binding was abolished by inclusion of excess unlabeled PYY3–36 (Fig. 4B).
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, A and C). No effect of saline injection was observed on the gastric vagal afferent activity (Fig. 5, B and C).
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Discussion |
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The present study showed that PYY3–36, synthesized by the L cells of the intestine and released into the general circulation (6, 18, 19), acts on the feeding reduction in part via the vagal afferent pathway. Peripheral administration of PYY3–36 to rats inhibits food intake and reduces weight gain (5). Circulating levels of PYY3–36 increase after meals in humans. These findings suggest that PYY3–36 functions as a satiety signal. PYY3–36-induced feeding reduction is sometimes controversial. In this study, we used rats for feeding experiments after satisfactory acclimation to handling and ip injection because the effect of PYY3–36 on feeding reduction was not observed in animals without appropriate habituation (20). We also used rats for feeding experiments whose 4-h food intake from the beginning of the dark phase was constant. In addition, considering that the effect of PYY3–36 is rapid and short-lived, we measured food intake within 4 h after PYY3–36 injection. Consequently bilateral subdiaphragmatic vagotomy blocked the feeding reduction by peripheral administration of PYY3–36. Furthermore, bilateral midbrain transections canceled PYY3–36-induced feeding reduction, indicating that PYY3–36-mediated satiety signals are relayed to the hypothalamus via the NTS.
We here demonstrated that PYY3–36 activated neurons in the hypothalamic arcuate nucleus of control, but not vagotomized, rats. Double immunostaining of the hypothalamic arcuate nucleus sections demonstrated that approximately 20% of MSH neurons are activated by peripheral administration of PYY3–36. This result suggests that PYY3–36 may stimulate MSH neurons of the arcuate nucleus to reduce feeding through the melanocortin-4 receptor (MC4-R) system. Very recently it has been reported that PYY3–36 also exhibits its inhibitory action on feeding in MC4-R-deficient mice (20). Furthermore, the anorectic effect of PYY3–36 has been demonstrated in Pomc knockout mice (21). MSH is a downstream product of the POMC gene (22) and is colocalized with cocaine- and amphetamine-regulated transcript (CART) in neurons of the arcuate nucleus (23). CART suppresses feeding independent of the MC4-R system when administered intracerebroventricularly (24). These findings imply that CART may play a role in the PYY3–36 cascade. An evaluation of the possible relationship between PYY3–36 and CART will be needed to elucidate the mechanism of PYY3–36-induced feeding reduction. PYY3–36’s signal is thought to be first input into the NTS and to probably transmit message for satiety to the hypothalamus using other transmitters. Halatchev et al. (20) reported that Fos immunoreactivity was not observed in the NTS after peripherally administered PYY3–36. Although we have not investigated Fos expression in the NTS after a single administration of PYY3–36, identification of substances in the NTS affected by PYY3–36 would be important for elucidation of neural pathway of peripheral PYY3–36.
PYY3–36, a member of the NPY family of peptides, shares 70% amino acid sequence homology with NPY and acts in feeding control through binding to the NPY receptor (25). To date, six functional NPY receptors (Y1-Y6) have been identified (26). NPY, an orexigenic hypothalamic peptide, induces food intake via binding to Y1- or Y5-R (27), whereas PYY3–36 inhibits food intake via binding to Y2-R (5). PYY3–36-induced feeding reduction is not observed in Y2r-null mice, confirming that Y2-R plays an important role in mediating PYY3–36 feeding inhibitory signals. Y2-R mRNA is expressed in more than 80% of NPY-positive neurons within the arcuate nucleus (28). PYY3–36 has been proposed to suppress NPY release via presynaptic Y2-R on NPY neurons, inhibiting feeding (5). PYY3–36 also inhibits the electrical activity of NPY nerve terminals, which activates neighboring POMC neurons (5). These findings indicate that PYY3–36 acts on feeding control directly via Y2-R within the arcuate nucleus. Y2-R mRNA, however, is also expressed in neurons of the nodose ganglion (29), a prominent swelling of the vagus located immediately before its entrance into the cranial cavity. A variety of receptors for gastrointestinal peptides, including CCK (30), ghrelin (10), and leptin (31), has been identified in neurons of the nodose ganglion. These receptors are transported to vagal afferent terminals through axonal transport. Here we demonstrated that Y2-R is also produced in vagal afferent neurons and transported to peripheral terminals. These findings indicate that peripheral PYY3–36 in part binds to the receptor present in the vagal afferent fibers, thereby inducing feeding reduction. We recently verified the colocalization of the ghrelin receptor with CCK-A receptor in neurons of the rat nodose ganglion (Date, Y., K. Toshinai, S. Koda, M. Miyazato, T. Shimbara, T. Tsuruta, A. Niijima, K. Kangawa, and M. Nakazato, unpublished data). In addition, the effect of ghrelin or CCK on feeding could be canceled by preadministration of either CCK or ghrelin, respectively. Given such an interaction of ghrelin with CCK in feeding regulation, PYY3–36 may also interact with ghrelin, CCK, or other peptides whose receptors are also located on the vagal afferent terminals to regulate feeding behavior.
The present electrophysiological study verified that PYY3–36 increases the firing rate of the gastric vagal afferent nerve. However, it does not exclude additional effects that PYY3–36 directly acts on the Y2-R of the hypothalamic arcuate nucleus. The arcuate nucleus is situated at the base of the hypothalamus and is incompletely isolated from the general circulation by the blood-brain barrier, allowing direct access of circulating factors to the arcuate nucleus neurons (32). Furthermore, a potent Y2-R agonist administered directly into the arcuate nucleus dose-dependently inhibits food intake in an identical way to PYY3–36 (5). Therefore, the effect of peripheral PYY3–36 on feeding reduction might be mediated in part through the Y2-R present in neurons of the hypothalamic arcuate nucleus.
The effect of a single administration of PYY3–36 on feeding reduction is rapid and short lived in mice (20). The chronic administration of PYY3–36 has no effect on cumulative food intake or body weight in mice (21). These PYY3–36 actions are similar to those of a satiety-factor CCK (33, 34). In human studies, plasma PYY3–36 levels of normal subjects rise immediately after a meal (6, 35), suggesting that PYY3–36 may be involved in the short-term feeding control rather than long-term regulation of body fat mass. In obese subjects, however, these increases in plasma PYY3–36 are delayed (36). The delay in PYY3–36 secretion acceleration after a meal may be an important factor in the pathophysiology of obesity and eating disorders. In addition, abnormalities in the release of or sensitivity to PYY3–36 also may be involved in alterations in food intake.
In conclusion, this study indicated that the vagal afferent system is one of the major pathways conveying PYY3–36’s signals for satiety. In addition, blockade of PYY3–36-induced feeding reduction in rats with midbrain transection implies that other transmitters of the NTS receiving PYY3–36’s signals affect neurons of the hypothalamus, thereby inducing feeding reduction. Further investigation of the mechanism controlling PYY3–36 secretion and its interaction with other feeding-related hormones of the periphery and/or central nervous system will help our understanding of the multifactorial regulation of feeding behavior.
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Acknowledgments |
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Footnotes |
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First Published Online February 17, 2005
Abbreviations: CART, Cocaine- and amphetamine-regulated transcript; CCK, cholecystokinin; MC4-R, melanocortin-4 receptor; NPY, neuropeptide Y; NTS, nucleus of the solitary tract; POMC, proopiomelanocortin; PYY, peptide YY; Y2-R, NPY Y2 receptor.
Received September 24, 2004.
Accepted for publication February 7, 2005.
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