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Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 3E2
2To whom correspondence should be addressed. E-mail: harvey.anderson{at}utoronto.ca.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • agonist • blood glucose • food intake • gut peptide • intraperitoneal administration • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,2
). GLP-1 seems to be a nutrient-specific hormone. Its secretion has been reported to be particularly sensitive to the ingestion of carbohydrates (3
) and long-chain unsaturated fatty acids (4
), but slightly if at all sensitive to proteins (5
) and amino acids (6
). The most established physiological role for GLP-1 is the regulation of glucose metabolism through its incretin effect (1
) and slowing of gastric emptying (7
). GLP-1 is also involved in food intake regulation in both animals and humans. Central administration in rodents (8
–12
) and peripheral infusions in humans (13
–16
) of GLP-1 reduce food intake. In contrast, peripheral injections of GLP-1 in rats have been found to have little (17
) or no effect (8
). The latter observations may be due to the short half-life of GLP-1 in rodents because dipeptidyl-peptidase IV (DPPIV), an enzyme present in capillaries surrounding intestinal cells, in the liver as well as in the circulation rapidly catabolizes the peptide (18
,19
).
To circumvent this problem, the agonist exendin-4 has been used to study the actions of GLP-1. Exendin-4 shares 53% amino acid identity with GLP-1 (7–36) (20
). It is more resistant to the action of DPPIV than GLP-1 (21
). It is also a specific agonist for the only GLP-1 receptor identified to date (20
,22
), having a binding affinity and half-time of receptor inactivation 6-fold higher and 3.5-fold higher, respectively, than wild-type GLP-1 (23
). Exendin-4 has been reported to be a more potent stimulator of insulin secretion than wild-type GLP-1 (24
,25
).
In a previous study, coadministration of exendin-4 (i.p.) and glucose decreased food intake compared to the effect of glucose alone (26
). When rats were allowed to choose between a high carbohydrate (CHO) and a high protein (PRO) diet, exendin-4, alone or in combination with glucose, primarily suppressed the intake of the PRO diet. This is surprising, however, because glucose alone decreases the rat’s preference for carbohydrate (27
). One would expect the combination of glucose and exendin-4 to further enhance avoidance of the CHO, not the PRO diet. Nevertheless, the results of our previous study (26
) suggested that there is a synergistic effect between glucose and exendin-4 and that their combined effect on food selection is to cause the rat to avoid protein. Whether preloads of fat and protein given with exendin-4 result in enhanced food intake suppression and change in food selection is unknown. Furthermore, the effect of exendin-4 on blood glucose after preloads of macronutrients is unknown, but such knowledge may provide an indication of the mechanism of action of exendin-4, and perhaps GLP-1 on food intake regulation.
Based on the recognized importance of GLP-1 to carbohydrate metabolism, we hypothesized that the effect of exendin-4 on feeding behavior after macronutrient preloads would be dependent on the composition of the preloads. The primary objective of this study was to determine the effect of exendin-4 when coadministered with carbohydrate, fat or protein preloads on subsequent food intake. The secondary objective was to assess the effect of exendin-4 on blood glucose when coadministered with these macronutrient preloads.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Male Wistar rats (Charles River, Quebec, Canada) were housed individually in hanging wire-mesh stainless steel cages in a room with a temperature of 22 ± 1°C and a 12-h light:12-h dark cycle (lights on at 0600 h), and had free access to water throughout and to a pelleted diet (Rodent Laboratory Chow 5001; LabChows, Strathroy, Ontario, Canada) for the first 3 d. On d 3 after arrival of the rats in the animal facility, the pelleted diet was removed and replaced with an AIN-93G powder diet (28
). Food was available only from 1800 h to 0800 h and was removed during the rest of the day, but water was provided for 24 h a day. The University of Toronto Animal Care Committee approved the protocol, and care and maintenance of the animals conformed to the guidelines of the Canadian Council on Animal Care.
The composition (in g/kg) for the AIN-93G was casein (203), cornstarch (529.4), and sucrose (100.1), soybean oil (70), cellulose (50), vitamin mixture (10), mineral mixture (35), choline bitartarate (2.5), and tertbutyl hydroquinone (0.014). The composition of this diet was similar to the diet we have used previously (12
) except that 3 g of casein were substituted for the same amount of L-cystine. Corn starch, high-protein casein (87%), and cellulose were purchased from Harland Teklad (Madison, WI). The vitamin mixture, mineral mixture, choline bitartarate and tertbutyl hydroquinone were purchased from Dyets (Bethlehem, PA), whereas sucrose and soybean oil were purchased from local suppliers in Toronto, Canada.
Glucose (1.0 g; Merck KGaA, Darmstadt, Germany) or whey protein (1.0 g; Sportpharma USA, Inc., Concord, CA) were dissolved in deionized water to a total volume of 2.5 mL. Corn oil (1.0 g Mazola oil; Dominion stores, Toronto, Canada) was weighed and added to water to make a total volume of 2.5 mL, shaken and given in a two-phase mixture (26
). In experiments involving preloads, all rats were fed an intragastric preload, in a volume of a 2.5 mL, given by gavage at 30 min before the onset of the dark cycle (1800 h) when food cups were presented. Equal amounts by weight of preloads were chosen to be able to compare their effects on biochemical parameters.
Exendin-4 (American Peptide Company, Sunnyvale, CA) was prepared as described previously (26
). It was diluted in sterile deionized water and divided into aliquots before being quickly frozen on dry ice. The aliquots were lyophilized in a freeze dryer and the resulting dried peptide stored at -20°C until used. When needed, freeze-dried peptide was allowed to come to room temperature and reconstituted using a phosphate-buffered saline (PBS; Sigma, St. Louis, MO) at pH 7.4. The reconstituted peptide was used within 1 h of preparation. All injections were given i.p. in a volume of 0.5 mL. Exendin-4 was given at a dose of 0.5 µg (peptide content) rat.
Before testing, the rats were adapted to the experimental procedures (29
). Animals were gavaged and/or injected with water and saline, respectively, over 4 d before the adaptation test, performed as follows. On d 1, one-half of the rats were fed a treatment (either preload or injection or both), while the rest were untreated. On the following day this testing order was reversed, with rats that received treatments on d 1 being left untreated and the rats that received no treatment on the previous day being given treatments. Experimentation began when it was determined that the process of gavaging and/or injecting had no effect on food intake. A naïve set of 12 rats was used to investigate the time course effect of exendin-4 on food intake suppression, whereas naïve sets of 16 rats were used to investigate the effect of administering exendin-4 with either glucose or corn oil on food intake. Rats that had been used in the exendin-4/glucose experiment were used to investigate the effect of coadministering exendin-4 and whey on food intake.
Exendin-4 was injected i.p. at 1725 h and nutrient preloads were provided by gavage at 1730 h. At 1800 h when the dark cycle started, food was provided. Food consumption was measured under red light to the nearest 0.1 g with adjustment for spillage at time-points.
In all experiments, except expt. 3, the rats served as their own control. Experiments 1 and 2 utilized a repeated measures design. Experiment 3 used a between-subject design. In expt. 2, each rat received each treatment with a 1-d washout between each treatment.
This study consisted of three main experiments. First, the duration of the effect of exendin-4 on food intake was measured in expt. 1 to determine the washout period needed between experiments. In expt. 2, the effect of coadministering exendin-4 with each of the three macronutrients on the intake of the maintenance diet was determined. In expt. 3, the effect of exendin-4 on blood glucose after glucose, corn oil or whey loads was investigated.
Experiment 1: duration of the effect of 0.5 µg of exendin-4 on food intake.
Because exendin-4 in doses of 10 and 20 µg was found to suppress activity and the food intake of rats the day after injection (26
), the objective of this experiment was to determine whether there was an extended carry-over effect of 0.5 µg of exendin-4.
Each rat [n = 12; average initial body weight (BW) = 250 g] was injected with the peptide vehicle (PBS) on d 1, 3 and 4. Exendin-4 (0.5 µg) was injected on d 2. The injections were given 35 min before feeding (1800 h) of the AIN-93G diet after which food intake was measured at 0.5, 1 and 2 h.
The objective of this series of experiments was to describe the interaction effect of the GLP-1 agonist, exendin-4 (0.5 µg), on food intake when given with the macronutrient preloads.
Experiment 2a: effect of exendin-4 and glucose preload on food intake.
Each rat (n = 16; BW = 288 g) received four treatments in random order. These were glucose, glucose plus exendin-4, water and water plus exendin-4.
Experiment 2b: effect of exendin-4 and corn oil preload on food intake.
Each rat (n = 16; BW = 266 g) received four treatments in random order. These were corn oil, corn oil plus exendin-4, water and water plus exendin-4.
Experiment 2c: effect of exendin-4 and whey protein preload on food intake.
Each rat (n = 16; BW = 346 g) received four treatments in random order. These were whey, whey plus exendin-4, water and water plus exendin-4.
Experiment 3: effect of exendin-4 on blood glucose after macronutrient loads.
The objective of this series of experiments was to describe the glycemic response to exendin-4 after glucose (n = 14; BW = 350 g), corn oil (n = 14; BW = 360 g) or whey (n = 12; BW = 332.75 g) loads. Rats, food-deprived for 9 h were divided into two groups of seven (glucose and corn oil) or six (whey) receiving either exendin-4 (0.5 µg) or the vehicle (PBS) 5 min before administration of the macronutrient load (1g) by gavage. The tail vein was pricked five times (before gavage and 15, 30, 60 and 120 min after gavage) on each conscious rat using a 23-G needle. Blood glucose was determined by Precision Q.I.D glucometer (Medisense, Inc., Bedford, MA).
Data were assessed by repeated measures one-way ANOVA (expt. 1), repeated measures two-way ANOVA to look for overall treatment effect and interaction between exendin-4 and the preloads followed by a one-way ANOVA with post hoc Duncan’s test to determine the effect of individual treatments (expt. 1 and 2), by Student’s t test to compare the blood glucose levels at each time of measurement (expt. 3) using the SAS system (SAS Institute, Cary, NC). Significance of difference was declared if P < 0.05. All data are expressed as means ± SEM.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Food intake of the maintenance diet was significantly reduced on d 2 after injection of 0.5 µg of exendin-4 compared to d 1, 3 and 4 when only PBS was injected (Table 1
). There was no significant difference between food intake on d 1, 3 and 4. These results show that this dose of exendin-4 (0.5 µg) is effective in reducing food intake in the few hours after food presentation but does not have a carryover effect to the subsequent day. Therefore, a 1-d washout period is sufficient to eliminate any residual effect of exendin-4 on food intake.
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Both glucose and exendin-4 treatments affected food intake based on the two-way ANOVA. The main effect of glucose was to decrease food intake compared to water alone during 0–0.5 h (F = 35.20; P = 0.0001), 0–1 h (F = 14.43; P = 0.002), 0–2 h (F = 4.37; P = 0.05), 0–3 h (F = 8.45; P = 0.01), 0–14 h (F = 9.42; P = 0.008), and of exendin-4 to reduce food intake during 0–0.5 h (F = 23.76; P = 0.0002), 0–1 h (F = 23.06; P = 0.0002), 1–2 h (F = 8.32; P = 0.01), 0–2 h (F = 67.61; P = 0.0001), 2–3 h (F = 11.06; P = 0.005), 0–3 h (F = 99.10; P = 0.0001), 0–14 h (F = 31.94; P = 0.0001; Table 2
).
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). The interaction occurred because the combination suppressed food intake, compared with control, by 2.0 g, which was less than the 2.9 g expected from the sum of the effect of each treatment alone.
The one-way ANOVA for each interval of measurement showed that when glucose and exendin-4 were coadministered, the decrease in food intake was significantly greater than when either glucose or exendin-4 were given alone only during 0–1 h, 0–2 h and 0–14 h (Table 2)
.
Experiment 2b: effect of exendin-4 and corn oil preload on food intake of the maintenance diet.
Both corn oil and exendin-4 treatments affected food intake based on the two-way ANOVA. The main effect of corn oil was to decrease food intake compared with water alone during 0–0.5 h (F = 5.83; P = 0.03), 0–1 h (F = 8.30; P = 0.01), 0–2 h (F = 9.81; P = 0.007), 0–3 h (F = 8.58; P = 0.01), 3–14 h (F = 17.01; P = 0.0009) and 0–14 h (F = 34.87; P = 0.0001), and of exendin-4 to do so during 0–0.5 h (F = 9.09; P = 0.009), 0.5–1 h (F = 4.51; P = 0.05), 1–2 h (F = 5.82; P = 0.03), 0–2 h (F = 8.17; P = 0.01), 2–3 h (F = 70.47; P = 0.0001), 0–3 h (F = 47.01; P = 0.0001) and 0–14 h (F = 63.94; P = 0.0001; Table 3
).
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. At these times the combined treatment had a smaller effect on reducing food intake than the sum of each treatment alone. For instance, during 0–0.5 h, the combination suppressed food intake, compared with control, by 1.2 g, which was less than the 2.1 g expected from the sum of the effect of each treatment alone. The interaction approached statistical significance during 0–2 h (F = 4.34; P = 0.055) and 0–3 h (F = 3.83; P = 0.07; Table 3
).
The one-way ANOVA showed that when combined, exendin-4 and corn oil resulted in a decrease in food intake that was significantly greater than when either treatment was given alone only during 3–14 h and 0–14 h (Table 3)
.
Experiment 2c: effect of exendin-4 and whey protein preload on food intake of the maintenance diet.
Both whey and exendin-4 treatments affected food intake based on the two-way ANOVA. The main effect of whey was to decrease food intake compared with water alone during 0–0.5 h (F = 23.30; P = 0.0002), 0–1 h (F = 18.40; P = 0.0006), 0–2 h (F = 18.28; P = 0.0007), 0–3 h (F = 10.14; P = 0.006) and 0–14 h (F = 13.12; P = 0.002), and of exendin-4 to also reduce food intake during 0–0.5 h (F = 12.66; P = 0.003), 0–1 h (F = 18.87; P = 0.0006), 1–2 h (F = 40.23; P = 0.0001), 0–2 h (F = 65.13; P = 0.0001), 0–3 h (F = 40.61; P = 0.0001), 0–14 h (F = 38.54; P = 0.0001; Table 4
).
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). Similar to what was observed with glucose and corn oil, the combined effect of exendin-4 and whey had a smaller effect on reducing food intake than the sum of each treatment alone. For example, during 0–1 h, the combination suppressed food intake, compared with control, by 2.3 g, which less than the 3.1 g expected from the sum of the effect of each treatment alone. The one-way ANOVA analysis showed that when combined, exendin-4 and whey resulted in a reduction in food intake that was significantly greater than when either treatment was given alone only during g 0–14 h (Table 4)
. Experiment 3: effect of exendin-4 on blood glucose after macronutrient loads.
Blood glucose levels were significantly lower at 15 min after exendin-4 than the control after the oral glucose load (P < 0.01; Fig. 1
A). Blood glucose concentrations were lower in exendin-4-treated rats, albeit not significantly, 30 and 60 min after the oral glucose load (P = 0.24 and 0.12, respectively).
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B).
Blood glucose levels were significantly higher in exendin-4-treated rats at 60 min (P < 0.01) and 120 min (P < 0.01), and tended to be higher at 15 min (P = 0.10) and 30 min (P = 0.070) than in control rats after the whey load (Fig. 1
C).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The rationale for testing the effect of exendin-4 on the rats’ feeding response after each of the three macronutrient preloads was twofold. First, the three macronutrients have different effects on the release of hormones known to affect food intake. For instance, carbohydrates are the strongest stimulants of GLP-1 and insulin secretion (3
), whereas proteins are the most potent CCK secretagogues in rats (30
). Second, the feeding response to each of the macronutrients depends not only on their energy content, but also on their non-energy attributes (26
,29
). Thus, when given in isoenergetic amounts, we have found that protein is the most powerful suppressor of food intake compared with the other macronutrients, and carbohydrate is more satiating than fat (29
).
Each of the macronutrient preloads and exendin-4 suppressed food intake, but exendin-4 had a stronger and more sustaining effect during the first 3 h of feeding than each of the macronutrients. Because both the nutrient and the drug suppressed food intake, evidence for involvement of each in a common mechanism of GLP-1 release and action was dependent on obtaining a statistically significant interaction between the two treatments. A statistically significant interaction term means that the effects of the two treatments were not independent. Conversely, lack of interaction suggests that the combined treatment resulted in the same response in food intake as would be expected from the added effects of both treatments. In these studies exendin-4 modified the feeding response to each of the macronutrients, but the feeding interval during which its effects were obvious depended on the macronutrient.
Because GLP-1 is involved in carbohydrate metabolism, we expected a stronger interaction between exendin-4 and the glucose preload than between exendin-4 and the other macronutrients in determining food intake. However, the action of exendin-4 on the feeding response was of greater duration when given with corn oil (Table 3)
and whey (Table 4)
. When the decrease in food intake caused by the combined treatments equals the sum of the effect of each of the treatments alone, then the action of exendin-4 and the macronutrient are independent. If the difference is negative, then an interaction is occurring and exendin-4 is reducing the impact of the nutrient on food intake.
When the glucose preload was given with 0.5 µg of exendin-4, there was an enhanced suppression of the intake of the AIN-93G diet during 0–14 h in this (Table 2)
and a previous study (26
). From this, it seems that exendin-4 is promoting the effect of glucose on food intake. However, the advantage of this design was that it allowed a comparison of the effect of the four treatments, control, glucose alone, exendin-4 alone and glucose and exendin-4 combined. It is clear that exendin-4 reduces, rather than increases the effect of glucose on food and only in the first 30 min of feeding.
Our results also show that exendin-4 affected the feeding response to corn oil during the first 2 h of feeding. Because corn oil ingestion stimulates GLP-1 release (4
,31
,32
), it was expected that the combination would have a stronger, not a weaker effect on food intake. However, the results suggest that exendin-4 interferes with, rather than promotes, the full expression of satiety signals arising from corn oil.
Our study is the first to show an interaction between the effect of peripheral GLP-1 signaling pathways and protein on food intake. The interaction between exendin-4 and whey on food intake during 0–1 and 0–2 h suggests that protein-induced satiety arises in part through a mechanism involving GLP-1. We have previously reported an interaction between protein and GLP-1 given intraventricularly (12
). Protein blocked the suppression of food intake by GLP-1 injected into the paraventricular nucleus during 2–14 h and 0–14 h, suggesting that protein consumption inhibits the pathways by which GLP-1 decreases food intake. Our current observations suggest that this interaction functions in the opposite direction in the periphery. That is, exendin-4 reduced the effect of protein on food intake during 0–1 and 0–2 h.
This interaction between exendin-4 and whey in food intake suppression is difficult to explain. GLP-1 release seems to depend on the source of protein (5
,6
). Thus, it might be assumed that whey protein is not effective in releasing GLP-1 and that the apparent interaction is occurring by an interaction of independent, not common, mechanisms. However, peptones, unlike proteins and amino acid mixtures, stimulate GLP-1 release from isolated vascularly perfused rat intestine and the murine enteroendocrine cell line STC-1 (6
). Thus, it may be that at least certain proteins, including whey, contribute to GLP-1 release via the production of peptones that contact L cells, although this has not been measured (33
). Then, it would be expected that the combination of exendin-4 and protein would reduce food intake to a lesser extent than the sum of the effects of each alone.
To link feeding behavior of rats with metabolic events, we investigated the effect of exendin-4 on blood glucose after oral glucose, whey and corn oil loads. Exendin-4 reduces blood glucose in normal and diabetic rats (24
,25
). Indeed, it has been suggested that exendin-4 might prove to be a treatment for type II diabetes in humans (24
). However, our results suggest that exendin-4 leads to a reduction in blood glucose only after a glucose load (Fig. 1
A), whereas it has no effect after a corn oil load (Fig. 1
B), and surprisingly causes hyperglycemia after a whey load (Fig. 1
C). The smaller decrease in blood glucose at 15 min after coadministration of exendin-4 and glucose compared with glucose alone is consistent with previous findings (24
,25
), and this may explain why exendin-4 reduced the effect of the glucose preloads on food intake. Postprandial hyperglycemia is associated with increased satiety (27
).
It is difficult, however, to place much interpretation on the response in blood glucose because exendin-4 did not affect glycemia after corn oil but increased blood glucose concentrations after whey. Whey itself in the absence of exendin-4 did not cause hyperglycemia. In fact, the glycemic response to whey was typical of protein (34
). The small but distinct changes in blood glucose after protein loads are mainly due to both insulinogenic and glucagogenic properties of amino acids. Why and how exendin-4 causes hyperglycemia after a protein load is unclear, but our findings challenge the recommendation of exendin-4 as a potential therapeutic agent for diabetes because it lowers plasma glucose (24
). Clearly this action depends on the composition of the food consumed. Furthermore, the hyperglycemia is not consistent with the effect of exendin-4 on the feeding response to whey. It reduced the effect of whey on food intake, even though blood glucose was significantly elevated over the same time.
Some aspects of the experimental design that may have led to the current conclusions require comment. First of all, as a result of giving the three macronutrients in equal weights, the energy content varied among the preloads: whereas the glucose and the whey preloads are isocaloric, the corn oil preload has more than twice as much energy. Equal weights of carbohydrate, fat and protein did not suppress food intake to the same extent (29
). We have previously showed that protein is the strongest suppressor of food intake, whereas fat is the weakest (29
). Thus, it remains to be determined whether the effect of exendin-4 on the feeding response to the macronutrients is affected by the quantity and energy content of the macronutrient dose.
Second, The dose of exendin-4 injected may have been inappropriate to test our hypothesis. The dose of 0.5 µg was chosen based on our previous observations that this dose modified macronutrient selection in rats and suppressed the intake of the maintenance diet when coadministered with glucose (26
). Furthermore, it was reported that 0.1–100 µg exendin-4/rat caused a dose-dependent reduction in food intake of diabetic fatty Zucker rats when given i.p. twice daily (25
). If a dose of exendin-4 can be found that does not affect food intake, but retains its metabolic effects, a clearer indication of the interaction between the macronutrients and GLP-1 in the regulation of food intake can be derived.
Third, the measure of food intake was the rat consumption of the AIN-93 diet, which is 63% carbohydrate (cornstarch and sucrose), 20% casein and 7% corn oil. Peters et al. (26
) observed that the GLP-1 antagonist exendin 9–39 selectively suppresses the intake of the CHO diet, whereas exendin-4, when given either alone or in combination with a glucose preload, selectively suppresses the intake of the PRO diet. Whether a clearer interpretation of the effect of the GLP-1 agonist in conjunction with macronutrient preloads on feeding behavior would emerge if the rats were given dietary choices remains to be determined.
In summary, these results show that exendin-4 modifies the effect of all three macronutrients on food intake during the first hours of feeding. However, exendin-4 had the least effect on glucose, whereas it had a greater interaction with protein and fat. Furthermore, the effect of exendin-4 on the blood glucose response to the macronutrients does not explain its effect on food intake.
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FOOTNOTES |
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3 Abbreviations used: BW, body weight; CCK, cholecystokinin; CHO, high carbohydrate diet; DPPIV dipeptidyl-peptidase GLP-1, glucagon-like peptide (7–36); PBS, phosphate buffer saline; PRO, high protein diet.
Manuscript received 3 October 2001. Initial review completed 6 December 2001. Revision accepted 14 February 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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