- Email: [email protected]
Effects of Histamine on Lipid Metabolic Disorder in Mice Loaded With Restraint Stress
J Pharmacol Sci 111, 117 – 123 (2009)2
Journal of Pharmacological Sciences ©2009 The Japanese Pharmacological Society
Full Paper
Effects of Histamine on Lipid Metabolic Disorder in Mice Loaded With Restraint Stress Rong Rong He1,2, Nan Yao1, Min Wang1, Xue Song Yang3, Chin Chin Yau4, Keiichi Abe4, Xin Sheng Yao1,2, and Hiroshi Kurihara1,* 1
Institute of Traditional Chinese Medicine & Natural Products, Jinan University, Guangzhou 510632, China College of Traditional Chinese Materia Medica, Shengyang Pharmaceutical University, Shengyang 110016, China 3 Medical College, Jinan University, Guangzhou 510632, China 4 BRAND’S Health Science Center, Cerebos Pacific Ltd., Singapore 048423, Singapore 2
Received March 22, 2009; Accepted July 18, 2009
Abstract. The present study was conducted to investigate the effects of histamine on the lipid metabolic disorder in mice loaded with restraint stress. When Kun Ming (KM) mice were exposed to restraint stress for 20 h, the histamine level in both plasma and cerebral regions significantly increased (P<0.01). Moreover, when a lipid emulsion (10% Intralipid®) was injected intravenously into the mice, the elimination period of plasma triglyceride was prolonged in the restraint group. Plasma triglyceride was 523 ± 44 mg/dl at 35 min after the Intralipid® administration in the restraint stress group, while it was 436 ± 41 mg/dl in the restrained mice given histamine at a dose of 50 mg/kg. The improved plasma triglyceride metabolism was well explained by the observations of the significantly up-regulated hepatic triglyceride lipase (HTGL) activity and mRNA expression in response to histamine. These results suggested that the effects of stress-induced histamine on lipid metabolic disorder in mice loaded with restraint stress arose from its anti-stress action and promotion of lipase activity. Keywords: histamine, energy metabolism, restraint stress, lipid emulsion Intralipid®, triglyceride disorders (4, 5). Stress is also well known for its direct influences on the central nervous system (6). A large number of experimental evidences supported that the histaminergic system performs its physiological functions through H1, H2, and H3 receptors (7). Recent studies suggested that the activities of histaminergic neurons are likely to increase the response to stress (8). On one hand, proper stress can enhance biosynthesis and the release of histamine (9). On the other hand, histamine has been implicated in a variety of responses to stress as well as noradrenergic neurons activity, prolactin, adrenocorticotropin, renin secretion, dopamine releases, and metabolism in different brain regions (10 – 14). Therefore, histamine plays an important role in mediating the activity of both the central nervous system and endocrine system (15). Although the effects of stress in histaminergic nervous and the endocrine system have been widely reported (16), less attention has been paid to the influence of histamine on utilizing blood lipids in stress-loaded animals. Thus, we demonstrated the relationship between
Introduction There have been a number of studies about the mechanisms of the symptoms caused by stress (1). Energy metabolism is important in various stress reactions (2). Generally, a source of energy is required to sustain physiological functions of the brain, central nervous system, heart, and muscles, and so on. This energy supplement is mainly from dietary glucose, lipid, or from glycogen stores and fat deposits. Moreover, Ricart-Jané’s study (3) indicated that stress caused lipid energy-substrate redistribution between tissues, which was required for the fight-or-flight response. Other studies also indicated that stress limited the supply of energy, which lead to poor utilization of biological energy sources, neurological or tissue dysfunctions, and resulted in tiredness and various other physiological *Corresponding author. [email protected] Published online in J-STAGE doi: 10.1254/jphs.09090FP
117
118
RR He et al
stress and blood lipid metabolism using Intralipid® as a tracer for the simple fat emulsion clearance test in mice exposed to restraint stress. Intralipid®, an artificial lipid emulsion used to supply energy and essential fatty acids, is commonly used in clinical practice (17) and also as a tracer for blood triglyceride (18). Materials and Methods Materials Histamine was purchased from Wako Pure Chemical Industries (Osaka). It was dissolved in phosphatebuffered saline (PBS) solution immediately before use. The 20% Intralipid® (lipid emulsion including 20% soybean oil, 1.2% lecithin and 2.2% glycerol) was purchased from Pharmacia AB Co. (Stockholm, Sweden). It was diluted with PBS to make a 10% soybean oil solution immediately before use. Animals Seven-week-old female Ku Ming (KM) mice were purchased from the Center for Laboratory Animal Science Research of Southern Medical University (Guangzhou, China). All mice were kept in a specific pathogen-free animal room under the controlled conditions of room temperature at 23 ± 1°C with a 12-h light-dark cycle (lights on from 06:00 to 18:00), and they were provided with standard laboratory diet and water. The animals were allowed to acclimatize to the environment for 1 week before the experiment. In the restraint stress experiment, each mouse was confined to an oval metal restraint cage for 20 h before the assay. Animals were handled in accordance with a protocol approved by the animal care committee of Jinan University. All the animal experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the United States National Institutes of Health. Measurement of histamine levels in plasma and brain regions The effects of restraint stress on histamine secretion in plasma and brain regions were investigated. In the starved control group, food and water were deprived for 20 h. In the restraint stress group, each mouse was individually confined to an oval restraint cage for 20 h before the assay. Blood samples were drawn from the heart under anesthesia with diethyl ether into a tube containing 2% sodium heparin (Wako Pure Chemical Industries) and then centrifuged at 5, 000 rpm for 5 min at 4°C. The plasma was then deproteinized by adding 6% perchloric acid (Merck, Darmstadt, Germany) to adjust the concentration to 3%, and the sample was
centrifuged at 15, 000 rpm for 15 min at 4°C. The supernatant was subsequently stored at −20°C before it was assayed. In addition, after the mice were sacrificed by drawing blood, brain tissue samples of the midbrain and brain cortex were quickly dissected. These tissues were weighed and soaked in PBS solution containing 3% perchloric acid (1 g tissue/ml). The materials were homogenized with a homogenizer (IKA Labortechnik, Staufen, Germany) at maximum setting for 30 s under an ice-cold condition. Then the homogenate was centrifuged at 15,000 rpm for 20 min at 4°C. The concentrations of histamine in both plasma and brain regions were determined by the high-performance liquid chromatography (HPLC)–fluorometry technique as described previously by Yamatodani et al. (19). This assay was carried out at room temperature. Samples were filtered through a 0.45-μm membrane filter and 10 μl of the sample was injected directly into a column packed with the TSKgel SP2SW Cation Exchanger (6 × 150 mm; Tosoh, Tokyo). Histamine was eluted with 0.25 M potassium phosphate at a flow rate of 0.6 ml/min. The histamine was post-labeled with οphthalaldehyde in an alkaline condition and detected fluorometrically in an F1080 Fluorometer (Hitachi, Tokyo), with monitoring at 360 and 450 nm, respectively. Plasma lipids tolerance test procedure The effects of restraint on triglyceride metabolism were investigated. Mice were divided into three groups. In the normal control group, no treatment was given to the mice. In the starved group, mice were deprived of food and water for 20 h. In the restrained and starved group, mice were confined to an oval metal restraint cage for 20 h before the assay. Intralipid® was injected through the tail vein at a dose of 0.1 ml/10 g of body weight. On the other hand, we investigated the effect of histamine on plasma triglyceride elimination. In the stress control and histamine groups, mice were confined to an oval metal restraint cage for 20 h while being starved before the assay. PBS solution or histamine were injected through the tail vein at a dose of 0.1 ml/10 g of body weight 35 min before the administration of Intralipid® to mice that had been restrained for 20 h while being starved. In the starved control group, only PBS solution was administered. Blood samples were taken from the heart under anesthesia with diethyl ether and kept in a tube containing 2% sodium heparin. Then, the blood samples were centrifuged at 5,000 rpm for 5 min at 4°C, and the supernatant was collected and stored at −20°C until the assay. Plasma triglyceride was measured by the glycerol kinase / glycerol-3phosphate oxidase (GK-GPO) method (20). The assay kit was purchased from International Reagents Corporation
Histamine on Lipid-Metabolic Disorder
(Kobe). Measurement of hepatic triglyceride lipase (HTGL) Histamine (Sigma, St. Louis, MO, USA) was injected into two groups of mice through the tail vein at a dose of 50 mg/kg of body weight. One group was sacrificed at 30 min after the histamine injection, and another group was sacrificed at 20 h after the histamine injection. The hepatic tissue was quickly dissected out during the PBS solution perfusion and then weighed. A 100-mg sample of tissue was removed immediately from each liver and kept in PBS solution under an ice-cold condition. Then the tissues were minced with scissors and homogenized with a homogenizer at the maximum setting for 30 s under an ice-cold condition in 1 ml of solution (containing 0.25 M sucrose, 1 mM ethylenediaminetetraacetic acid (EDTA), 10 mM Trizma hydrochloric acid (Tris ⋅ HCl), and 12 mM deoxycholate, pH 7.4). The homogenate was collected by centrifuging at 12,000 rpm 4°C for 20 min; it was diluted with 4 volumes of the homogenization solution and then decanted and immediately stored at −20°C until the HTGL activity measurement. The HTGL activity assay was carried out using the BALB-DTNB method as described previously by Kurooka and Kitamura (21). Reverse transcription polymerase chain reaction (RTPCR) analysis of HTGL mRNA expression The mice were sacrificed at different times after the histamine was injected through the tail vein at a dose of 50 mg/kg. The hepatic tissue was quickly dissected out during the PBS solution perfusion. Total RNAs were extracted from the liver samples by using Trizol (Invitrogen, Carlsbad, CA, USA). A 3-μg amount of total RNA was reverse-transcribed at 42°C for 1 h in a 20-μl reaction mixture containing mouse Moloney leukemia virus reverse transcriptase (Tiangen, Beijing, China) with oligo (dT) primers (Tiangen) followed by RT-PCR amplification. Thereafter, cDNA was amplified together with Taq polymerase (Tiangen), using specific primers with 35 cycles at 94°C for 30 s, an annealing temperature of 58°C for 50 s, and then 72°C for 50 s, with final incubation at 72°C for 7 min. The RT-PCR primers for mouse HTGL mRNA were (F) 5'-TGG ACGGGAAGAACAAG-3' and (R) 5'-GGAGTCAAT GAAGAGGTGC-3', and the product size was 326 base pairs. The primers for the mouse housekeeping gene beta-actin (β-actin) mRNA were (F) 5'-GAGGGA AATCGTGCGTGAC-3' and (R) 5'-GCTGGAAGGTG GACAGTGAG-3', and the product size was 446 base pairs. The RT-PCR products were fractionated on a 1% agarose gel and visualized by ethidium bromide staining. The band intensity of ethidium bromide fluores-
119
cence was measured by using an image analysis system (Bio-Rad, Hercules, CA, USA), quantified by a Bandscan (Glyko, Novato, CA, USA) and expressed as the ratio to β-actin. Statistical analyses The data were each presented as a mean ± S.E.M. Significant differences between the two groups were analyzed with Student’s t-test. One-way analysis of variance (ANOVA) was applied to analyze differences in data of biochemical parameters among the experimental groups, followed by Dunnett’s test for pair-wise multiple comparisons. Differences were considered as statistically significant at P<0.05. Results Effect of restraint stress on histamine We investigated the effects of restraint stress on the concentrations of histamine in plasma and brain regions by HPLC with a fluorescence detector. As shown in Table 1, the basal value of histamine obtained from the control mice was 5 ± 0.6 pmol/ml in plasma. When the mice were exposed to restraint stress for 20 h, the average plasma histamine value was significantly increased to 74 ± 9 pmol/ml (P<0.01). On the other hand, the histamine level was 596 ± 47 pmol/ml in the midbrain and was significantly increased compared with the level in the non-stress control mice (332 ± 43 pmol/ml, P<0.01). However, the effect of restraint on histamine was weaker in the cortex. The results suggested that the histaminergic neuron might play an important role in stress responses. Effect of restraint stress on plasma triglyceride elimination The metabolism of lipids was found to respond remarkably to the restraint stress in this study. Figure 1A shows the chronological changes of the triglyceride elimination rate in plasma after the injection of Table 1. Histamine concentration in the plasma and brain regions of KM mice exposed to restraint stress Group
Plasma (pmol/ml)
Cortex (pmol/g)
Midbrain (pmol/g)
Starved control
5 ± 0.6
159 ± 13
332 ± 43
Restraint stress
74 ± 9**
182 ± 18
596 ± 47**
In the starved control group, food and water were deprived for 20 h. In the restraint stress group, each mouse was starved and individually confined to an oval restraint cage for 20 h before the assay. The results represent the mean ± S.E.M. of the values obtained from 7 KM mice in each experimental group. **P<0.01: significantly different from the starved control mice as determined by Student’s t-test.
120
RR He et al
Fig. 1. Time-course changes of plasma triglyceride elimination rate after Intralipid® loading. Intralipid® was dissolved in PBS solution to the concentration of 10% soybean oil and immediately injected into the vein in a volume of 0.1 ml/10 g of body weight. In the normal control group (A), no treatment was given to the mice. In the starved group (B), mice were deprived of food for 20 h. In the restrained and starved group (C), mice were placed in restraint cages and starved for 20 h before the assay.
Intralipid®. The average level was 422 ± 40 mg/dl at 35 min after the injection of Intralipid®. When the mice starved for 20 h, the elimination rate was higher at 35 min and the average level was 350 ± 39 mg/dl as shown in Fig. 1B. The plasma triglyceride level was 523 ± 44 mg/dl at 35 min (P<0.01), and the clearance rate was lower in the mice that were exposed to stress for 20 h than the starved mice tested in the same way (Fig. 1C). The results suggested a good correlation between the elimination of triglyceride in blood and the response to stress. It also indicated that plasma triglyceride metabolism was definitely disrupted by the stress and decreased the utilization of triglyceride as an energy source. Effect of histamine on plasma triglyceride elimination in restrained mice In this study, we also investigated the effect of histamine administered through the tail vein on the elimination of plasma triglyceride in restrained mice. As shown in Fig. 2, when mice were fixed in the restraint cage for 20 h, the amount of plasma triglyceride level at 35 min after the injection of Intralipid® increased from 350 ± 39 to 523 ± 44 mg/dl (P<0.01). The concentration of plasma triglyceride was 463 ± 47 mg/dl in the lowdose histamine (25 mg/kg) group, 436 ± 41 mg/dl in the middle-dose histamine (50 mg/kg) group, and 423 ± 43 mg/dl in the high-dose histamine (100 mg/kg) group, showing an improvement by 11.5, 16.7 (P<0.01), and 19.2 (P<0.01), respectively, compared with the stress control group. Results indicated that plasma triglyceride metabolism in these mice under restraint stress was improved by the histamine, and the effects were dose dependent.
Fig. 2. Effects of histamine on triglyceride elimination in plasma obtained from KM mice loaded with restraint stress. Seven-week-old female KM mice were placed in the restraint cages and starved for 20 h. Histamine or PBS solution was administered through the tail vein at a dose of 0.1 ml/10 g of body weight after 20-h restraint stress. Intralipid® was diluted with PBS solution to the concentration of 10% soybean oil and immediately injected into the vein in a volume of 0.1 ml/10 g of body weight. The triglyceride concentration in plasma was measured at 35 min after administering Intralipid®. The results represent the mean ± S.E.M. of the values obtained from 7 mice in each group. **P<0.01, ##P<0.01: significantly different from the starved control and stressed control mice, respectively, as determined by the ANOVA test followed by Dunnett’s test.
Effects of histamine on HTGL activity in hepatic tissue Figure 3 shows the alteration of HTGL levels in hepatic tissue after administration of histamine. The basal value was 1421 ± 357 U/g in normal mice. The amount of HTGL in the starved control mice was 1603 ± 263 U/g. When histamine was given for 30 min, the HTGL activity was 1674 ± 352 U/g. However, when treated with histamine for 20 h, the HTGL activity significantly increased to 2147 ± 304 U/g compared with the basal value (P<0.01). The results showed that histamine moderately affects the HTGL levels in hepatic tissue.
Histamine on Lipid-Metabolic Disorder
121
there was no significant increase of HTGL mRNA expression in the starved group. As show in Fig. 4A, compared with the starved control, the expression significantly up-regulated after 50 mg/kg histamine was injected (P<0.01). When the histamine was given for 30 min or 20 h, HTGL mRNA expressions were both remarkably up-regulated (Fig. 4B). Discussion Fig. 3. Effects of histamine on HTGL activity in hepatic tissue. Histamine or PBS solution was administered through the tail vein at a dose of 0.1 ml/10 g of body weight for 30 min or 20 h before the HTGL activity assay. The results represent the mean ± S.E.M. of the values obtained from 7 mice in each group. **P<0.01: significantly different from the starved control mice as determined by the ANOVA test followed by Dunnett’s test.
Fig. 4. Effects of histamine on HTGL mRNA expression. A: Timecourse changes of HTGL mRNA expression after histamine injection. B: A representative of RT-PCR analysis of HTGL mRNA expression in mouse liver. Results were generated as relative intensity units by densitometry and expressed as the ratio of HTGL to β-actin. The results represent the mean ± S.E.M. of the values obtained from 7 mice in each group. **P<0.01: significantly different from the starved control mice as determined by the ANOVA test followed by Dunnett’s test.
Effects of histamine on the mRNA expression of HTGL in hepatic tissue The mRNA expression of HTGL in mouse liver was determined by RT-PCR. Figure 4 shows the chronological changes of mRNA expression after the injection of histamine. Compared with the normal control group,
Compared with the starved control mice, we found that the plasma triglyceride elimination rate was definitely prolonged in the restraint stress group. Generally, stress loading requires a large quantity of carbohydrates and fatty acids as an energy source from liver glycogen and adipose tissues (18). Researchers demonstrated that stress reduces production of insulin and causes energy metabolic decline (19). As the decline in energy metabolism is a cause of fatigue from stress (20), this means improvement of the energy metabolism can promote fatigue recovery and stress relaxation. These studies supported our results by suggesting that stress limits the supply of energy to organs, leading to poor utilization of biological energy. Therefore, the elevated levels of plasma lipids in the restrained mice may be a reflection of the degraded tissue function, while the decline in the elimination rate of plasma lipids may be a sign of stress. On the other hand, we investigated the effects of stress on histamine levels in plasma and brain. When mice were fixed in a restraint cage for 20 h, plasma histamine concentration significantly increased and showed an upward tendency in the cerebrum. Studies indicated that the histamine was mainly released from mast cells and enterochromaffin-like cells (21). Neuropeptides, such as substance P and neurokinin A, might stimulate histamine release from mast cells (22), and these neuropeptides were mediated by stress (23). All the above suggested that histamine was implicated in the host stress response. Previous studies indicated that stress enhanced the production of hormones, which was likely required for tolerating the life-threatening effect of stress (24). Studies also demonstrated various stressors had effects on the autonomic nervous system, and the activity of histaminergic neurons is likely to be increased in response to stress (25). However, less attention was paid to the role of stress-induced histamine in plasma lipid utilization. In the present experiment, we investigated the effects of histamine on the basic metabolism of plasma lipids in mice loaded with restraint stress and found that loading with histamine remarkably increased the elimination rate of plasma triglyceride. The effect of histamine seemed to be
122
RR He et al
improving lipid utilization as an energy source. Since the direct influences of histamine on the mechanism of lipid utilization has not yet been systematically investigated, HTGL activity measurement was performed to record the changes of liver lipase following histamine treatment. HTGL is the rate-limiting enzyme for hydrolysis of triglyceride and thus controls the uptake of fatty acids into tissues (26). The present results showed that the lipase level in hepatic tissue improved by 33.9% (P<0.01) after peripheral loading with 50 mg/kg of histamine for 20 h. When the same dose of histamine was given for 30 min, the HTGL activity was not increased significantly, but HTGL mRNA expression was significantly up-regulated (P<0.01). Therefore, histamine promoted lipid metabolism by increasing lipase activity, which might be due to the markedly up-regulated lipase mRNA expression in response to histamine. Our results also implicated that histaminergic neurons may be one of the factors controlling the stress-induced physiological stress-response. Many researchers indicated that there is innervation of histaminergic neurons in a number of brain regions (27) and this might be important in the response capacity of animals to stress (28). Histaminergic neurons could modulate energy imbalance during stress through central histaminergic neuron receptors (29). The histamine H3 receptor has been demonstrated in association with stress-induced brain activity (30, 31). Some reports suggested that there are changes of histamine contents and histamine H1 and H3 receptors in the brains of mice subjected to fooddeprived stress and revealed that there is a discrepancy between the levels of H1 and H3 receptors in the acute and chronic phases of stress conditions (8). Also, histamine nerve systems played a crucial role in maintaining homeostatic energy balance (32, 33). In our studies, restraint stress increases histamine turnover in the brain, and in turn, histamine up-regulates HTGL expression in hepatic tissue. The latter may optimize lipid metabolism, improve metabolic dysfunction, and increase utilizing triglyceride as an energy source. Therefore, the effect of histamine may be also partly related to the alleviation of the adverse effects of stress on bio-homeostasis. Based on our findings, restraint-induced adaptability of plasma histamine improves stress-suppressed energy metabolism. These results suggested that the effects of histamine on lipid metabolic disorder in mice loaded with restraint stress arose from its anti-stress activity and promotion of lipase activity. Acknowledgments We thank Takehiko Watanabe, Ph.D. and Kazuhiko Yanai, Ph.D.
(Department of Pharmacology, Tohoku University School of Medicine) for helpful advice on the perfusion method and comments on this manuscript.
References 1 Kaneko H, Nakanishi K. Proof of the Mysterious Efficacy of Ginseng: basic and clinical trials: clinical effects of medical Ginseng, Korean Red Ginseng: specifically, its anti-stress action for prevention of disease. J Pharmacol Sci. 2004;95:158–162. 2 Tavazzi B, Amorini AM, Fazzina G, Pierro DD, Tuttobene M, Giardina B, et al. Oxidative stress induces impairment of human erythrocyte energy metabolism through the oxygen radicalmediated direct activation of AMP-deaminase. J Biol Chem. 2001;276:48083–48092. 3 Ricart-Jané D, Cejudo-Martín P, Peinado-Onsurbe J, LópezTejero MD, Llobera M. Changes in lipoprotein lipase modulate tissue energy supply during stress. J Appl Physiol. 2005;99: 1343–1351. 4 von Känel R, Mills PJ, Fainman C, Dimsdale JE. Effects of psychological stress and psychiatric disorders on blood coagulation and fibrinolysis: a biobehavioral pathway to coronary artery disease. Psychosom Med. 2001;63:531–544. 5 Kurihara H, Yao XS, Nagai H, Tsuruoka N, Shibata H, Kiso Y, et al. Anti-stress effect of BRAND’s essence of chicken (BEC) on plasma glucose levels in mice loaded with restraint stress. J Health Sci. 2006;52:252–258. 6 De Kloet ER. Hormones and the stressed brain. Ann N Y Acad Sci. 2004;1018:1–15. 7 Chang RSL, Tran VT, Snyder SH. Heterogeneity of histamine H1-receptors: species variations in [3H] mepyramine binding of brain membranes. J Neurochem. 1979;32:1653–1663. 8 Endou M, Yanai K, Sakurai E, Fukudo S, Hongo M, Watanabe T. Food-deprived activity stress decreased the activity of the histaminergic neuron system in rats. Brain Res. 2001;891:32–41. 9 Huang ZL, Mochizuki T, Watanabe H, Maeyama K. Activation of sensory nerves participates in stress-induced histamine release from mast cells in rats. Neurosci Lett. 1999;270:181–184. 10 Fleckenstein AE, Lookingland KJ, Moore KE. Histaminergic neurons mediate restraint stress-induced increases in the activity of noradrenergic neurons projecting to the hypothalamus. Brain Res. 1994;653:273–277. 11 Ravindran R, Rathinasamy SD, Samson J, Senthilvelan M. Noise-stress-induced brain neurotransmitter changes and the effect of Ocimum sanctum (Linn) treatment in albino rats. J Pharmacol Sci. 2005;98:354–360. 12 Knigge U, Matzen S, Hannibal T, Jørgensen H, Warberg J. Involvement of histamine in the mediation of the stress-induced release of alpha-melanocyte-stimulating hormone in male rats. Neuroendocrinology. 1991;54:646–652. 13 Matzen S, knigge U, Warberg J. Brain regulation of renin secretion involves central histaminergic neurons. Neuroendocrinology. 1990;52:175–180. 14 Fleckenstein AE, Lookingland KJ, Moore KE. Differential role of histamine in mediating stress-induced changes in central dopaminergic neuronal activity in the rat. Brain Res. 1994;653:267–272. 15 Watanabe T, Yanai K. Studies on functional roles of the histaminergic neuron system by using pharmacological agents, knockout mice and positron emission tomography. Tohoku J
Histamine on Lipid-Metabolic Disorder Exp Med. 2001;195:197–217. 16 Knigge U, Matzen S, Warberg J. Histamine as a neuroendocrine regulator of the stress-induced release of peripheral catecholamines. Endocrinology. 1990;126:1430–1434. 17 Kalfarentzos F, Kokkinis K, Leukaditi K, Maroulis J, Onoufriou A, Alexopoulos K. Comparison between two fat emulsions: Intralipid 30 cent vs intralipid 10 cent in critically ill patients. Clin Nutr. 1998;17:31–34. 18 Kurihara H, Fukami H, Koda H, Tsuruoka N, Sugiura N, Shibata H, et al. Effects of oolong tea on metabolism of plasma fat in mice under restraint stress. Biosci Biotechnol Biochem. 2002;66:1955–1958. 19 Harada E. Lowering of pancreatic amylase activity induced by cold exposure, fasting and adrenalectomy in rats. Comp Biochem Physiol A Comp Physiol. 1991;98:333–338. 20 Newsholme EA. Tired out: biochemical explanations of physical and mental fatigue. Biochemist. 2006;28:27–29. 21 Yang ZB, Tanaka T, Kiso Y, Watanabe T, Yanai K. The changes of histamine concentrations in the plasma and brain in response to acute stress. In: Watanabe T, Timmerman H, editors. Histamine research in a new millennium, Amsterdam: Elsevier; 2001. p. 486–490. 22 Hua XY, Back SM, Tam EK. Substance P enhances electrical field stimulation induced mast cell degranulation in rat trachea. Am J Physiol. 1996;270:L985–L991. 23 Theoharides TC, Spanos C, Pang X, Alferes L, Ligris K, Letourneau R, et al. Stress-induced intracranial mast cell degranulation: a corticotropin releasing hormone mediated effect. Endocrinology, 1995;136:5745–5750. 24 Csaba G, Kovács P, Pállinger É. Increased hormone levels in Tetrahymena after long-lasting starvation. Cell Biol Int. 2007; 31:924–928.
123
25 Kjaer A, Knigge U, Olsen L, Vilhardt H, Warberg J. Mediation of the stress-induced prolactin release by hypothalamic histaminergic neurons and the possible involvement of vasopressin in this response. Endocrinology. 1991;128:103–110. 26 Jiang XC, Moulin P, Quinet E, Goldberg IJ, Yacoub LK, Agellon LB, et al. Mammalian adipose tissue and muscle are major sources of lipid transfer protein mRNA. J Biol Chem. 1991;266: 4631–4639. 27 Hasenoehrl RU, Huston JP. Histamine. In: Gernot R, Bettina P, Editors. From messengers to molecules. Netherlands: Springer; 2004. p. 174–195. 28 Palkovits M, Toth Z, Gallatz K, Buzas E, Falu A. Activity of brain histaminergic neurons in response to stress. In situ hybridization histochemical studies on rats and transgenic mice. Neirokhimiya. 2003;20:120–126. 29 Sakata T, Ookuma K, Fujimoto K, Fukagawa K. Yoshimatsu H. Histaminergic control of energy balance in rats. Brain Res Bull. 1991;27:371–375. 30 Madeo M, Granata T, Facciolo RM, Tripepi S, Canonaco M. Feeding differences in pubertal and aged golden hamsters (Mesocricetus auratus) are related to specific cerebral expression pattern in histamine subtype 3 receptor. Behav Neurosci. 2006;120:1235–1241. 31 Brown RE, Stevens DR, Haas HL. The physiology of brain histamine. Prog Neurobiol. 2001;63:637–672. 32 Sakata T, Yoshimatsu H, Kurokawa M. Hypothalamic neuronal histamine: implications of its homeostatic control of energy metabolism. Nutrition. 1997;3:403–411. 33 Sakata T, Masaki T, Yoshimatsu H. [Central regulation of energy metabolismdriven by genetic and ambient factors. Its implications of L-histidine as brain foods.] Hissu Aminosan Kenkyu. 2004;171:15–24. (in Japanese)
Journal of Pharmacological Sciences ©2009 The Japanese Pharmacological Society
Full Paper
Effects of Histamine on Lipid Metabolic Disorder in Mice Loaded With Restraint Stress Rong Rong He1,2, Nan Yao1, Min Wang1, Xue Song Yang3, Chin Chin Yau4, Keiichi Abe4, Xin Sheng Yao1,2, and Hiroshi Kurihara1,* 1
Institute of Traditional Chinese Medicine & Natural Products, Jinan University, Guangzhou 510632, China College of Traditional Chinese Materia Medica, Shengyang Pharmaceutical University, Shengyang 110016, China 3 Medical College, Jinan University, Guangzhou 510632, China 4 BRAND’S Health Science Center, Cerebos Pacific Ltd., Singapore 048423, Singapore 2
Received March 22, 2009; Accepted July 18, 2009
Abstract. The present study was conducted to investigate the effects of histamine on the lipid metabolic disorder in mice loaded with restraint stress. When Kun Ming (KM) mice were exposed to restraint stress for 20 h, the histamine level in both plasma and cerebral regions significantly increased (P<0.01). Moreover, when a lipid emulsion (10% Intralipid®) was injected intravenously into the mice, the elimination period of plasma triglyceride was prolonged in the restraint group. Plasma triglyceride was 523 ± 44 mg/dl at 35 min after the Intralipid® administration in the restraint stress group, while it was 436 ± 41 mg/dl in the restrained mice given histamine at a dose of 50 mg/kg. The improved plasma triglyceride metabolism was well explained by the observations of the significantly up-regulated hepatic triglyceride lipase (HTGL) activity and mRNA expression in response to histamine. These results suggested that the effects of stress-induced histamine on lipid metabolic disorder in mice loaded with restraint stress arose from its anti-stress action and promotion of lipase activity. Keywords: histamine, energy metabolism, restraint stress, lipid emulsion Intralipid®, triglyceride disorders (4, 5). Stress is also well known for its direct influences on the central nervous system (6). A large number of experimental evidences supported that the histaminergic system performs its physiological functions through H1, H2, and H3 receptors (7). Recent studies suggested that the activities of histaminergic neurons are likely to increase the response to stress (8). On one hand, proper stress can enhance biosynthesis and the release of histamine (9). On the other hand, histamine has been implicated in a variety of responses to stress as well as noradrenergic neurons activity, prolactin, adrenocorticotropin, renin secretion, dopamine releases, and metabolism in different brain regions (10 – 14). Therefore, histamine plays an important role in mediating the activity of both the central nervous system and endocrine system (15). Although the effects of stress in histaminergic nervous and the endocrine system have been widely reported (16), less attention has been paid to the influence of histamine on utilizing blood lipids in stress-loaded animals. Thus, we demonstrated the relationship between
Introduction There have been a number of studies about the mechanisms of the symptoms caused by stress (1). Energy metabolism is important in various stress reactions (2). Generally, a source of energy is required to sustain physiological functions of the brain, central nervous system, heart, and muscles, and so on. This energy supplement is mainly from dietary glucose, lipid, or from glycogen stores and fat deposits. Moreover, Ricart-Jané’s study (3) indicated that stress caused lipid energy-substrate redistribution between tissues, which was required for the fight-or-flight response. Other studies also indicated that stress limited the supply of energy, which lead to poor utilization of biological energy sources, neurological or tissue dysfunctions, and resulted in tiredness and various other physiological *Corresponding author. [email protected] Published online in J-STAGE doi: 10.1254/jphs.09090FP
117
118
RR He et al
stress and blood lipid metabolism using Intralipid® as a tracer for the simple fat emulsion clearance test in mice exposed to restraint stress. Intralipid®, an artificial lipid emulsion used to supply energy and essential fatty acids, is commonly used in clinical practice (17) and also as a tracer for blood triglyceride (18). Materials and Methods Materials Histamine was purchased from Wako Pure Chemical Industries (Osaka). It was dissolved in phosphatebuffered saline (PBS) solution immediately before use. The 20% Intralipid® (lipid emulsion including 20% soybean oil, 1.2% lecithin and 2.2% glycerol) was purchased from Pharmacia AB Co. (Stockholm, Sweden). It was diluted with PBS to make a 10% soybean oil solution immediately before use. Animals Seven-week-old female Ku Ming (KM) mice were purchased from the Center for Laboratory Animal Science Research of Southern Medical University (Guangzhou, China). All mice were kept in a specific pathogen-free animal room under the controlled conditions of room temperature at 23 ± 1°C with a 12-h light-dark cycle (lights on from 06:00 to 18:00), and they were provided with standard laboratory diet and water. The animals were allowed to acclimatize to the environment for 1 week before the experiment. In the restraint stress experiment, each mouse was confined to an oval metal restraint cage for 20 h before the assay. Animals were handled in accordance with a protocol approved by the animal care committee of Jinan University. All the animal experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the United States National Institutes of Health. Measurement of histamine levels in plasma and brain regions The effects of restraint stress on histamine secretion in plasma and brain regions were investigated. In the starved control group, food and water were deprived for 20 h. In the restraint stress group, each mouse was individually confined to an oval restraint cage for 20 h before the assay. Blood samples were drawn from the heart under anesthesia with diethyl ether into a tube containing 2% sodium heparin (Wako Pure Chemical Industries) and then centrifuged at 5, 000 rpm for 5 min at 4°C. The plasma was then deproteinized by adding 6% perchloric acid (Merck, Darmstadt, Germany) to adjust the concentration to 3%, and the sample was
centrifuged at 15, 000 rpm for 15 min at 4°C. The supernatant was subsequently stored at −20°C before it was assayed. In addition, after the mice were sacrificed by drawing blood, brain tissue samples of the midbrain and brain cortex were quickly dissected. These tissues were weighed and soaked in PBS solution containing 3% perchloric acid (1 g tissue/ml). The materials were homogenized with a homogenizer (IKA Labortechnik, Staufen, Germany) at maximum setting for 30 s under an ice-cold condition. Then the homogenate was centrifuged at 15,000 rpm for 20 min at 4°C. The concentrations of histamine in both plasma and brain regions were determined by the high-performance liquid chromatography (HPLC)–fluorometry technique as described previously by Yamatodani et al. (19). This assay was carried out at room temperature. Samples were filtered through a 0.45-μm membrane filter and 10 μl of the sample was injected directly into a column packed with the TSKgel SP2SW Cation Exchanger (6 × 150 mm; Tosoh, Tokyo). Histamine was eluted with 0.25 M potassium phosphate at a flow rate of 0.6 ml/min. The histamine was post-labeled with οphthalaldehyde in an alkaline condition and detected fluorometrically in an F1080 Fluorometer (Hitachi, Tokyo), with monitoring at 360 and 450 nm, respectively. Plasma lipids tolerance test procedure The effects of restraint on triglyceride metabolism were investigated. Mice were divided into three groups. In the normal control group, no treatment was given to the mice. In the starved group, mice were deprived of food and water for 20 h. In the restrained and starved group, mice were confined to an oval metal restraint cage for 20 h before the assay. Intralipid® was injected through the tail vein at a dose of 0.1 ml/10 g of body weight. On the other hand, we investigated the effect of histamine on plasma triglyceride elimination. In the stress control and histamine groups, mice were confined to an oval metal restraint cage for 20 h while being starved before the assay. PBS solution or histamine were injected through the tail vein at a dose of 0.1 ml/10 g of body weight 35 min before the administration of Intralipid® to mice that had been restrained for 20 h while being starved. In the starved control group, only PBS solution was administered. Blood samples were taken from the heart under anesthesia with diethyl ether and kept in a tube containing 2% sodium heparin. Then, the blood samples were centrifuged at 5,000 rpm for 5 min at 4°C, and the supernatant was collected and stored at −20°C until the assay. Plasma triglyceride was measured by the glycerol kinase / glycerol-3phosphate oxidase (GK-GPO) method (20). The assay kit was purchased from International Reagents Corporation
Histamine on Lipid-Metabolic Disorder
(Kobe). Measurement of hepatic triglyceride lipase (HTGL) Histamine (Sigma, St. Louis, MO, USA) was injected into two groups of mice through the tail vein at a dose of 50 mg/kg of body weight. One group was sacrificed at 30 min after the histamine injection, and another group was sacrificed at 20 h after the histamine injection. The hepatic tissue was quickly dissected out during the PBS solution perfusion and then weighed. A 100-mg sample of tissue was removed immediately from each liver and kept in PBS solution under an ice-cold condition. Then the tissues were minced with scissors and homogenized with a homogenizer at the maximum setting for 30 s under an ice-cold condition in 1 ml of solution (containing 0.25 M sucrose, 1 mM ethylenediaminetetraacetic acid (EDTA), 10 mM Trizma hydrochloric acid (Tris ⋅ HCl), and 12 mM deoxycholate, pH 7.4). The homogenate was collected by centrifuging at 12,000 rpm 4°C for 20 min; it was diluted with 4 volumes of the homogenization solution and then decanted and immediately stored at −20°C until the HTGL activity measurement. The HTGL activity assay was carried out using the BALB-DTNB method as described previously by Kurooka and Kitamura (21). Reverse transcription polymerase chain reaction (RTPCR) analysis of HTGL mRNA expression The mice were sacrificed at different times after the histamine was injected through the tail vein at a dose of 50 mg/kg. The hepatic tissue was quickly dissected out during the PBS solution perfusion. Total RNAs were extracted from the liver samples by using Trizol (Invitrogen, Carlsbad, CA, USA). A 3-μg amount of total RNA was reverse-transcribed at 42°C for 1 h in a 20-μl reaction mixture containing mouse Moloney leukemia virus reverse transcriptase (Tiangen, Beijing, China) with oligo (dT) primers (Tiangen) followed by RT-PCR amplification. Thereafter, cDNA was amplified together with Taq polymerase (Tiangen), using specific primers with 35 cycles at 94°C for 30 s, an annealing temperature of 58°C for 50 s, and then 72°C for 50 s, with final incubation at 72°C for 7 min. The RT-PCR primers for mouse HTGL mRNA were (F) 5'-TGG ACGGGAAGAACAAG-3' and (R) 5'-GGAGTCAAT GAAGAGGTGC-3', and the product size was 326 base pairs. The primers for the mouse housekeeping gene beta-actin (β-actin) mRNA were (F) 5'-GAGGGA AATCGTGCGTGAC-3' and (R) 5'-GCTGGAAGGTG GACAGTGAG-3', and the product size was 446 base pairs. The RT-PCR products were fractionated on a 1% agarose gel and visualized by ethidium bromide staining. The band intensity of ethidium bromide fluores-
119
cence was measured by using an image analysis system (Bio-Rad, Hercules, CA, USA), quantified by a Bandscan (Glyko, Novato, CA, USA) and expressed as the ratio to β-actin. Statistical analyses The data were each presented as a mean ± S.E.M. Significant differences between the two groups were analyzed with Student’s t-test. One-way analysis of variance (ANOVA) was applied to analyze differences in data of biochemical parameters among the experimental groups, followed by Dunnett’s test for pair-wise multiple comparisons. Differences were considered as statistically significant at P<0.05. Results Effect of restraint stress on histamine We investigated the effects of restraint stress on the concentrations of histamine in plasma and brain regions by HPLC with a fluorescence detector. As shown in Table 1, the basal value of histamine obtained from the control mice was 5 ± 0.6 pmol/ml in plasma. When the mice were exposed to restraint stress for 20 h, the average plasma histamine value was significantly increased to 74 ± 9 pmol/ml (P<0.01). On the other hand, the histamine level was 596 ± 47 pmol/ml in the midbrain and was significantly increased compared with the level in the non-stress control mice (332 ± 43 pmol/ml, P<0.01). However, the effect of restraint on histamine was weaker in the cortex. The results suggested that the histaminergic neuron might play an important role in stress responses. Effect of restraint stress on plasma triglyceride elimination The metabolism of lipids was found to respond remarkably to the restraint stress in this study. Figure 1A shows the chronological changes of the triglyceride elimination rate in plasma after the injection of Table 1. Histamine concentration in the plasma and brain regions of KM mice exposed to restraint stress Group
Plasma (pmol/ml)
Cortex (pmol/g)
Midbrain (pmol/g)
Starved control
5 ± 0.6
159 ± 13
332 ± 43
Restraint stress
74 ± 9**
182 ± 18
596 ± 47**
In the starved control group, food and water were deprived for 20 h. In the restraint stress group, each mouse was starved and individually confined to an oval restraint cage for 20 h before the assay. The results represent the mean ± S.E.M. of the values obtained from 7 KM mice in each experimental group. **P<0.01: significantly different from the starved control mice as determined by Student’s t-test.
120
RR He et al
Fig. 1. Time-course changes of plasma triglyceride elimination rate after Intralipid® loading. Intralipid® was dissolved in PBS solution to the concentration of 10% soybean oil and immediately injected into the vein in a volume of 0.1 ml/10 g of body weight. In the normal control group (A), no treatment was given to the mice. In the starved group (B), mice were deprived of food for 20 h. In the restrained and starved group (C), mice were placed in restraint cages and starved for 20 h before the assay.
Intralipid®. The average level was 422 ± 40 mg/dl at 35 min after the injection of Intralipid®. When the mice starved for 20 h, the elimination rate was higher at 35 min and the average level was 350 ± 39 mg/dl as shown in Fig. 1B. The plasma triglyceride level was 523 ± 44 mg/dl at 35 min (P<0.01), and the clearance rate was lower in the mice that were exposed to stress for 20 h than the starved mice tested in the same way (Fig. 1C). The results suggested a good correlation between the elimination of triglyceride in blood and the response to stress. It also indicated that plasma triglyceride metabolism was definitely disrupted by the stress and decreased the utilization of triglyceride as an energy source. Effect of histamine on plasma triglyceride elimination in restrained mice In this study, we also investigated the effect of histamine administered through the tail vein on the elimination of plasma triglyceride in restrained mice. As shown in Fig. 2, when mice were fixed in the restraint cage for 20 h, the amount of plasma triglyceride level at 35 min after the injection of Intralipid® increased from 350 ± 39 to 523 ± 44 mg/dl (P<0.01). The concentration of plasma triglyceride was 463 ± 47 mg/dl in the lowdose histamine (25 mg/kg) group, 436 ± 41 mg/dl in the middle-dose histamine (50 mg/kg) group, and 423 ± 43 mg/dl in the high-dose histamine (100 mg/kg) group, showing an improvement by 11.5, 16.7 (P<0.01), and 19.2 (P<0.01), respectively, compared with the stress control group. Results indicated that plasma triglyceride metabolism in these mice under restraint stress was improved by the histamine, and the effects were dose dependent.
Fig. 2. Effects of histamine on triglyceride elimination in plasma obtained from KM mice loaded with restraint stress. Seven-week-old female KM mice were placed in the restraint cages and starved for 20 h. Histamine or PBS solution was administered through the tail vein at a dose of 0.1 ml/10 g of body weight after 20-h restraint stress. Intralipid® was diluted with PBS solution to the concentration of 10% soybean oil and immediately injected into the vein in a volume of 0.1 ml/10 g of body weight. The triglyceride concentration in plasma was measured at 35 min after administering Intralipid®. The results represent the mean ± S.E.M. of the values obtained from 7 mice in each group. **P<0.01, ##P<0.01: significantly different from the starved control and stressed control mice, respectively, as determined by the ANOVA test followed by Dunnett’s test.
Effects of histamine on HTGL activity in hepatic tissue Figure 3 shows the alteration of HTGL levels in hepatic tissue after administration of histamine. The basal value was 1421 ± 357 U/g in normal mice. The amount of HTGL in the starved control mice was 1603 ± 263 U/g. When histamine was given for 30 min, the HTGL activity was 1674 ± 352 U/g. However, when treated with histamine for 20 h, the HTGL activity significantly increased to 2147 ± 304 U/g compared with the basal value (P<0.01). The results showed that histamine moderately affects the HTGL levels in hepatic tissue.
Histamine on Lipid-Metabolic Disorder
121
there was no significant increase of HTGL mRNA expression in the starved group. As show in Fig. 4A, compared with the starved control, the expression significantly up-regulated after 50 mg/kg histamine was injected (P<0.01). When the histamine was given for 30 min or 20 h, HTGL mRNA expressions were both remarkably up-regulated (Fig. 4B). Discussion Fig. 3. Effects of histamine on HTGL activity in hepatic tissue. Histamine or PBS solution was administered through the tail vein at a dose of 0.1 ml/10 g of body weight for 30 min or 20 h before the HTGL activity assay. The results represent the mean ± S.E.M. of the values obtained from 7 mice in each group. **P<0.01: significantly different from the starved control mice as determined by the ANOVA test followed by Dunnett’s test.
Fig. 4. Effects of histamine on HTGL mRNA expression. A: Timecourse changes of HTGL mRNA expression after histamine injection. B: A representative of RT-PCR analysis of HTGL mRNA expression in mouse liver. Results were generated as relative intensity units by densitometry and expressed as the ratio of HTGL to β-actin. The results represent the mean ± S.E.M. of the values obtained from 7 mice in each group. **P<0.01: significantly different from the starved control mice as determined by the ANOVA test followed by Dunnett’s test.
Effects of histamine on the mRNA expression of HTGL in hepatic tissue The mRNA expression of HTGL in mouse liver was determined by RT-PCR. Figure 4 shows the chronological changes of mRNA expression after the injection of histamine. Compared with the normal control group,
Compared with the starved control mice, we found that the plasma triglyceride elimination rate was definitely prolonged in the restraint stress group. Generally, stress loading requires a large quantity of carbohydrates and fatty acids as an energy source from liver glycogen and adipose tissues (18). Researchers demonstrated that stress reduces production of insulin and causes energy metabolic decline (19). As the decline in energy metabolism is a cause of fatigue from stress (20), this means improvement of the energy metabolism can promote fatigue recovery and stress relaxation. These studies supported our results by suggesting that stress limits the supply of energy to organs, leading to poor utilization of biological energy. Therefore, the elevated levels of plasma lipids in the restrained mice may be a reflection of the degraded tissue function, while the decline in the elimination rate of plasma lipids may be a sign of stress. On the other hand, we investigated the effects of stress on histamine levels in plasma and brain. When mice were fixed in a restraint cage for 20 h, plasma histamine concentration significantly increased and showed an upward tendency in the cerebrum. Studies indicated that the histamine was mainly released from mast cells and enterochromaffin-like cells (21). Neuropeptides, such as substance P and neurokinin A, might stimulate histamine release from mast cells (22), and these neuropeptides were mediated by stress (23). All the above suggested that histamine was implicated in the host stress response. Previous studies indicated that stress enhanced the production of hormones, which was likely required for tolerating the life-threatening effect of stress (24). Studies also demonstrated various stressors had effects on the autonomic nervous system, and the activity of histaminergic neurons is likely to be increased in response to stress (25). However, less attention was paid to the role of stress-induced histamine in plasma lipid utilization. In the present experiment, we investigated the effects of histamine on the basic metabolism of plasma lipids in mice loaded with restraint stress and found that loading with histamine remarkably increased the elimination rate of plasma triglyceride. The effect of histamine seemed to be
122
RR He et al
improving lipid utilization as an energy source. Since the direct influences of histamine on the mechanism of lipid utilization has not yet been systematically investigated, HTGL activity measurement was performed to record the changes of liver lipase following histamine treatment. HTGL is the rate-limiting enzyme for hydrolysis of triglyceride and thus controls the uptake of fatty acids into tissues (26). The present results showed that the lipase level in hepatic tissue improved by 33.9% (P<0.01) after peripheral loading with 50 mg/kg of histamine for 20 h. When the same dose of histamine was given for 30 min, the HTGL activity was not increased significantly, but HTGL mRNA expression was significantly up-regulated (P<0.01). Therefore, histamine promoted lipid metabolism by increasing lipase activity, which might be due to the markedly up-regulated lipase mRNA expression in response to histamine. Our results also implicated that histaminergic neurons may be one of the factors controlling the stress-induced physiological stress-response. Many researchers indicated that there is innervation of histaminergic neurons in a number of brain regions (27) and this might be important in the response capacity of animals to stress (28). Histaminergic neurons could modulate energy imbalance during stress through central histaminergic neuron receptors (29). The histamine H3 receptor has been demonstrated in association with stress-induced brain activity (30, 31). Some reports suggested that there are changes of histamine contents and histamine H1 and H3 receptors in the brains of mice subjected to fooddeprived stress and revealed that there is a discrepancy between the levels of H1 and H3 receptors in the acute and chronic phases of stress conditions (8). Also, histamine nerve systems played a crucial role in maintaining homeostatic energy balance (32, 33). In our studies, restraint stress increases histamine turnover in the brain, and in turn, histamine up-regulates HTGL expression in hepatic tissue. The latter may optimize lipid metabolism, improve metabolic dysfunction, and increase utilizing triglyceride as an energy source. Therefore, the effect of histamine may be also partly related to the alleviation of the adverse effects of stress on bio-homeostasis. Based on our findings, restraint-induced adaptability of plasma histamine improves stress-suppressed energy metabolism. These results suggested that the effects of histamine on lipid metabolic disorder in mice loaded with restraint stress arose from its anti-stress activity and promotion of lipase activity. Acknowledgments We thank Takehiko Watanabe, Ph.D. and Kazuhiko Yanai, Ph.D.
(Department of Pharmacology, Tohoku University School of Medicine) for helpful advice on the perfusion method and comments on this manuscript.
References 1 Kaneko H, Nakanishi K. Proof of the Mysterious Efficacy of Ginseng: basic and clinical trials: clinical effects of medical Ginseng, Korean Red Ginseng: specifically, its anti-stress action for prevention of disease. J Pharmacol Sci. 2004;95:158–162. 2 Tavazzi B, Amorini AM, Fazzina G, Pierro DD, Tuttobene M, Giardina B, et al. Oxidative stress induces impairment of human erythrocyte energy metabolism through the oxygen radicalmediated direct activation of AMP-deaminase. J Biol Chem. 2001;276:48083–48092. 3 Ricart-Jané D, Cejudo-Martín P, Peinado-Onsurbe J, LópezTejero MD, Llobera M. Changes in lipoprotein lipase modulate tissue energy supply during stress. J Appl Physiol. 2005;99: 1343–1351. 4 von Känel R, Mills PJ, Fainman C, Dimsdale JE. Effects of psychological stress and psychiatric disorders on blood coagulation and fibrinolysis: a biobehavioral pathway to coronary artery disease. Psychosom Med. 2001;63:531–544. 5 Kurihara H, Yao XS, Nagai H, Tsuruoka N, Shibata H, Kiso Y, et al. Anti-stress effect of BRAND’s essence of chicken (BEC) on plasma glucose levels in mice loaded with restraint stress. J Health Sci. 2006;52:252–258. 6 De Kloet ER. Hormones and the stressed brain. Ann N Y Acad Sci. 2004;1018:1–15. 7 Chang RSL, Tran VT, Snyder SH. Heterogeneity of histamine H1-receptors: species variations in [3H] mepyramine binding of brain membranes. J Neurochem. 1979;32:1653–1663. 8 Endou M, Yanai K, Sakurai E, Fukudo S, Hongo M, Watanabe T. Food-deprived activity stress decreased the activity of the histaminergic neuron system in rats. Brain Res. 2001;891:32–41. 9 Huang ZL, Mochizuki T, Watanabe H, Maeyama K. Activation of sensory nerves participates in stress-induced histamine release from mast cells in rats. Neurosci Lett. 1999;270:181–184. 10 Fleckenstein AE, Lookingland KJ, Moore KE. Histaminergic neurons mediate restraint stress-induced increases in the activity of noradrenergic neurons projecting to the hypothalamus. Brain Res. 1994;653:273–277. 11 Ravindran R, Rathinasamy SD, Samson J, Senthilvelan M. Noise-stress-induced brain neurotransmitter changes and the effect of Ocimum sanctum (Linn) treatment in albino rats. J Pharmacol Sci. 2005;98:354–360. 12 Knigge U, Matzen S, Hannibal T, Jørgensen H, Warberg J. Involvement of histamine in the mediation of the stress-induced release of alpha-melanocyte-stimulating hormone in male rats. Neuroendocrinology. 1991;54:646–652. 13 Matzen S, knigge U, Warberg J. Brain regulation of renin secretion involves central histaminergic neurons. Neuroendocrinology. 1990;52:175–180. 14 Fleckenstein AE, Lookingland KJ, Moore KE. Differential role of histamine in mediating stress-induced changes in central dopaminergic neuronal activity in the rat. Brain Res. 1994;653:267–272. 15 Watanabe T, Yanai K. Studies on functional roles of the histaminergic neuron system by using pharmacological agents, knockout mice and positron emission tomography. Tohoku J
Histamine on Lipid-Metabolic Disorder Exp Med. 2001;195:197–217. 16 Knigge U, Matzen S, Warberg J. Histamine as a neuroendocrine regulator of the stress-induced release of peripheral catecholamines. Endocrinology. 1990;126:1430–1434. 17 Kalfarentzos F, Kokkinis K, Leukaditi K, Maroulis J, Onoufriou A, Alexopoulos K. Comparison between two fat emulsions: Intralipid 30 cent vs intralipid 10 cent in critically ill patients. Clin Nutr. 1998;17:31–34. 18 Kurihara H, Fukami H, Koda H, Tsuruoka N, Sugiura N, Shibata H, et al. Effects of oolong tea on metabolism of plasma fat in mice under restraint stress. Biosci Biotechnol Biochem. 2002;66:1955–1958. 19 Harada E. Lowering of pancreatic amylase activity induced by cold exposure, fasting and adrenalectomy in rats. Comp Biochem Physiol A Comp Physiol. 1991;98:333–338. 20 Newsholme EA. Tired out: biochemical explanations of physical and mental fatigue. Biochemist. 2006;28:27–29. 21 Yang ZB, Tanaka T, Kiso Y, Watanabe T, Yanai K. The changes of histamine concentrations in the plasma and brain in response to acute stress. In: Watanabe T, Timmerman H, editors. Histamine research in a new millennium, Amsterdam: Elsevier; 2001. p. 486–490. 22 Hua XY, Back SM, Tam EK. Substance P enhances electrical field stimulation induced mast cell degranulation in rat trachea. Am J Physiol. 1996;270:L985–L991. 23 Theoharides TC, Spanos C, Pang X, Alferes L, Ligris K, Letourneau R, et al. Stress-induced intracranial mast cell degranulation: a corticotropin releasing hormone mediated effect. Endocrinology, 1995;136:5745–5750. 24 Csaba G, Kovács P, Pállinger É. Increased hormone levels in Tetrahymena after long-lasting starvation. Cell Biol Int. 2007; 31:924–928.
123
25 Kjaer A, Knigge U, Olsen L, Vilhardt H, Warberg J. Mediation of the stress-induced prolactin release by hypothalamic histaminergic neurons and the possible involvement of vasopressin in this response. Endocrinology. 1991;128:103–110. 26 Jiang XC, Moulin P, Quinet E, Goldberg IJ, Yacoub LK, Agellon LB, et al. Mammalian adipose tissue and muscle are major sources of lipid transfer protein mRNA. J Biol Chem. 1991;266: 4631–4639. 27 Hasenoehrl RU, Huston JP. Histamine. In: Gernot R, Bettina P, Editors. From messengers to molecules. Netherlands: Springer; 2004. p. 174–195. 28 Palkovits M, Toth Z, Gallatz K, Buzas E, Falu A. Activity of brain histaminergic neurons in response to stress. In situ hybridization histochemical studies on rats and transgenic mice. Neirokhimiya. 2003;20:120–126. 29 Sakata T, Ookuma K, Fujimoto K, Fukagawa K. Yoshimatsu H. Histaminergic control of energy balance in rats. Brain Res Bull. 1991;27:371–375. 30 Madeo M, Granata T, Facciolo RM, Tripepi S, Canonaco M. Feeding differences in pubertal and aged golden hamsters (Mesocricetus auratus) are related to specific cerebral expression pattern in histamine subtype 3 receptor. Behav Neurosci. 2006;120:1235–1241. 31 Brown RE, Stevens DR, Haas HL. The physiology of brain histamine. Prog Neurobiol. 2001;63:637–672. 32 Sakata T, Yoshimatsu H, Kurokawa M. Hypothalamic neuronal histamine: implications of its homeostatic control of energy metabolism. Nutrition. 1997;3:403–411. 33 Sakata T, Masaki T, Yoshimatsu H. [Central regulation of energy metabolismdriven by genetic and ambient factors. Its implications of L-histidine as brain foods.] Hissu Aminosan Kenkyu. 2004;171:15–24. (in Japanese)