Aminoglucose-induced feeding suppression is regulated by hypothalamic neuronal histamine in rats

181

Brain Research, 631 (1993) 181-186 © 1993 Elsevier Science Publishers B.V. All rights reserved 0006-8993/93/$06.00

BRES 19520

Research Reports

Aminoglucose-induced feeding suppression is regulated by hypothalamic neuronal histamine in rats Masahiro Kang, Hironobu Yoshimatsu, Mamoru Kurokawa, Akihiko Oohara, Toshiie Sakata * Department of Internal Medicine I, School of Medicine, Oita Medical University, Hasama, Oita, 879-55, Japan (Accepted 27 July 1993)

Key words: 1-Deoxy-D-glucosamine; 1-Deoxy-N-acetylglucosamine; Turnover of neuronal histamine in the hypothalamus; a-Fluoromethylhistidine; Chlorpheniramine; Feeding suppression

Central mechanisms involved in feeding suppression produced by 1-deoxy-D-glucosamine (1-DGIcN) and 1-deoxy-N-acetylglucosamine (1DGIcNAc) are unclear. To clarify the mechanisms, we investigated the role of hypothalamic neuronal histamine (HA) in feeding suppression induced by 1-DGIcN and 1-DGIcNAc in rats. Food intake was suppressed for 3 days after a single infusion of 24/xmol 1-DGlcN into the third cerebroventricle (i.c.v.). Depletion of presynaptic HA due to intraperitoneal infusion (i.p.) of a-fluoromethylhistidine (FMH), a specific inhibitor of the HA synthesizing enzyme histidine decarboxylase (HDC), abolished feeding suppression completely. Blockade of postsynaptic H l-receptors by i.p. injection of 26 p,mol chlorpheniramine also abolished the suppression. Oral administration of 2.4 mmol 1-DGIcNAc suppressed food intake. However, depletion of neuronal HA due to FMH did not affect the suppression. I.c.v. infusion of 24/zmol 1-DGIcN increased turnover rate of HA at 1 h after the infusion. Hypothalamic HA concentration, but not that of tele-methylhistamine (t-MH), increased at 24 h after i.c.v. infusion of 1-DGIcN, which suggests a correlation between HA concentration and the behavioral response. These results indicate that 1-DGlcN, but not 1-DGIcNAc, modulates feeding suppression through HA neurons in the hypothalamus. Differences in mechanisms of feeding suppression by these aminoglucoses may depend on the principal sites of action in the brain a n d / o r peripheral organs.

INTRODUCTION

Our series of studies on glucose and its analogues have shown that structural characteristics contribute to different effects on feeding behavior 31. Removal of a hydroxyl group from carbon-1 on a pyranose ring potentiated inhibition of feeding and the removal from carbon-2 elicited initial feeding followed by feeding suppression 25. D-Glucosamine (2-amino-2-deoxy-o-glucose) showed elicitation of feeding behavior 2'3, while 2-deoxy-o-glucose (2-DG) showed initial feeding and delayed suppression 1°'2s. D - G l u c o s e 9 a n d 1 - d e o x y - D glucosamine (2-amino- 1,5-anhydro-2-deoxy-o-glucitol: 1-DGIcN) 2'27 produced an inhibitory effect on feeding behavior. 1-Deoxy-N-acetylglucosamine (2-acetamido1,5-anhydro-2-deoxy-D-glucitol: 1-DGIcNAc), an Nacetyl form of 1-DGIcN, produced an inhibitory effect on feeding behavior 19. The primary site of action of

* Corresponding author. Fax: (81) (975) 49-4480.

1-DGIcNAc is in peripheral organs, not in the brain. Chemosensitive neurons of the lateral hypothalamic area (LHA) and the ventromedial hypothalamus (VMH) were shown to be involved in feeding modulation induced by these analogues 2'26. Induction of feeding depends on increased neural activity in the LHA and decreased activity in the VMH 2. However, the precise mechanisms have not been properly explored and remained unclear. Hypothalamic neuronal histamine (HA) has been shown to suppress feeding behavior through the hypothalamic Hi-receptor 4'28'3°. Our previous study showed that a decrease in blood glucose or intracellular glucoprivation in the brain activated turnover of hypothalamic neuronal HA20. The present study aims to clarify involvement of hypothalamic neuronal HA in prolonged feeding suppression induced by 1-DGlcN and 1-DGlcNAc.

182 MATERIALS

AND METHODS

General procedure of behavioral measurement Mature male Wistar king A rats, 280-300 g, were used. They were housed in a sound-proof room which was automatically illuminated daily from 08.00 h to 20.00 h (a 12/12 h l i g h t / d a r k cycle) and maintained at 2 1 + 1 ° C with humidity at 55_+5%. The rats were allowed free access to rat pellets (mean n u m b e r _+S.E.M., 47.5 _+0.5 mg, Kanae Co. Ltd., Japan) and tap water. To equilibrate arousal level, all rats were handled for 5 min daily for six successive days before each experiment. Each rat was housed in a 3 0 × 25 × 25 cm testing chamber equipped with a pellet-sensing eatometer (Astec, Japan) 2~. T h e n u m b e r of food pellets was automatically recorded in a minicomputer system in a separate room 29.

Reagents The test solutions of 1-DGIcN and 1-DGIcNAc (gifts from Chugai Pharmaceutical Co. Ltd., Japan) were freshly dissolved in phosphate buffered saline (PBS) at concentrations of 2.40 M. Chlorpheniramine maleate (CHP) (Sigma, USA) and o~-fluoromethylhistidine (FMH) (a gift from Dr. J. Kollonitsch, Merck Sharp and D o h m e Research Laboratories) were also freshly dissolved in PBS at concentrations of 0.026 M and 0.16 M, respectively. Pargyline hydrochloride (Sigma, USA), an inhibitor of m o n o a m i n e oxidase B, was also freshly dissolved in PBS at a concentration of 0.1 M. PBS (pit 7.35-7.40) contains 137 m m o l / l NaCI, 2.68 m m o l / l KC1, 8.10 m m o l / l N a 2 H P O 4 and 1.47 m m o l / l K H z O 4.

Surgery O n e week before testing, a stainless steel cannula (23 gauge) was implanted u n d e r pentobarbital sodium anesthesia (50 m g / k g ) into the third cerebroventricle (i.c.v.) of each rat to the depth of 7.8 m m from the cortical surface at a point on the midline 6.0 m m anterior to ear bar zero, according to the atlas of K6nig and Klippel 8. After completion of the experiments, pontamine sky blue dye (1-/~1) was infused into the i.c.v, cannula to verify the position in the third ventricle.

i.p. pretreatment with 160 /~mol/rat F M H :it 18.30 h (FMtlDGIcNAc group). The second group was administered po with the same dose of I-DGIcNAc after i.p. pretreatmenl with PBS (PBS DGlcNAc group). The third group was administered po with PBS after i.p. pretreatment with PBS (PBS-PBS group). Schedule and analysis were the same as for the i.c.v, infusion of 1-DGIcN experiments, as applicablc.

Evaluation of histamine and its turnover rate Brain samples were collected by decapitation 1 h (acute phase) or 24 h (chronic phase) after i.c.v, infusion of 2 4 / z m o l / r a t 1-DGIcN at 14.00 h (n = 5 for each). Each control was infused i.c.v, with PBS at 14.00 h (n = 5 for each). The bypothalamus was quickly dissected on an ice plate according to the procedure of GIowinski and Iversen 5, then homogenized in 0.3 ml of 0.40 M perchloric acid containing 1.25 tzM pros-methylhistamine as an internal standard. After centrifugation at 1,000 g, 0.25 ml of the supernatant was used for the assay. These amines were extracted into n-butanol under NaCI by shaking with benzene. After adjusting the pH to 6.0. the extracts were applied to P-cellulose columns. The columns were washed successively with 0.01 M phosphate buffer (pH 6.0, 2 ml × 2), distilled water (1 ml) and 0.12 M HCI (0.4 ml). The amines were eluted with 0.12 M HCI (1.0 ml) and, after evaporation, were subjected to a reaction with o-phthalaldehyde at p i t 10.0 in the presence of 2mercaptoethanol. The resulting fluorophores were then injected into a high performance liquid chromatography (HPLC) system 17. The system was composed of an LC-6A pump (Shimadzu, Japan) and a reverse phase column (Chemcosorb ODS-H, Chemco Scientific, Japan). The mobile phase was a solution of 0.06 M N a e H P O 4 and methanol (47:53, vol/vol). The excitation and emission wavelengths were set 340 and 450 nm, respectively. Linear accumulation of tete-methylhistamine (t-MH) after i.p. injection of 0.1 m m o l / r a t pargyline, an inhibitor of m o n o a m i n e oxidase B (MAO-B), was used to estimate of H A turnover rate TM. In the present study, H A turnover at the acute phase was estimated by t-MH accumulation after pargyline treatment TM. Pargyline was injected i.p. 10 min before i.c.v, infusion of 24 ~.mol 1-DGIcN. Concentrations of H A and t-MH were evaluated by H P L C 1 h after i.c.v. infusion of 1-DGIcN. Statistical evaluation of the data was carried out by the M a n n - W h i t n e y U-test.

Measurement of feeding behavior Lc.v. infusion of 1-DGlcN. Matched on the basis of 24-h food intake on the infusion day, 54 rats were divided into three groups. Each rat was infused through an i.c.v, cannula with a 10-~1 volume of 1-DGIcN at a dose of 24 / ~ m o l / r a t ( n = 36) or the same volume of PBS (n = 18) at a rate of 1 /~l/min. Each infusion was started at 19.30 h in unanesthetized and unrestrained conditions 29. T h e first group (n = 7) was pretreated intraperitoneally (i.p.) with a 1-ml volume of F M H at a dose of 160/.~mol/rat at 18.30 h, 1 h before i.c.v, infusion of 1-DGlcN (FMH-DGIcN group). In the second group (n = 5), the same dose of F M H was injected i.p. 24 h after i.c.v, infusion of I-DGIcN (DGIcN-FMH group). The third group (n = 6) was pretreated i.p. with a 1-ml volume of chlorpheniramine (CHP) at a dose of 26 / x m o l / r a t at 18.30 h, 1 h before i.c.v, infusion of I-DGicN (CHP-DGlcN group). The same volume of PBS was injected i.p. according to the same schedule as that in the appropriate 1-DGIcN groups (n = 7 in PBS-DGIcN group, five in DGIcN-PBS group, six in PBS-DGIcN group). The remaining 18 rats which were i.c.v, infused with PBS were also pretreated i.p. with PBS according to the corresponding schedules of the experimental groups (n = 7, n = 5, n = 6 for each PBS-PBS group). Daily 24-h cumulative food intake was m e a s u r e d at 18.00 h. Statistical evaluation of the data was based on one-way or two-way analysis of variance with replication in which orthogonal decomposition for linear comparison was carried out. The difference between two m e a n s was carried out by the m e t h o d of least significant difference. Oral administration of 1-DGlcNAc. To adapt to the gastric cannulation, each rat was administered 1 ml of distilled water via a gastric cannula for 1 week before testing. Matched on the basis of 24-h food intake on administration day, 15 rats were equally divided into three groups. The first group was administered orally (po) 1 ml of 1DGIcNAc at a dose of 2400 ~ m o l / r a t via a gastric cannula 1 h after

RESULTS

Effects of a-fluoromethylhistidine on feeding suppression due to 1-DGIcN Fig. 1 shows the effect of F M H pretreatment on time course of food intake after 1-DGIcN infusion. Infusion of 1-DGIcN with pretreatment of PBS suppressed food intake (F5,36 = 6.98, P < 0.01). This suppression lasted 3 days (day 3; P < 0.01, day 4; P < 0.01, day 5; P < 0.05, day 6; P > 0.1 vs the corresponding levels before 1-DGIcN infusion). After pretreatment with FMH, 1-DGIcN failed to decrease food intake (F5,36 = 0 . 3 5 ,

P>

0.1).

Food

intake

in

the

PBS-PBS

control group was not affected. Fig. 2 shows the change of food intake in response to 1-DGIcN in which the same dose of F M H was injected i.p. 24 h after 1-DGIcN infusion. Food intake in the DGIcN-FMH group decreased on the first day after 1-DGlcN infusion but returned to the previous level after F M H treatment (F5,24 = 9.60, P < 0.01) (day 3; P < 0 . 0 1 , day 4; P > 0 . 1 , day 5; P > 0 . 1 , day 6; P > 0.1 vs the corresponding levels before 1-DGlcN

183

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TIME

Fig. 1. Effects of FMH pretreatment on feeding suppression due to I-DGIcN. Each value, mean 5: S.E.M. Open circles, i.c.v, infusion of 2 4 / ~ m o l / r a t 1-deoxy-D-glucosamine after i.p. pretreatment of phosphate buffered saline (PBS). Open squares, i.c.v, infusion of 24 ~ m o l / r a t 1-deoxy-D-glueosamine after i.p. pretreatment of 160 ~ m o l / r a t FMH. Closed circles, i.c.v, infusion of PBS after i.p. pretreatment of PBS. * P < 0.05, * * P < 0.01 vs the corresponding values before 1-DGlcN infusion. In this and succeeding figures: infusion of the test solution at 19.30 h; i.c.v., intracerebroventricular infusion; i.p., intraperitoneal injection.

infusion). Sustained suppression of food intake was confirmed in the DGlcN-PBS group (Fig. 1) (F5,24 = 22.53, P < 0.01). There was no effect on food intake in the PBS-PBS control group.

Effects of histamine Hi-receptor antagonist on feeding suppression due to 1-DGIcN Fig. 3 shows feeding response to 1-DGlcN infusion after pretreatment of CHP. CHP attenuated the suppressive effect of 1-DGIcN on food intake on the first day after 1-DGIcN infusion (day 3; P > 0.1), but did not block the effect on the second day after the infu-

I DAY5

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COURSE

Fig. 3. Effects of chlorpheniramine pretreatment on feeding suppression due to 1-DGlcN. Each value, mean 5: S.E.M. Open circles, i.c.v. infusion of 24 /zmol/rat 1-deoxy-D-glucosamine after i.p. pretreatment of PBS. Open squares, i.c.v, infusion of 24 /.~mol/rat 1-deoxyD-glucosamine after i.p. pretreatment of 26 ~ m o l / r a t chlorpheniramine. Closed circles, i.c.v, infusion of PBS after i.p. pretreatment of PBS. * P < 0.05, * * P < 0.01 vs. the corresponding values before 1-DGlcN infusion.

sion (day 4; P < 0.01), compared to the initial level. This feeding suppression on the second day was less potent than that of the PBS-DGIcN group (Fl,60 = 12.66, P <0.01). Sustained feeding suppression was once again confirmed in the PBS-DGIcN group (Figs. 1 and 2) (F5,30 = 8.23, P < 0.01). Food intake in PBS-PBS control group was not affected.

Effects of a-fluoromethylhistidine on feeding suppression due to 1-DGlcNAc Effects of F M H pretreatment on food intake after

po administration of 1-DGIcNAc is shown in Fig. 4. The PBS-DGlcNAc group showed decreased food in-

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Fig. 2. Effects of F M H posttreatment on feeding suppression due to 1-DGlcN. Each value, mean 5: S.E.M. Open circles, i.p. injection of PBS 24 h after i.c.v, infusion of 2 4 / z m o l / r a t 1-deoxy-o-glucosamine. Open squares, i.p. injection of 160 p.mol/rat F M H 24 h after i.c.v. infusion of 24 /zmol/rat 1-deoxy-D-glucosamine. Closed circles, i.p. injection of PBS 24 h after i.c.v, infusion of PBS. * P < 0.05, * * P < 0.01 vs the corresponding values before 1-DGIcN infusion.

L

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Fig. 4. Effects of FMH pretreatment on feeding suppression due to I-DGIcNAc. Each value, mean 5: S.E.M. Open circles, oral (go) administration of 2 4 0 0 / z m o l / r a t 1-deoxy-N-acetylglucosamine after i.p. pretreatment of PBS. Open squares, po administration of 2400 /zmol/rat 1-deoxy-N-acetylglucosamine after i.p. pretreatment of 160 /zmol/rat FMH. Closed circles, po administration of PBS after i.p. pretreatment of PBS.

184 TABLE I

Contents of hypothalamic histamine (HA) and tele-methylhistamine (t-MH) after infusion Of 1-deo.
PBS-pretreated

Pargyline-pretreated

n

HA (nmol / g)

t-MH (nmol / g)

n

HA (nmol /g)

t-MH (nmol / g)

5 5

3.062 _+0.26/) 3.294 ± 0.117

1.320 ± I).085 1.248 ± 0.027

5 5

2.737 ± 0,358 3.372 ± 0,434

2.257 ± 1).134 3.640 ± 1).144 ~

5 5

3.474± 0,148 5.527 + 0.594 *

1.427±1).158 1.510 ±/).091

Each value, mean_+ SEM. n, number of rates tested, n.t., not test. * = P < 0.01 vs corresponding PBS.

take (F3,16 = 4.68, P < 0.05). FMH did not block feeding suppression induced by 1-DGIcNAc (FMHDGlcNAc group)(F3,16 = 4.63, P < 0.05). Food intake in the PBS-PBS control group was not affected. Effects of 1-DGIcN infusion on concentrations of histamine and its turnover rate Table I shows changes in concentrations of HA and t-MH in the hypothalamus after 1-DGIcN infusion. 1-DGIcN showed no influence on steady-state level of HA or t-MH without pargyline treatment when the amines were measured 1 h after 1-DGIcN infusion (acute phase). At this acute phase, however, pargylineinduced accumulation of t-MH in the 1-DGIcN group was greater than that in the PBS control group (P < 0.01), whereas HA concentration was not affected. Hypothalamic HA concentration without pargyline treatment increased more than that in the PBS control ( P < 0.01), but t-MH concentration was not significantly different, when the amines were measured 24 h after 1-DGIcN infusion. DISCUSSION In the present study, the feeding suppression produced by 1-DGIcN was demonstrated to be abolished completely by FMH pretreatment. In addition, pretreatment with an H~-receptor antagonist also attenuated the suppressive effect of 1-DGIcN on food intake. We have demonstrated that histaminergic suppression of feeding is mediated through the H~-receptor in the VMH and the paraventricular nucleus ( P V N ) 4'21'30. FMH decreases neuronal HA by specifically inhibiting histidine decarboxylase (HDC) 7, an essential enzyme for synthesis of neuronal HA level 34. These results indicate that hypothalamic neuronal HA is involved in feeding suppression induced by 1-DGlcN through the H a-receptor. The time course of the suppressive effects of 1-DGIcN differed after pretreatment with FMH and the Hi-receptor antagonist. This may result from the

differences in length of their actions. FMH has been shown to decrease HA level during at least 48 h after administration ~1, but H 1-receptor antagonist blocks HA action during 24 h at most 6. Feeding suppression due to 1-DGIcN lasted 3 days 2. A question can be raised as to how this prolonged suppressive effect of 1-DGlcN is related to neuronal HA. One possible explanation is that HA per se which is released from the nerve terminal to the extracellular space in response to 1-DGIcN shows persistent effects on behavior. Another possibility is that the release of HA may be accelerated for a prolonged period by 1-DGlcN. The change in food intake due to 1-DGlcN was observed when FMH was injected i.p. at 24 h after 1-DGIcN treatment. FMH abolished feeding suppression due to 1-DGlcN even after feeding was already suppressed. The results indicate that sustained suppression due to 1-DGIcN is derived from its prolonged excitation of histaminergic neurons resulting in release of HA and suppression of food intake. To ascertain the contribution of HA in feeding suppression due to I-DGIcN, hypothalamic neuronal HA and t-MH were measured by HPLC. Steady-state levels of hypothalamic HA and t-MH without pargylinc treatment did not change 1 h after administration of 1-DGlcN. Pargyline-induced accumulation of hypothalamic t-MH, but not HA, increased significantly 1 h after 1-DGlcN infusion. In the brain, methylation of HA is the major metabolic pathway for neuronal HA3< Increase in brain t-MH concentration in response to 1-DGlcN after inhibition of degradation with pargyline, an inhibitor of MAO-B, indicates that increased HA turnover may be the mechanism mediating the suppressive effect of 1-DGlcN on food intake. In our previous study, insulin-induced hypoglycemia or intracellular glucoprivation induced by 2-DG was shown to increase HA turnover 2°. Because a hydroxyl group at carbon-1 facilitates further phosphorylation, 1-DGIcN in which a hydroxyl group is removed, is not easily phosphorylated 2. Thus, 1-DGlcN and 1-DGlcN 6-phos-

185 phate accumulate intracellularly after transport into the cell. The accumulation leads to ATP deficiency in the neuron due to impairment of glucose utilization. This intracellular glucoprivation produced by 1-DGIcN may activate the hypothalamic HA system. However, this histaminergic response in the acute phase cannot necessarily explain the behavioral response since feeding suppression was observed in the long-lasting period after 1-DGlcN administration. To clarify this inconsistency, changes in hypothalamic neuronal HA and t-MH were also measured in the chronic phase without pargyline treatment. Hypothalamic HA, but not t-MH, increased in this chronic phase. Increase in hypothalamic HA concentration may result from increased synthesis and/or decreased release from the nerve terminal. The present results, however, indicate an increase in both synthesis and release of HA in the acute phase. The behavioral experiments and the evaluation of amines in the chronic phase indicate that extracellular accumulation of HA may result from continuous release from nerve terminals and decreased transmethylation probably due to 1-DGIcN. Oral but not i.c.v, administration of 1-DGIcNAc was shown in our previous study to suppress food intake and to be abolished by bilateral truncal vagotomy 19. This suggests that the primary site of action of 1DGlcNAc may be in peripheral organs. The signal seems to be conveyed to the brain through vagal sensory fibers. Chemosensitive units responding to glucose or other chemical substances have been identified in the liver ~3'15'16 and in the gastrointestinal tract 12'15. Visceral signals from hepatic and intestinal chemosensors are conveyed to the LHA through relay neurons in the nucleus of the tractus solitarius ( N T S ) 1'22'24 or parabrachial nucleus (PBN) 22'32. The reason why feeding suppression induced by 1-DGlcNAc is not abolished by FMH pretreatment may be because histaminergic neurons in the hypothalamus are not involved in signal transmission from visceral organs to the hypothalamus. Thus, the findings of the present study show that feeding suppression caused by aminoglucose depends on the dynamics of HA neurotransmission. HA neurons have been shown to regulate glucose metabolism in the brain 23 and peripheral organs 14. These studies indicate that the energy deficit produced by direct administration of aminoglucose, but not neuronal information from peripheral organs, activates HA neurons which may play an important role in behavioral control and energy metabolism. Acknowledgements. We thank Dr. J. Kollonitsh, Merk Sharp and Dohme Research Laboratories, USA for the supply of FMH, Dr. R.

Kaifu, Chugai pharmaceutical Co. Ltd. for synthesizing 1-DGIcN, 1-DGlcNAc, Dr. D.S. Knight, for help in preparation of the manuscript and Prof. Y. Niho, Department of Internal Medicine I, Kyushu University, for valuable advice. Supported partly by Grantsin-Aid 62591025 and 02454129 from the Japanese Ministry of Education, Science and Culture; by Research Grants from the Japanese Fisheries Agency for Research into Efficient Exploitation of Marine Products for Promotion of Health, 1989, 1990, 1991.

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