Article pubs.acs.org/JAFC
Diunsaturated Aldehyde, trans,trans-2,4-Decadienal in the Intestinal Lumen Suppresses Gastric Emptying through Serotonin Signaling in Rats Tohru Hira,*,† Asuka Yahagi,‡ Saki Nishimura,§ Masayoshi Sakaino,§ Takatoshi Yamashita,§ and Hiroshi Hara† †
Research Faculty of Agriculture, Hokkaido University, Sapporo 060-8589, Japan Graduate School of Agriculture, Hokkaido University, Sapporo 060-8589, Japan § Fundamental Research Laboratory, Research and Development Division, J-Oil Mills, Inc., Yokohama 104-0044, Japan ‡
ABSTRACT: We recently demonstrated that a diunsaturated aldehyde, trans,trans-2,4-decadienal (2,4-decadienal), potently stimulated secretion of cholecystokinin in the enteroendocrine cell line. Gut hormones such as cholecystokinin and serotonin play critical roles in reducing postprandial gastric emptying. In the present study, we first demonstrated that oral administration of 2,4-decadienal (50−100 mg/kg) reduced gastric emptying rate in rats, assessed by both the acetaminophen absorption test and the phenol red recovery method. In contrast, saturated aldehyde, alcohol, and fatty acids having the same chain length as 2,4decadienal did not affect the gastric emptying rate. Duodenal administration of 2,4-decadienal potently reduced gastric emptying rate, but intraperitoneal administration did not. Furthermore, the gastric inhibitory effect of 2,4-decadienal was attenuated by treatment with a serotonin receptor antagonist. These results demonstrated that 2,4-decadienal in the small intestinal lumen has a potent inhibitory effect on gastric emptying, possibly through stimulation of the serotonin-producing enteroendocrine cells. KEYWORDS: gastric emptying, trans,trans-2,4-decadienal, unsaturated aldehyde, serotonin, enteroendocrine cells
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INTRODUCTION Gastric emptying occurs after meal ingestion and primarily affects subsequent digestion and absorption of nutrients in the intestine. Luminal nutrients such as lipids, proteins/peptides, and carbohydrates in the small intestine (rather than the stomach contents) are critical for delaying gastric emptying through neuroendocrine pathways (enteroendocrine and vagal).1,2 Delayed gastric emptying facilitates efficient digestion and absorption of essential nutrients. Accordingly, the rate of gastric emptying significantly affects postprandial glycemia and lipidemia,3−5 and suppressing the rate of gastric emptying can contribute to attenuation of postprandial hyperglycemia and/or hyperlipidemia. In contrast to intact lipids, the effects of lipid peroxides on gastric emptying are unknown. Lipid peroxides including alcohols, ketones, and aldehydes contribute both desirable and undesirable flavors to foods.6 Some aldehydes are used as food additives to confer desirable flavors at relatively low doses. However, these peroxides at above-threshold doses can induce nausea and a heavy feeling in the stomach. Such physiological responses might involve reduced gastric emptying. We have recently demonstrated that a diunsaturated aldehyde, trans,trans-2,4-decadienal (2,4-decadienal) potently stimulated cholecystokinin (CCK) secretion in the murine enteroendocrine cell line, STC-1.7 CCK is one of the gut hormones that plays a major role in suppressing gastric emptying, similar to glucagonlike peptide-1 (GLP-1) and serotonin. Thus, it was hypothesized that luminal 2,4-decadienal would affect the rate of gastric emptying in vivo. In the present study, we investigated the effects of oral administration of 2,4-decadienal on the rate of gastric emptying © 2015 American Chemical Society
in rats by using the acetaminophen absorption test and the phenol red recovery method. We further determined the site of action, signaling pathway, and specificity of the structure in the 2,4-decadienal-induced effect.
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MATERIALS AND METHODS
Animals. Male Sprague−Dawley rats (7-weeks-old) were purchased from Japan SLC (Hamamatsu, Japan). The experiments were performed in a temperature-controlled room maintained at 23 ± 2 °C with a 12 h light-dark cycle (8:00−20:00, light period). All animals had free access to water and were fed a semipurified diet containing 25% casein, based on an AIN-93G diet, for 4−6 days as an acclimation period, and then divided into test groups based on body weight. Rats were fasted overnight the day before the experiment. The study was approved by the Hokkaido University Animal Ethics Committee, and the animals were maintained in accordance with the guidelines for care and use of laboratory animals at Hokkaido University (permission no. 08-0138). Acetaminophen Test. 2,4-Decadienal (Tokyo Chemical Industry Co., Ltd., Tokyo, Japan; at 50 or 100 mg/kg body weight) or its vehicle (2% ethanol in saline) was orally administered at a dose of 10 mL/kg body weight through a feeding tube (5 Fr, Atom Medical Co., Tokyo, Japan). These suspensions contained acetaminophen (100 mg/kg body weight) as an absorbable marker to assess gastric emptying.8,9 Tail vein blood samples (60 μL) were collected prior to (0 min) and 15, 30, 45, 60, 90, and 120 min after oral administration. Blood samples were immediately mixed with heparin (final concentration at 50 IU/mL, Nacalai Tesque, Inc., Kyoto, Japan) on Received: Revised: Accepted: Published: 8177
June 25, 2015 August 27, 2015 August 31, 2015 August 31, 2015 DOI: 10.1021/acs.jafc.5b03126 J. Agric. Food Chem. 2015, 63, 8177−8181
Article
Journal of Agricultural and Food Chemistry ice. Plasma was separated from blood by centrifugation at 2300×g for 10 min at 4 °C, and then frozen at −80 °C until analysis. Plasma acetaminophen concentrations were measured using acetaminophen detection kit (Kanto Chemical Co., Inc., Tokyo, Japan). In a separate experiment, the effects of various aliphatic compounds having the same carbon chain length as 2,4-decadienal were investigated. 2,4-Decadienal, decanal (saturated aldehyde, Tokyo Chemical Industry Co., Ltd.), decanol (saturated alcohol, Kanto Chemical Co., Inc., Tokyo, Japan), decanoic acid (saturated fatty acid, Tokyo Chemical Industry Co., Ltd.), or vehicle (2% ethanol in saline) was orally administered at a dose of 100 mg/kg body weight; all these solutions contained acetaminophen (100 mg/kg body weight). Tail vein blood samples (60 μL) were collected, and plasma acetaminophen concentrations were measured as described above. Phenol Red Test. 2,4-Decadienal (100 mg/kg body weight) or its vehicle (1.5% carboxymethyl cellulose and 2% ethanol in saline) was orally administered (10 mL/kg body weight) through a feeding tube (6 Fr, Atom Medical Co., Tokyo, Japan). The suspensions contained phenol red (5 mg/kg body weight), as a nonabsorbable marker, in addition to acetaminophen (100 mg/kg body weight) to assess gastric emptying rate.10,11 Portal blood was collected into a syringe containing heparin (final concentration 50 IU/mL), aprotinin (final concentration 500 KIU/mL), and dipeptidyl peptidase-IV inhibitor (final concentration 50 μM, Millipore, MA, U.S.A.) 15 min after oral administration from animals under isoflurane anesthesia (MSD K.K., Tokyo, Japan). Plasma was separated and stored as described above. Rats were euthanized by exsanguination immediately after the procedure, and the luminal contents of the stomach, as well as that of the proximal and distal small intestine were collected. The interiors of these tissues were flushed twice with cold saline, and the washout solution was collected. The debris was removed by centrifugation at 8400×g for 10 min at 4 °C. After adding 1 N NaOH to the supernatant (1/30 volume of the supernatant), concentration of phenol red was measured spectrophotometrically at 560 nm. The gastric emptying rate was calculated as follows. Gastric emptying rate (%) = [{the amount of phenol red administrated (mg) − the amount of phenol red remained in the stomach (mg)}/the amount of phenol red administrated (mg)] × 100 Effect of Intraperitoneal Administration of 2,4-Decadienal on Gastric Emptying Rate. We examined the effect of intraperitoneal administration of 2,4-decadienal on gastric emptying. Rats were divided into control, intraperitoneal 2,4-decadienal, and oral 2,4decadienal groups. Control rats were intraperitoneally administered sterilized saline (10 mL/kg) immediately after oral pretreatment with 10 mL/kg phenol red (5 mg/kg) dissolved in saline containing 1.5% carboxymethyl cellulose. The intraperitoneal 2,4-decadienal group was administered 2,4-decadienal intraperitoneally (100 mg/kg) suspended in sterilized saline immediately after oral pretreatment with phenol red solution. An oral 2,4-decadienal group was administered saline intraperitoneally immediately after oral administration of 2,4decadienal (100 mg/kg) suspended in the phenol red solution. The gastric content was collected 15 min after intraperitoneal or oral administration, and the gastric emptying rate was determined as described above. Effect of Duodenal Administration of 2,4-Decadienal on Gastric Emptying Rate. To administer 2,4-decadienal directly into the small intestinal lumen, a catheter was implanted into the duodenum in rats fed with reduced amount of the diet (10 g) on the day before the surgical operation. A middle incision was made under pentobarbital anesthesia (40 mg/kg body weight; Nembutal Injection, Dainippon Sumitomo Pharma, Osaka, Japan or Somnopentyl Injection, Kyoritsu Seiyaku Co., Tokyo, Japan). A silicone catheter (Silascon no. 00; internal diameter 0.5 mm; outer diameter 1.0 mm; Dow Corning Co., Kanagawa, Japan), the tip of which housed a small segment (2−3 mm) of a polyethylene tube (Hibiki Fr No. 4; Kunii Co., Tokyo, Japan), was inserted into the duodenum (2 cm distal to the pyloric part of the stomach) and fixed with a thread. The free end of the catheter was dorsally exteriorized, which allowed the experiment to be carried out in conscious and unrestrained rats. Rats were used for subsequent experiments after a recovery period of 3−4 days. After
overnight fasting, 2,4-decadienal (0−25 mg/kg) was administered into the duodenal lumen through the catheter, followed by oral administration of acetaminophen or phenol red solution, as described above. Statistical Analysis. All results are expressed as mean ± SEM. Significant differences among the groups were determined using Student’s t test (P < 0.05) for two-group comparison or Dunnett’s posthoc test (P < 0.05) for multiple group comparison as described in the figure legends.
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RESULTS AND DISCUSSION Plasma acetaminophen concentrations in the tail vein blood increased immediately after oral administration of acetaminophen at 100 mg/kg, and then gradually decreased after 45 min (Figure 1A and B). Appearance of acetaminophen in peripheral
Figure 1. Effects of oral administration of 2,4-decadienal on gastric emptying rate (acetaminophen absorption test). 2,4-Decadienal (decadienal) at 100 mg/kg (A, n = 6 in each treatment), or 50 and 100 mg/kg (B, n = 4 in each treatment) were orally administered to fasted rats together with acetaminophen. Tail vein blood was collected and acetaminophen concentrations were measured in the plasma. Values are expressed as means ± SEM of changes in acetaminophen concentration from the basal level (0 min). Plots with asterisks (*) have significant difference compared to the value of control group at the same time point (p < 0.05, A: Student’s t test, B: Dunnett’s test).
blood was delayed by oral coadministration of 2,4-decadienal (50 and 100 mg/kg), suggesting delayed gastric emptying in the presence of 2,4-decadienal. We used 100 mg/kg dose of 2,4-decadienal in further experiments because of its apparent effect on plasma acetaminophen levels. To further investigate the inhibitory effect of 2,4-decadienal on gastric emptying rate, we used an unabsorbable marker such as phenol red. In this experiment, luminal contents 15 min after the oral administration were collected, not only from the stomach, but also from the proximal and the distal small intestine, and the remaining amounts of phenol red in the lumen were determined (Figure 2A). The remaining amount of phenol red in the stomach lumen was much higher in the 2,4decadienal group than the amount in the control group. The gastric emptying rate calculated using the amount of remaining phenol red was significantly lower in the 2,4-decadienal group than the gastric emptying rate of the control group (Figure 2B). Indeed, amounts of luminal phenol red in the proximal and the distal small intestine were lower in the 2,4-decadienal group than that in the control group (Figure 2A). These results confirm the inhibitory effect of orally administered 2,4decadienal on gastric emptying. Plasma acetaminophen levels in the portal vein were lower in rats treated with oral 2,4decadienal (Figure 2C), further supporting the gastric inhibitory effect of 2,4-decadienal. 8178
DOI: 10.1021/acs.jafc.5b03126 J. Agric. Food Chem. 2015, 63, 8177−8181
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Journal of Agricultural and Food Chemistry
Figure 2. Effects of oral administration of 2,4-decadienal on gastric emptying rate (phenol red recovery method). 2,4-Decadienal (decadienal) at 100 mg/kg was orally administered to fasted rats together with phenol red and acetaminophen (n = 6 in each treatment). Portal blood and luminal contents (stomach and proximal and distal small intestine) were collected 15 min after oral administration. The gastric emptying rate (B) was calculated by using the amount of luminal phenol red in the stomach (A). Portal acetaminophen (C) levels were measured in the plasma. Values are expressed as means ± SEM. Bars with asterisks (*) have significant difference compared to the value of control group (p < 0.05, Student’s t test).
In our previous in vitro study, 2,4-decadienal (diunsaturated aldehyde), but not decanal (saturated aldehyde), decanol (saturated alcohol), and decanoic acid (saturated fatty acid), stimulated CCK secretion from enteroendocrine STC-1 cells.7 In the present study, the effect of the structure−activity relationship on gastric emptying was examined in vivo. As shown in Figure 3, oral administration of 2,4-decadienal
Figure 4. Effect of intraperitoneal administration of 2,4-decadienal, on gastric emptying rate. 2,4-Decadienal solution (decadienal) was orally or intraperitoneally coadministered to fasted rats together with oral phenol red. Gastric emptying rate was determined by measuring luminal phenol red collected from the stomach 15 min after the administration (n = 7−8 in each treatment). Values are expressed as means ± SEM. Asterisks (*) indicate significant difference compared to the value of control group (p < 0.05, Dunnett’s test). Figure 3. Effects of oral administration of various aliphatic compounds on gastric emptying rate. Aliphatic compounds (decanal, decanol, or decanoic acid) having the same carbon chain length as 2,4-decadienal (decadienal) were orally administered (100 mg/kg) to fasted rats in the acetaminophen absorption test (n = 6 in each treatment). Values are expressed as means ± SEM. Asterisks (*) indicate significant difference compared to the value of control group (p < 0.05, Dunnett’s test).
Duodenal administration of 2,4-decadienal reduced acetaminophen appearance in plasma of the tail vein in a dosedependent manner (Figure 5). Compared to control treatment, 10 mg/kg dose of 2,4-decadienal had significantly lower acetaminophen concentration at 15 min, similar to the
attenuated the elevated plasma acetaminophen levels, but decanal, decanol, or decanoic acid had no effects on plasma acetaminophen levels. The structure−activity relationship consistent with that in our previous in vitro study suggests that 2,4-decadienal acts directly on enteroendocrine cells, rather than after absorption from the intestine. To determine whether 2,4-decadienal acts in the gastrointestinal lumen or after absorption, gastric emptying rate was measured after oral or intraperitoneal administration of 2,4decadienal. Gastric emptying rate significantly reduced after oral administration 2,4-decadienal, but not after intraperitoneal administration of 2,4-decadienal, compared to that after control treatment (Figure 4). The result indicates that 2,4-decadienal exerted its inhibitory effects on gastric emptying in the gastrointestinal lumen, and led us to investigate whether the effect was triggered in the small intestinal lumen, by using rats equipped with the duodenal catheter.
Figure 5. Effect of duodenal administration of 2,4-decadienal on gastric emptying rate. 2,4-Decadienal (decadienal: 0, 5, 10, and 25 mg/ kg) was administered into the duodenal lumen through the duodenal catheter followed by oral administration of acetaminophen in fasted rats (n = 6 in each treatment). Values are expressed as means ± SEM. Asterisks (*) indicate significant difference compared to the value of control group at the same time point (p < 0.05, Dunnett’s test). 8179
DOI: 10.1021/acs.jafc.5b03126 J. Agric. Food Chem. 2015, 63, 8177−8181
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Journal of Agricultural and Food Chemistry reduction caused by 100 mg/kg dose of oral administration. Duodenal administration of 25 mg/kg dose led to a much greater and sustained (∼60 min) reduction in acetaminophen levels. Because the effective duodenal dose (10 mg/kg) is lower than the oral dose (50−100 mg/kg), the result indicates that 2,4-decadienal exerts its gastric inhibitory effect in the small intestinal lumen, rather than in the gastric lumen. Gut hormones such as CCK, serotonin, and GLP-1 inhibit gastric emptying,1−5 and 2,4-decadienal potently stimulates CCK secretion in the enteroendocrine STC-1 cells.7 Because 2,4-decadienal exerts its effects rapidly (∼15 min) after oral and duodenal administration, we investigated the involvement of CCK and serotonin that are produced in the proximal small intestine, rather than GLP-1 that is released from the distal small intestine and the large intestine. When a CCK-A receptor antagonist, devazepide was intraperitoneally injected, gastric inhibitory effect of orally administered 2,4-decadienal decreased, but single administration of devazepide accelerated gastric emptying (Figure 6A). Therefore, involvement of CCK
signaling has not been clarified in the present study. In contrast, a serotonin type 3 receptor (5HT3R) antagonist, tropisetron, treatment reversed the gastric inhibitory effect of duodenal 2,4decadienal in the acetaminophen test (Figure 6B). Although a single administration of tropisetron led to significantly higher acetaminophen levels at 15 min compared to control/vehicle treatment, the effect was limited to that time point, and it was smaller than the reversible effect on 2,4-decadienal-reduced gastric emptying. Phenol red test (Figure 6C) confirmed the involvement of serotonin signal, since reduced gastric emptying rate caused by duodenal 2,4-decadienal was clearly attenuated by tropisetron treatment. These results further support the notion that 2,4-decadienal acts directly on serotonin-producing enteroendocrine cells, namely, enterochromaffin cells. We previously demonstrated that 2−4-decadienal stimulated CCK secretion via transient-receptor potential ankyrin 1 (TRPA1).7 TRPA1 functions in serotonin-producing enteroendocrine cells, not only in CCK-producing cells.12,13 A recent study in mice demonstrated TRPA1 is expressed in enteoroendocrine cells expressing serotonin and the cells coexpressing serotonin and CCK, but not in the cells only expressing CCK.14 Thus, compared to CCK secretion, serotonin secretion may be more responsive to TRPA1 activation in the upper small intestine. However, the gastric inhibitory effect of 2,4-decadienal was not completely canceled by the tropisetron treatment (Figure 6B and C), suggesting partial involvement of the TRPA1-CCK signaling pathway. Treatment with the combination of the CCK-A receptor antagonist and the serotonin receptor antagonist may demonstrate the role of CCK secretion in 2,4-decadienal-delayed gastric emptying in the future study. In addition, further studies will be necessary in the future to elucidate the cellular mechanisms that stimulate serotonin secretion from the serotonin-producing enteroendocrine cells. Gastric emptying decreases in the presence of luminal lipids, proteins, and glucose. In previous studies, duodenal (not oral) administration of lipid (50−100 mg/250−300 g body weight) or glucose (50−100 mg/250−300 g body weight) reduced gastric emptying in rats.11,15,16 Another study17 demonstrated that oral administration of peptone or lipid (250−1250 mg/ 250−300 g body weight) reduced gastric emptying in rats. Although the experimental conditions were different from that employed in the present study, our findings suggest that 2,4decadienal has more potent inhibitory effect on gastric emptying than these macronutrients. 2,4-Decadienal is one of the flavoring compounds in chicken meat,18 and is used as a flavoring agent and fragrance, but the physiological effects of orally administered 2,4-decadienal have not been studied. A recent study demonstrated that orally administered 2,4-decadienal was metabolized to 2,4-decadienoic acid and a cysteine-conjugated compound.19 Unsaturated aldehydes are generated during lipid peroxidation and play critical roles in oxidative stress.20,21 The structure activity relationship demonstrated in the present study suggests that serotonin-producing enteroendocrine cells sense luminal unsaturated aldehydes to prevent the excess absorption and ingestion of potent peroxides such as unsaturated aldehydes through delaying gastric emptying followed by suppression of appetite. 2,4-Decadienal might be involved in deteriorated lipidinduced appetite suppression or nausea through potent inhibition of gastric emptying. In a previous study investigating the chronic effect of 2,4-decadienal, the no-observed-adverseeffect level was determined to be 100 mg/kg in rats and mice.22 Although the dose of 100 mg/kg used in the present study was
Figure 6. Effect of CCK-A receptor antagonist (devazepide) and 5HT3 receptor antagonist (tropisetron) on luminal 2,4-decadienalinduced reduction in gastric emptying rate. (A) Devazepide (Dvz) at 0.5 mg/kg or its vehicle (10% TWEEN80 + 10% DMSO in saline) was intraperitoneally injected 10 min before the oral administration of 2,4decadienal (decadienal: 100 mg/kg), followed by oral administration of acetaminophen in fasted rats (n = 5−6 in each treatment). (B) Tropisetron (Tropi) at 0.5 mg/kg or its vehicle (saline) was intraperitoneally injected just before the duodenal administration of 2,4-decadienal (decadienal: 0, 10 mg/kg), followed by oral administration of acetaminophen in fasted rats (n = 6−7 in each treatment). Tail vein blood was collected, and acetaminophen concentrations were measured in the plasma. (C) Tropisetron (Tropi) at 0.5 mg/kg or its vehicle (saline) was intraperitoneally injected just before the duodenal administration of 2,4-decadienal (decadienal: 0, 10 mg/kg), followed by oral administration of phenol red in fasted rats (n = 6−7 in each treatment). Gastric emptying rate was determined by measuring luminal phenol red collected from the stomach 15 min after the administration (n = 4−5 in each treatment). Values are expressed as means ± SEM. Asterisks (*) indicate significant difference compared to the value of control/vehicle group (p < 0.05, Dunnett’s test). 8180
DOI: 10.1021/acs.jafc.5b03126 J. Agric. Food Chem. 2015, 63, 8177−8181
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(6) Endo, Y.; Hayashi, C.; Yamanaka, T.; Takayose, K.; Yamaoka, M.; Tsuno, T.; Nakajima, S. Linolenic Acid as the Main Source of Acrolein Formed During Heating of Vegetable Oils. J. Am. Oil Chem. Soc. 2013, 90, 959−964. (7) Nakajima, S.; Hira, T.; Yahagi, A.; Nishiyama, C.; Yamashita, T.; Imagi, J.; Hara, H. Unsaturated aldehydes induce CCK secretion via TRPA1 in STC-1 cells. Mol. Nutr. Food Res. 2014, 58, 1042−1051. (8) Heading, R. C.; Nimmo, J.; Prescott, L. F.; Tothill, P. The dependence of paracetamol absorption on the rate of gastric emptying. Br. J. Pharmacol. 1973, 47, 415−21. (9) Maida, A.; Lovshin, J. A.; Baggio, L. L.; Drucker, D. J. The glucagon-like peptide-1 receptor agonist oxyntomodulin enhances beta-cell function but does not inhibit gastric emptying in mice. Endocrinology 2008, 149, 5670−8. (10) Feldman, S.; Gibaldi, M. Effect of bile salts on gastric emptying and intestinal transit in the rat. Gastroenterology 1968, 54, 918−21. (11) Nishimukai, M.; Hara, H.; Aoyama, Y. The addition of soybean phosphatidylcholine to triglyceride increases suppressive effects on food intake and gastric emptying in rats. J. Nutr. 2003, 133, 1255−8. (12) Doihara, H.; Nozawa, K.; Kawabata-Shoda, E.; Kojima, R.; Yokoyama, T.; Ito, H. TRPA1 agonists delay gastric emptying in rats through serotonergic pathways. Naunyn-Schmiedeberg's Arch. Pharmacol. 2009, 380, 353−7. (13) Nozawa, K.; Kawabata-Shoda, E.; Doihara, H.; Kojima, R.; Okada, H.; Mochizuki, S.; Sano, Y.; Inamura, K.; Matsushime, H.; Koizumi, T.; Yokoyama, T.; Ito, H. TRPA1 regulates gastrointestinal motility through serotonin release from enterochromaffin cells. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 3408−13. (14) Cho, H. J.; Callaghan, B.; Bron, R.; Bravo, D. M.; Furness, J. B. Identification of enteroendocrine cells that express TRPA1 channels in the mouse intestine. Cell Tissue Res. 2014, 356, 77−82. (15) Hölzer, H. H.; Turkelson, C. M.; Solomon, T. E.; Raybould, H. E. Intestinal lipid inhibits gastric emptying via CCK and a vagal capsaicin-sensitive afferent pathway in rats. Am. J. Physiol. 1994, 267, G625−9. (16) Raybould, H. E.; Glatzle, J.; Robin, C.; Meyer, J. H.; Phan, T.; Wong, H.; Sternini, C. Expression of 5-HT3 receptors by extrinsic duodenal afferents contribute to intestinal inhibition of gastric emptying. Am. J. Physiol Gastrointest Liver Physiol 2003, 284, G367−72. (17) White, W. O.; Schwartz, G. J.; Moran, T. H. Role of endogenous CCK in the inhibition of gastric emptying by peptone and Intralipid in rats. Regul. Pept. 2000, 88, 47−53. (18) Jayasena, D. D.; Ahn, D. U.; Nam, K. C.; Jo, C. Flavour chemistry of chicken meat: a review. Asian-Australas. J. Anim. Sci. 2013, 26, 732−42. (19) Pan, K. L.; Huang, W. J.; Hsu, M. H.; Lee, H. L.; Liu, H. J.; Cheng, C. W.; Tsai, M. H.; Shen, M. Y.; Lin, P. Identification of trans,trans-2,4-decadienal metabolites in mouse and human cells using liquid chromatography-mass spectrometry. Chem. Res. Toxicol. 2014, 27, 1707−19. (20) Quiles, J. L.; Huertas, J. R.; Battino, M.; Ramírez-Tortosa, M. C.; Cassinello, M.; Mataix, J.; Lopez-Frias, M.; Mañas, M. The intake of fried virgin olive or sunflower oils differentially induces oxidative stress in rat liver microsomes. Br. J. Nutr. 2002, 88, 57−65. (21) Grimsrud, P. A.; Xie, H.; Griffin, T. J.; Bernlohr, D. A. Oxidative stress and covalent modification of protein with bioactive aldehydes. J. Biol. Chem. 2008, 283, 21837−41. (22) Chan, P. C. NTP toxicity studies of toxicity studies of 2,4decadienal (CAS No. 25152−84−5) administered by gavage to F344/ N Rats and B6C3F1 mice. Toxic Rep. Ser. 2011, 1−94.
not found to be very toxic, it is not possible to ingest this dose in a single meal. However, a small amount of 2,4-decadienal ingested together with other macronutrients could potentiate its inhibitory effects on gastric emptying. Because rapid gastric emptying contributes to postprandial hyperglycemia and lipidemia, suppressing gastric emptying is a promising target for preventing or reducing glucose intolerance and dyslipidemia. Although the physiological relevance of structure−activity relationships observed in the present study is still unclear, potent activation of enteroendocrine cells by 2,4-decadienal7 could explain the potent effect in vivo. Further studies are needed to elucidate the molecular and signaling mechanisms involved in the gastric inhibitory effect of orally administered 2,4-decadienal. In summary, oral administration of 2,4-decadienal reduced gastric emptying in rats, as assessed by the acetaminophen absorption test and the phenol red recovery method. Structure−activity relationship study revealed the specific potential of 2,4-decadienal to reduce gastric emptying in vivo. Furthermore, duodenal but not intraperitoneal 2,4-decadienal reduced gastric emptying, and the gastric inhibitory effect was mediated via serotonin signaling. These results demonstrate that orally administered 2,4-decadienal has potent inhibitory effect on gastric emptying by acting directly on serotoninproducing enteroendocrine cells.
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AUTHOR INFORMATION
Corresponding Author
*Tel/Fax: +81-11-706-2811. E-mail:
[email protected]. ac.jp (T.H.). Author Contributions
All authors are involved in research design; A.Y. and T.H. conducted research and analyzed data; and T.H. and A.Y. wrote the paper. T.H. had primary responsibility for final content. All authors read and approved the final manuscript. Notes
The authors declare no competing financial interest.
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ABBREVIATIONS USED 2,4-decadienal,trans,trans-2,4-decadienal; 5HT3R,serotonin type 3 receptor; CCK,cholecystokinin
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REFERENCES
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DOI: 10.1021/acs.jafc.5b03126 J. Agric. Food Chem. 2015, 63, 8177−8181
