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Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada M5S 3E2
3To whom correspondence should be addressed. E-mail: harvey.anderson{at}utoronto.ca.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • cholecystokinin • food intake • devazepine • fat • carbohydrate
Cholecystokinin (CCK) is a peptide released from the endocrine cells in the intestinal mucosa upon ingestion of food. Both exogenous and endogenous CCK have been associated with the suppression of food intake in many species (1,2). The effects of CCK on gastrointestinal function and food intake are mediated by two distinct receptors, CCK-A and CCK-B (3). The primary receptors in the peripheral system are CCK-A and occur on the pancreatic acinar cells, gall bladder, smooth muscle of the pylorus and vagal afferents.
Several lines of evidence suggest that CCK release affects satiation through a paracrine mechanism involving CCK-A receptors (CCKAR) on the vagal afferents (4). For example, a CCK monoclonal antibody that completely blocks the response to CCK-8, the active hormone, in rats had no effect on their feeding responses to a meal (5). A paracrine mode of action is also consistent with morphological studies showing that close proximity exists between vagal afferent fibers and the basolateral membranes of CCK immunoreactive epithelial cells (6). Furthermore, a direct sensitivity of vagal afferents to exogenous CCK and to oleic acid–activated jejunal afferent neurons was shown in rats by using electrophysiologic techniques (7). Finally, dissociation is often observed between plasma CCK responses to a nutrient preload and food intake.
It would be expected, therefore, that the suppression of food intake caused by all proteins, fats and carbohydrates would be prevented or reduced by peripheral CCKAR blockers. For proteins, the literature is consistent. Devazepide partially reverses food intake suppression caused by preloads of albumin (8), casein and soy and their respective hydrolysates (9), and peptones (4,10).
In contrast, reports of the effect of CCKAR blockers on food intake after the ingestion of fats and carbohydrates are inconsistent, suggesting that the suppression of food intake occurs independently of CCK and CCKAR. Fats suppress food intake in rats (11), and it has been shown that medium-chain triglyceride (MCT) oil, beef tallow, fish oil and corn oil given intraduodenally increase plasma CCK with the response greatest for MCT oil (12). However, CCKAR blockers failed to block the anorexic effect of corn oil in rats (8) and in humans (13) and of MCT oil or oleic acid in rats (14), but did block the inhibition of sham feeding in rats fed infusions of a soybean oil, egg phospholipid emulsion in the duodenum (4).
Preloads of carbohydrates also suppress food intake in rats with little difference among cornstarch, sucrose and glucose, but with a greater effect of fructose (15). Again the role of CCK and CCKAR in the feeding response is not clear. Plasma CCK concentrations have been reported to increase only after sucrose (16) but not after glucose, cornstarch or maltose (17,18). Yet CCKAR antagonists attenuated the effect of intestinal maltose in food-deprived sham-fed rats (19), but had no effect in rats given preloads after cornstarch (8) or glucose (20).
On the basis of the literature, CCK and CCKAR do not appear to play a role in the suppression of food intake in rats after the consumption of the majority of fats and carbohydrates. However, an alternative explanation may reside in the timing, dose and route of administration of the CCKAR blockers and the time of administration of the preloads and duration of food intake measurement. Therefore, we hypothesized that the ingestion of all fats and carbohydrates stimulates satiety through CCKAR. To test the hypothesis, we gave rats preloads of several carbohydrates (cornstarch, sucrose, glucose and fructose) and fats (coconut oil, beef tallow, olive oil and safflower oil) and varied the time of devazepide administration in relation to the time of the preloads.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Male Wistar rats (Charles River, St-Constant, Canada), were housed individually in wire-mesh stainless steel cages in a room with a temperature of 22 ± 1°C and a 12-h light:dark cycle (lights on at 0600 h); they had free access to water throughout and to pelleted diet (Rodent Laboratory 5001; Lab Chows, Strathroy, Ontario) for the first 3 d. On d 3 after arrival, the pelleted diet was removed and replaced with defined diets.
Diets were formulated to contain 0 g protein [Protein-Free (PF) diet], 20 g protein (maintenance diet), or 83 g/100 g high protein casein [High-Protein (HP) diet] based on the AIN 93G diet (21) (Table 1). L-Cystine was not added to the formulation of these test diets because the rats were past their most rapid growth phase and sufficient cystine is in the casein at 20 g/100 g diet (21). The diets were presented in 250-mL glass food cups (7.6 cm high) equipped with stainless steel screen inserts and spill-proof lids (4.5 cm diameter opening) as previously described (22). The University of Toronto Animal Care Committee approved the protocol.
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Fat preloads were prepared from commercially available sources. The fats chosen for these studies were coconut oil (ICN, Costa Mesa, CA) [8:0, 8%; 10:0, 6.4%; 12:0, 48.5%; 14:0, 17.6%], beef tallow (Harlan Teklad, Madison, WI) [16:0, 25.5%; 18:0, 21.6%; 18:1, 38.7%], olive oil (Mastro, Toronto, Canada) [16:0, 13.7; 18:1, 71.1%; 18:2, 10%] and safflower oil (Master Choice, Toronto, Canada) [16:0, 6.5%; 18:1, 13.1%; 18:2, 72.2%], on the basis of providing good separation of chain length and fatty acid separation. One gram of fat was added to deionized water to make a total volume of 4 mL, and then stirred with a magnetic stirrer until gavaged using a 16-gauge feeding needle (22). Because both coconut oil and beef tallow were solid at room temperature, they were first melted by heating to 40 and 55°C, respectively, and then deionized water was added to reach the appropriate volume. Both fat mixtures were then stirred with a magnetic stirrer and cooled to 30°C before gavage. Each rat received 4 mL of the 2-phase mixture.
Each carbohydrate was administered intragastrically to rats at a concentration of 1 g/4 mL deionized water. Stock solutions of sucrose, glucose and fructose were prepared by dissolving 125 g of carbohydrate to a total volume of 500 mL by adding the appropriate amount of water and stirred with a magnetic stirrer for 30 min. The stock solutions were prepared by adding small amounts of carbohydrate and water every few minutes. Because cornstarch dissolves poorly in water, 50-mL solutions were prepared on each test day. These solutions were mixed vigorously until gavaged, to prevent settling of cornstarch at the bottom of the beaker. Cornstarch (Allied Food Service, Toronto, Canada), sucrose (Sigma Chemical, St. Louis, MO), D-fructose (Sigma Chemical) and D-glucose (Bio Basic, Toronto, Canada) were utilized in these experiments.
Drug preparation.
The CCKAR antagonist devazepide (donated by ML Laboratories PLC, London, UK) was dispersed in a 2.5 g/L methocel solution (8,22). Because devazepide is fat, but not water soluble, it was suspended in a vehicle of methylcellulose (BDH Toronto, Toronto, Canada). The methocel solution was prepared by adding 0.25 g of methylcellulose powder to 100 g of hot (80°C) deionized water. The methocel solution was stirred for 1 min and allowed to chill to 5°C for 2–3 h. A glass homogenizer (Tissue Grinder, Pyrex Brand, No.7725; Thomas Scientific, Swedesboro, NJ) was used to mix in the devazepide (0.5 g/ L). Each rat received a 1-mL injection of 0.25 mg devazepide/kg body, a dose that given alone does not affect food intake (9).
Procedures.
On arrival, rats were given a week to adapt to the new environment, diet, intraperitoneal injection and gavage procedure before any experimental studies were conducted, as described previously (8). On d 3, the pelleted diet was replaced with the maintenance diet. To verify that food intake did not vary from baseline levels after gavage and intraperitoneal injection, an adaptation test was conducted. On each day leading up to the adaptation test, rats were gavaged (4 mL deionized water) and injected (1 mL of 9 g/L saline), 30 min (1730 h) before the introduction of food cups (1800 h). Two days before the adaptation test, rats were given access to one of the following diets during the first 3 h of feeding: maintenance diet (Experiment 1), PF diet (Experiments 2 and 3) or HP diet (Experiment 4) followed by the maintenance diet for the remainder of the night. During the test days, one half of the rats were administered saline injections (1 mL of 0.9% saline) and the test volume of deionized water (4 mL) by gavage on d 1 at 1730 h, whereas the other half were untreated. At 1800 h, they were given access to food. On the next day, this testing order was reversed. All four experiments began when food intake after the water gavage and saline injection did not differ from the food intake of untreated rats during the first 3 h of feeding.
Experiment 1: Fat source and food intake.
To describe the effect of selected fat sources on food intake suppression in rats, the following experiment was performed: rats [n = 16; mean initial body weight (BW) = 375.4 ± 5.19 g] were gavaged with 1.0 g fat (coconut oil, beef tallow, olive oil and safflower oil)/4 mL deionized water at 1730 h, 30 min before the introduction of food cups; food intake from the maintenance diet was measured at 1, 2, 3 and 14 h under red light.
Experiment 2: Effect of devazepide on food intake suppression after fat preloads.
Because all fats suppressed food intake when given in 1.0-g preloads, four experiments were conducted to compare the effect of devazepide on food intake after fat preloads. The fat sources, sample size and body weights are as follows: Experiment 2a (coconut oil, n = 14; BW = 259.4 ± 6.14 g), Experiment 2b (beef tallow, n = 12; BW = 248.9 ± 5.01 g), Experiment 2c (olive oil, n = 12, BW = 315.8 ± 6.43 g) and Experiment 2d (safflower oil, n = 12, BW = 320.1 ± 5.69 g).
Experiment 3: Effect of devazepide on food intake suppression after carbohydrate preloads.
Previous work using a similar design as in Experiment 1 described the effect of 1.0-g carbohydrate preloads on food intake in rats (15). The carbohydrate sources, sample size and body weights are as follows: Experiment 3a (cornstarch, n = 14, BW = 255.0 ± 3.93 g), Experiment 3b (sucrose, n = 12, BW = 250.8 ± 3.96 g), Experiment 3c (glucose, n = 13, BW = 259.1 ± 5.19 g), and Experiment 3d (fructose, n = 11, BW = 256.0 ± 3.18 g).
Experiment 4: Effect of carbohydrate source on food intake suppression via CCKAR when the test diet is 83% protein.
The objective of this study was to determine whether the composition of the test diet modifies the relationship between carbohydrate-induced suppression of food intake and the activity of CCKAR. Therefore, a HP diet, which was free of carbohydrate rather than the PF diet was fed during the 0- to 3-h food intake measurement. The diet was given right after either cornstarch or glucose. The carbohydrate sources, sample size and body weights are as follows: Experiment 4a (cornstarch, n = 12, BW = 229.5 ± 3.30 g) and Experiment 4b (glucose, n = 13, BW = 213.6 ± 4.18 g).
Experiment 1 was a two-way factorial design with fat source and days (in blocks) as the two factors. The preferred design for these experiments is to conduct a simple paired comparison of the effect of treatment with the control. Therefore, food intake after each fat treatment was compared with a control treatment within each 3-d block, which included a 1-d washout period between treatment and control. Because the same rats were used to assess the effect of all four fat sources on food intake, the order of the fat treatments in a block was randomized for each rat. The experiment required 15 d to complete. Specifically, on d 1, two groups of four were randomly assigned one of the test fats, and two groups of four received control treatments. Day 2 was a washout day. On d 3, each of the groups that had received the control treatment on d 1 now received one of the test fats and the second two that received the test fats on d 1 received the control treatment. After another washout day on d 4, this design was repeated until each rat received each treatment paired with a control treatment during four 3-d blocks.
In all other experiments (Experiments 2–4), a simple paired design was used for all treatments. One half the rats were fed the test treatment (preload + devazepide), whereas the other half received the control treatment (preload alone) on d 1. On the next day, this testing order was reversed. A washout day was given in between test treatments. Devazepide was injected, in random order, at 60 or 30 min before or with each of the macronutrient preloads given 30 min (1730 h) before the onset of the dark cycle. At 1800 h, the PF diet (Experiment 2 and Experiment 3) or HP diet (Experiment 4) was given to rats for 3 h. Food consumption was measured to the nearest 0.1 g with adjustment for spillage under red light every hour for 3 h. Then the test diets were replaced with the maintenance diet until 0800 h.
Devazepide was injected, in random order, at 60 or 30 min before or with each of the macronutrient preloads before the onset of the dark cycle to provide maximum saturation of the CCKAR during food intake measurements. A 2-h pretreatment with devazepide inhibits by 90% and a 4-h pretreatment inhibits by 61% the effect on food intake of CCK-8 injection to rats (23). Therefore, it was anticipated that the pretreatment times should provide adequate blockage of the CCKAR for the duration of the 0- to 3-h feeding period. Finally, by measuring food intake 30 min after gavage, the potential confounding effect of osmolarity of the preloads was also reduced (24). In Experiments 2–4, each fat or carbohydrate source was given with the three devazepide treatments to separate groups of rats (i.e., three separate tests were conducted with each fat or carbohydrate source).
Statistics.
In Experiment 1, the effect of fat treatments on food intake was determined by subtracting food intake after the fat treatments from food intake after the control for each rat. These differences were subjected first to a two-way ANOVA procedure with fat source and day (block) as the main factors. This analysis was used to determine whether the treatment effects of the fat preloads were affected by the order (Block) in which they were administered. Duncan’s Multiple Range Test was used to compare the effect of fat source and day on the difference in food intake. Finally, Student’s paired t test was used to determine whether the individual fats suppressed food intake compared with the water control treatment.
In Experiments 2–4, the results are expressed as the difference in food intake after the preload plus devazepide treatment minus food intake after the preload alone; statistical significance was determined by Student’s paired t test.
A computer program (SAS 6.1, SAS Institute, Cary NC) was used to perform the statistical analysis. A probability level of P < 0.05 was accepted for declaring statistical significance.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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On the basis of the two-way ANOVA, there was an effect on food intake of fat source only at 1–2 h (f = 2.92; P = 0.04) and of day at 0–1 h (f = 2.90; P = 0.04) and 0–2 h (f = 4.56; P = 0.01). The effect of fat source on food intake at 1–2 h occurred because olive oil had a weaker effect than the other fats (Table 2).
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) = -2.90 ± 0.39 g and Block 2: = 0.00 ± 0.43 g], coconut oil (Block 3: = -2.65 ± 1.04 g and Block 2: = -0.90 ± 0.18 g) and olive oil (Block 3: = -1.65 ± 0.39 g and Block 2: = -0.88 ± 0.49 g). In contrast, food intake suppression in response to beef tallow did not differ during blocks 2 and 3 (Block 3: = -0.55 ± 0.43 g and Block 2: = -0.53 ± 0.23 g).
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Experiment 2: effect of devazepide on food intake suppression after fat preloads (Fig. 1)
2a) Coconut oil. When devazepide was administered with the coconut oil preload 30 min before food cup introduction, food intake during the cumulative feeding interval of 0–3 h (P = 0.01) was greater than when rats were given the coconut oil preload alone. Devazepide administered 30 min before the coconut oil preload did not increase food intake compared with the coconut oil preload alone, but when given at 60 min before the fat preload, it increased food intake during the 0- to 1-h (P < 0.05), 0- to 2-h (P < 0.001) and 0- to 3-h (P < 0.001) intervals.
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2c) Olive oil. Devazepide administered with the olive oil preload had no effect on food intake during any of the measurement intervals. When devazepide was given 30 min before the olive oil preload, there was an increase in food intake during the 0- to 3-h interval (P < 0.05). Devazepide administration 60 min before the olive oil preload increased food intake during the 0- to 1-h (P < 0.01), 0- to 2-h (P < 0.05) and 0- to 3-h (P < 0.05) intervals.
2d) Safflower oil. When administered with the safflower oil preload, devazepide increased food intake but only when the cumulative data over 0–2 h (P < 0.05) were compared with the safflower oil preload alone. When administered 30 min before the preload, devazepide significantly increased food intake but only when the cumulative 0- to 3-h interval data (P < 0.05) were compared with the safflower oil preload alone.
Experiment 3: effect of devazepide on food intake suppression after carbohydrate preloads (Fig. 2)
3a) Cornstarch. When devazepide was administered 30 min before the cornstarch preload, food intakes during the 0- to 1-h (P < 0.01), 0- to 2-h (P < 0.05) and 0- to 3-h (P < 0.01) intervals were greater than when rats were given the cornstarch preload alone. Devazepide administered with or 60 min before the cornstarch preload did not increase food intake compared with the cornstarch preload alone.
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3c) Glucose. Devazepide increased food intake after glucose preloads. Devazepide administered with the glucose preload increased food intake at 0–3 h (P < 0.05). Devazepide administered 30 min before the glucose preload significantly increased food intake during the 0- to 2-h (P < 0.05) and 0- to 3-h (P < 0.05) intervals, compared with the glucose preload alone. When administered 60 min before the glucose preload, devazepide increased food intake during the 0- to 1-h (P < 0.05), 0- to 2-h (P < 0.05) and 0- to 3-h (P < 0.01) intervals compared with the glucose preload alone.
3d) Fructose. Devazepide increased food intake after fructose preloads. Devazepide administered with the fructose preload increased food intake at the 0- to 2-h (P < 0.01) and 0- to 3-h (P < 0.01) intervals compared with fructose alone. When administered 30 min before the fructose preload, devazepide increased food intake at the 0- to 2-h (P < 0.01) and 0- to 3-h (P < 0.05) intervals compared with the fructose preload alone. Devazepide increased food intake at the 0- to 1-h (P < 0.05), 0- to 2-h (P < 0.05) and 0- to 3-h (P < 0.001) intervals when given 60 min before the fructose preload.
Experiment 4: effect of carbohydrate source on food intake suppression via CCKAR when the test diet is 83% protein (Fig 2)
4a) Cornstarch. The effect of cornstarch on food intake from the HP-diet was reversed by devazepide, but only when devazepide was given 30 min before the cornstarch preload. Devazepide increased food intake during the 0- to 1-h (P < 0.05) and 0- to 3-h (P < 0.01) intervals compared with the cornstarch preload alone. Devazepide administration 60 min before the cornstarch preload or given with cornstarch did not differ from the control at any food intake measurement time intervals.
4b) Glucose. The effect of glucose on food intake from the HP-diet was reversed by devazepide, but only when devazepide was given with the glucose preload. Devazepide given with the glucose preload increased food intake at the 0- to 1-h (P < 0.01) measurement time interval compared with the glucose preload alone. Devazepide administered 30 min before the glucose preload or 60 min before the glucose preload did not differ from the control in cumulative food consumption.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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All of the selected fats suppressed food intake by activation of CCKAR, but it is clear that time of injection of devazepide was a major variable in detecting the response (Fig. 1). The effect of devazepide on the feeding response to coconut oil, olive oil and safflower oil was weak and was absent for beef tallow when it was given either with or 30 min before the preload. In contrast, when devazepide was given 60 min before gavage, the reversal of the food intake suppression by coconut oil and olive oil was strong but again of relatively minor significance for safflower oil and beef tallow. The increase in food intake when devazepide was given 60 min before the coconut oil preload reversed the food intake suppression by 69 and 96% from baseline during the 0- to 1-h (coconut oil + devazepide = 1.64 ± 0.27 g vs. coconut oil alone = 0.97 ± 0.33 g) and 0- to 2-h (coconut oil + devazepide = 2.43 ± 0.31 g vs. coconut oil alone = 1.24 ± 0.33 g) intervals, respectively.
Even though CCKAR were activated by ingestion of all the test fats, CCK release does not appear to be the primary determinant of early suppression of food intake. All fats strongly suppressed food intake in h 1 of feeding (Table 2). Yet, the increase in food intake when devazepide was given occurred in h 1 only for coconut and olive oil and only when devazepide was given 60 min before gavage (Fig. 1), suggesting that other mechanisms played a greater role (25,26).
Thus the current results show that previous failures to demonstrate that devazepide reverses food intake suppression by fats (8,14) were because of inappropriate times of its administration in relation to the preload treatment and the food intake measurements. For example, Trigazis et al. (8) gave corn oil and devazepide together 30 min before the rats had access to food. Because corn oil is somewhat similar in composition to olive or safflower oil, the present results suggest that devazepide should be given 30 or 60 min before corn oil gavage before it can be concluded that corn oil does not suppress food intake, at least in part, via CCKAR. Similarly, when Meyer et al. (14) gave devazepide (0.1 and 1.0 mg/kg intraperitoneally) 20 min before gavage with MCT or corn oil, no reversal was observed in the suppression of energy consumption caused by these fats. Because MCT is similar in composition to coconut oil, the present results suggest that devazepide should be given 60 min before the MCT oil before it can be concluded that MCT oils suppress food intake via a CCK-independent mechanism.
Devazepide also reduced food intake suppression caused by all carbohydrate sources, but the effect was not consistently related to the time of devazepide administration or to any specific feeding interval (Fig. 2). Reversal of the effect of glucose during the 0- to 1-h feeding interval was two to three times greater when expressed as a percentage increase from control compared with the other carbohydrates. Food consumption during the 0- to 1-h interval when devazepide was given 60 min before the carbohydrate preloads was as follows: cornstarch (cornstarch + devazepide = 1.59 ± 0.20 g vs. cornstarch alone = 1.44 ± 0.20 g; % increase = 10%), sucrose (sucrose + devazepide = 2.16 ± 0.21 g vs. sucrose alone = 1.57 ± 0.25 g, % increase = 38%), glucose (glucose + devazepide = 1.22 ± 0.24 g vs. glucose alone = 0.64 ± 0.21 g, % increase = 91%) and fructose (fructose + devazepide = 1.50 ± 0.18 g vs. fructose alone = 1.15 ± 0.13 g, % increase = 30%). Devazepide had little effect when given at the same time as the carbohydrate sources.
Again these results suggest that reported failures to reverse food intake suppression by carbohydrates (8,20) were probably a result of inappropriate time of CCKAR blocker administration in relation to the preload and food intake measurements. Trigazis et al. (8) gave cornstarch and devazepide together 30 min before the rats had access to food and Woltman and Reidelberger (20) gave devazepide 15 min before a 2-h duodenal infusion of glucose. No earlier studies have been done to test whether fructose or sucrose suppresses food intake by signaling CCKAR.
Only for glucose was the reversal in food intake by devazepide possibly responsible for a substantial portion of the suppression caused by glucose in h 1. The reversal was 10, 38, 30 and 91% for cornstarch, sucrose, fructose and glucose, respectively, suggesting that much of the decrease in food intake occurring after cornstarch, sucrose or fructose was through other mechanisms.
The composition of the test diet may be a factor determining the effect of devazepide on the reversal of food intake suppression after carbohydrate preloads, but this was not clearly resolved in the present study. The logic for feeding a PF-diet during the first 3 h of feeding in Experiments 2 and 3 was because casein is a strong stimulant for CCK release (16). The effect of devazepide on glucose-, but not cornstarch-induced food intake suppression was affected by the diet (Fig. 2). It is difficult to offer an explanation for the contrasting results when the preload was cornstarch rather than glucose. Ingestion of the HP-diet would be expected to activate many satiety systems both pre- and postabsorptively and perhaps overwhelm the effect of devazepide in reversing food intake suppression after carbohydrates. Whether the presence of protein in the test diet at 20–25%, the usual concentration in test diets, would affect the response to devazepide after carbohydrate or fat preloads remains to be tested.
For the purpose of the present study, it is likely that the effect of devazepide was primarily peripheral for two reasons. First, it has a high affinity for the CCKAR (Ki = 0.1 nmol/L) but a very weak affinity for the CCK-B receptor (Ki = 375 nmol/L), which is the primary receptor found within the brain (27). Second, a recent study with a CCKAR antagonist, A-70104, that does not penetrate the blood brain barrier, produced similar results to devazepide in blocking the anorexic response to CCK-8 in sham-fed rats (4).
In summary, this study provides for the first time clear evidence that many fats and carbohydrates affect food intake suppression by CCKAR. However, the magnitude of the role of CCKAR in food intake suppression is modified by the composition of the fat or carbohydrate.
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FOOTNOTES |
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2 Supported by Natural Sciences and Engineering Research Council of Canada (NSERC).
4 Abbreviations used: BW, body weight; CCK, cholecystokinin; CCKAR, cholecystokinin-receptor; HP, high protein; MCT, medium-chain triglyceride; PF, protein-free.
Manuscript received 20 December 2002. Initial review completed 1 January 2003. Revision accepted 29 March 2002.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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