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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 MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • agonist • amino acids • food intake • gut hormone • protein
Protein suppresses food intake more than carbohydrate and fat (1), and several mechanisms have been proposed to account for its satiating effect. Changes in plasma and brain amino acid concentrations have been associated with the modulatory effects of proteins on food intake (2). However, these changes occur relatively late after protein ingestion by rats (3,4) and thus cannot account for the initiation of satiety, which begins as a result of signals arising from the gut. Protein ingestion triggers satiety signals from the gut, primarily through the release of peptide hormones, such as cholecystokinin (CCK) (5,6), which contributes to food intake suppression (7), and also through the release of biologically active encrypted peptides arising from digestion of the protein (8,9). Protein-induced satiety is also mediated through the activation of opioid-like receptors (9,10) by peptides released from digestion of proteins (11–13). The blocking of CCK-A (14,15) and opioid-like receptors results in reversal of food intake suppression caused by proteins (9,10).
Another gut hormone that may account for satiety after protein ingestion is glucagon-like peptide-1 (GLP-1) (7-36), which is released by the endocrine L-cells of the ileum (16,17). GLP-1 secretion has been reported to be particularly sensitive to the ingestion of carbohydrates (18) and some fats (19). Ingestion and intestinal perfusion of proteins and their hydrolysis products also stimulate GLP-1 secretion in rats and humans (20–24). However, the role of peripheral GLP-1 in modulating feeding behavior has not been established, in contrast to its activity in the central nervous system (CNS) where it has been shown to suppress food intake (25).
Because bioactive GLP-1 has a very short half-life in plasma due to the rapid degradation by dipeptidyl peptidase IV (DPP IV) (26,27), long-acting GLP-1 analogs such as exendin-4 (Ex-4) have been used to examine the peripheral actions of GLP-1 (28,29). Ex-4 shares 53% amino acid identity with GLP-1 (30), is resistant to the action of DPP IV (31) and is a highly specific agonist for the only GLP-1 receptor identified to date (30,32). Peripheral administration of Ex-4 potently suppresses food intake (33), modulates macronutrient selection in rats (1) and decreases energy intake in healthy humans (34), suggesting that pharmacological activation of the GLP-1 signaling pathway in the periphery modulates the feeding behavior. In addition, we recently reported that whey protein interacts with Ex-4 to suppress food intake in rats (33).
The primary objective of this study was to test the hypotheses that another potential satiety mechanism involved in food intake suppression after protein ingestion arises through the GLP-1 signaling pathway, and that this effect is mediated by the products of protein digestion. Whey and casein were given by gavage as the intact proteins, peptide-containing hydrolysates or free amino acids matching the composition of the proteins in the presence or absence of Ex-4 injections.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS 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 16-h light/8-h dark cycle (lights on at 1800 h), and had free access to water throughout and to a pelleted diet (Rodent Laboratory Chow #5001; LabChows, Strathroy, Ontario) 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 (35). Diets were available only from 1000 to 1800 h, and removed during the rest of the day, although water was provided for 24 h a day. The University of Toronto Animal Care Committee approved the protocol, and the 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 (200), cornstarch (529.4), sucrose (100.1), soybean oil (70), cellulose (50), L-cystine (15), vitamin mixture (10), mineral mixture (35), choline bitartrate (2.5) and tertbutyl hydroquinone (0.014) (31). Cornstarch, high protein casein (87%) and cellulose were purchased from Harland Teklad (Madison, WI). The vitamin mixture, mineral mixture, L-cysteine, choline bitartrate and tertbutyl hydroquinone were purchased from Dyets (Bethlehem, PA). Sucrose and soybean oil were purchased from local suppliers in Toronto, Canada.
Nutrient preloads.
Compositions of the intact protein and protein hydrolysate preloads as reported by the manufacturer for moisture, ash and carbohydrate are given in Table 1. Nitrogen values were determined for intact proteins and protein hydrolydates (AACS Method 46-12), and protein content was determined on the basis of conversion factors for whey and casein (36). Amino acid mixtures were formulated after the composition of whey and casein (36). The osmolality of the preloads was measured by use of an osmometer (Table 1). All rats were fed an intragastric preload of 0.5 g of pure protein, protein equivalent or amino acid mixture by gavage in a volume of 4 mL deionized water 30 min before the onset of the dark cycle. The amount of protein given was based on the limited solubility of casein in water.
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Ex-4 (American Peptide Company, Sunnyvale, CA) was prepared as described previously (33). 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 was stored at -20°C until later analysis. When needed, freeze-dried peptide was brought to room temperature and reconstituted by use of 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 intraperitoneally (i.p.) in a volume of 0.5 mL. Ex-4 was given at a dose of 0.5 µg/rat (peptide content).
Procedures.
Before testing, the rats were adapted to the experimental procedures as previously described (14). 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 (injection and preload), whereas the other half were untreated. On d 2, this testing order was reversed. Experimentation began when it was determined that the processes of gavaging and injecting had no effect on food intake. Naïve sets of 16 rats were used to investigate the effect of administering Ex-4 with either intact protein, or protein hydrolysate, or amino acid mixture preloads on food intake.
A preliminary experiment also investigated the effect of osmolality spanning the range of the preloads (0–1300 mosm/kg water) by adding sodium chloride. Because no differences in food intake were found, the osmolality of the preloads was not equalized.
Exendin-4 was injected i.p. at 0925 h and nutrient preloads were provided by gavage at 0930 h. At 1000 h when the dark cycle started, food was provided. Food consumption was measured under a red light to the nearest 0.1 g with adjustment for spillage at various times.
Design.
The present study consisted of three experiments. In expt. 1, the effect of the osmolality of preload solutions on food intake was investigated. In expts. 2 through 4, the effect of coadministering Ex-4 with preloads of intact whey (WP) and casein (CP) proteins (expt. 1), whey and casein hydrolysates (WH and CH, respectively) (expt. 2) and amino acid mixtures formulated after whey (AAWP) and casein (AACP) (expt. 3) on the intake of the maintenance diet was determined.
In all experiments, the rats served as their own control in a repeated-measures 2-way factorial design with the effect of Ex-4 and the effect of the preload as the main factors. Each rat received each treatment (control, Ex-4 alone, preload alone, Ex-4 and preload combined) with a 1-d washout between the treatments. Food intake was measured at 1, 2, 3 and 8 h.
Experiment 1: Effect of Ex-4 and WP and CP preloads on food intake.
The objective of this experiment was to describe the effect of the GLP-1 agonist, Ex-4, on food intake when given with intact protein preloads. Each rat (n = 16, body weight = 243 g) received six treatments in random order: control (water and PBS), Ex-4, WP, Ex-4 and WP, CP, Ex-4 and CP.
Experiment 2: Effect of Ex-4 and WH and CH preloads on food intake.
The objective of this experiment was to describe the effect of the GLP-1 agonist, Ex-4, on food intake when given with protein hydrolysate preloads. Each rat (n = 16, body weight = 252 g) received six treatments in random order: control (water and PBS), Ex-4, WH, Ex-4 and WH, CH, Ex-4 and CH.
Experiment 3: Effect of Ex-4 and AAWP and AACP on food intake.
The objective of this experiment was to describe the effect of the GLP-1 agonist, Ex-4, on food intake when given with amino acid mixture preloads. Each rat (n = 16, body weight = 288 g) received six treatments in random order: control (water and PBS), Ex-4, AAWP, Ex-4 and AAWP, AACP, Ex-4 and AACP.
Statistical Analysis.
In all three experiments, data were assessed by repeated-measures two-way ANOVA to look for main treatment effects and interactions between Ex-4 and the preloads followed by a one-way ANOVA with post hoc Duncan’s test to determine the effect of individual treatments by use of the SAS system (SAS Institute, Cary, NC). Differences were considered significant at P < 0.05.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Both Ex-4 and the intact protein preloads affected food intake (Table 2). Based on the two-way ANOVA, the main effect of Ex-4 was to reduce food intake during 0–1 h (P = 0.009), 0–2 h (P = 0.002), 0–3 h (P = 0.0001) and 0–8 h (P = 0.004), and that of the preloads to also decrease food intake but only during 0–1 h (P = 0.004).
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Experiment 2: Effect of Ex-4 and protein hydrolysate preloads on food intake.
Both Ex-4 and the protein hydrolysate preloads affected food intake (Table 3). Based on the two-way ANOVA, the main effect of Ex-4 was to reduce food intake during 0–1 h (P < 0.0001), 0–2 h (P < 0.0001), 0–3 h (P < 0.0001) and 0–8 h (P < 0.0001), and that of the preloads to also decrease food intake during 0–1 h (P = 0.04), 0–2 h (P = 0.03) and 0–3 h (P = 0.01).
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Experiment 3: Effect of Ex-4 and amino acid mixture preloads on food intake.
Both Ex-4 and the preloads of amino acid mixtures affected food intake (Table 4). Based on the two-way ANOVA, the main effect of Ex-4 was to reduce food intake during 0–1 h (P < 0.0001), 0–2 h (P < 0.0001), 0–3 h (P < 0.0001) and 0–8 h (P < 0.0001), and that of the preloads to also decrease food intake during 0–1 h (P = 0.01), 0–2 h (P = 0.01), 0–3 h (P = 0.04) and 0–8 h (P = 0.004).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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There were two reasons for testing the effect of Ex-4 on the rats’ feeding response after preloads of two sources of intact proteins, protein hydrolysates and amino acid mixtures. First, we wanted to provide further evidence that a mechanism explaining protein-induced suppression of food intake involved the GLP-1 signaling pathway. We previously reported an interaction between whey and Ex-4 in the suppression of food intake (33), but have not tested any other protein source. Second, we wanted to determine the components of proteins that are responsible for the effects of proteins on food intake by this pathway.
The effect of Ex-4 on food intake was markedly reduced when given with the preloads (Tables 2, 3, 4). The statistical interaction between Ex-4 and the preloads implies that the effects of the drug and preload treatments were not independent. If they were, the conclusion would be that the treatments resulted in the activation of two independent satiety signaling pathways. Thus the combination effect would be expected to approximate the sum of the effect of each of the treatments. Because the effect of Ex-4 was reduced when administered with the preloads, the data suggest that GLP-1, whose secretion is presumably stimulated by the preloads (20–23), competed with its agonist Ex-4 on the GLP-1 receptor and thus reduced the effect of Ex-4 on food intake.
The effect of proteins on plasma GLP-1 concentrations in humans adds support to a proposed role for GLP-1 in food intake suppression after protein ingestion. Protein consumption equivalent to that in 352 g of turkey meat elicits a transient peak in plasma GLP-1 after 30 min, followed by a steady rise over 3 h (21). Similarly, both whey and casein preloads increase plasma GLP-1 in humans (23). An increase in plasma GLP-1 has been found after ileal perfusion of peptones, which are oligopeptides obtained by digestion of proteins in vitro (24), and an oral amino acid load (25 g) produces a sharp and rapid increase in plasma GLP-1 in humans (17).
The effect of protein ingestion on GLP-1 secretion is less certain in rats. Ileal perfusion of peptones increases GLP-1 secretion in isolated vascularly perfused rat ilea, but neither intact proteins nor amino acid mixtures elicits a GLP-1 response (20). We are unaware of reports of the plasma GLP-1 response to oral protein or amino acid ingestion by rats.
Only indirect evidence for GLP-1 action in suppressing food intake after protein ingestion arises from these studies for three reasons. First, Ex-4 is a pharmacological GLP-1 analog, and therefore cannot be assumed to describe the role of peripheral endogenous GLP-1 in food intake regulation. Second, the modes of action of Ex-4 on food intake may include other actions in addition to the activation of GLP-1 receptors on vagal afferents and the relay of satiety signals by the vagus nerve to the CNS (3). Direct activation of the GLP-1 receptors in brain areas involved in the regulation of feeding behavior may be another mode of action. GLP-1 is known to access the brain through either transport across the blood–brain barrier (BBB) (37,38), or through brainstem regions that are BBB free (39). However, it is not known whether Ex-4 does likewise. In addition, GLP-1 suppresses gastrointestinal motility (40) and thus the feeding response to Ex-4 might also be explained by delayed gastric emptying. However, the latter is unlikely to be the sole explanation of the feeding response after Ex-4 because the effect of Ex-4 on food intake depended on the source of the preload (Tables 2, 3, 4). For example, the effect of Ex-4 was reduced more during 0–1 h when given with CP than when given with WP (Table 2), whereas the opposite was observed with the amino acid mixture preloads (Table 4).
To support direct evidence for the involvement of GLP-1 in the postnutrient regulation of feeding behavior requires the use of either exogenous GLP-1 or GLP-1 receptor antagonist. The use of exogenous GLP-1 fails to show any effect because of the rapid degradation of the peptide by DPP IV (25). On the other hand, the GLP-1 receptor antagonist Ex 9-39 is available and does not suppress food intake in rats (1), suggesting that this may be an appropriate antagonist for investigating the role of peripheral endogenous GLP-1 in macronutrient-induced satiety. An appropriate dose would be expected to attenuate food intake suppression caused by proteins, their hydrolysates and amino acid mixtures.
The reduction in the effect of Ex-4 (and thereby the present involvement of GLP-1) was dependent on the type and protein source of the preloads (Tables 2, 3, 4). It is difficult to explain these differences other than to observe that there are other mechanisms that also account for food intake suppression after protein ingestion. For example, CP is more slowly digested than WP (36), and peptides arising from its digestion suppress food intake through other gut peptides, that is, CCK and opioid peptides (9). One explanation for the stronger effect of AAWP on Ex-4 might be that it contains a higher ratio of tryptophan to large neutral amino acids (
40%) than AACP (36), which would contribute more to the conversion in the CNS of tryptophan to serotonin, a neurotransmitter involved in the suppression of appetite (2). This remains to be investigated.
In summary, our results suggest that the GLP-1 signaling pathway is among the mechanisms involved in the suppression of food intake after protein ingestion and that the pathway is activated as a result of the release of free amino acids during digestion.
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FOOTNOTES |
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3 Abbreviations used: AACP, amino acid mixture formulated after casein; AAWP, amino acid mixture formulated after whey; BBB, blood–brain barrier; CP, intact casein protein; CCK, cholecystokinin; CH, casein hydrolysate; CNS, central nervous system; DPP IV, dipeptidyl peptidase IV; Ex-4, exendin-4; GLP-1, glucagon-like peptide-1 (7-36); i.p., intraperitoneally; WH, whey hydrolysate; WP, intact whey protein.
Manuscript received 19 December 2002. Initial review completed 17 February 2003. Revision accepted 8 April 2003.
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 G. H. Anderson, S. N. Tecimer, D. Shah, and T. A. Zafar Protein Source, Quantity, and Time of Consumption Determine the Effect of Proteins on Short-Term Food Intake in Young Men J. Nutr., November 1, 2004; 134(11): 3011 - 3015. [Abstract] [Full Text] [PDF]
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G. H. Anderson and S. E. Moore Dietary Proteins in the Regulation of Food Intake and Body Weight in Humans J. Nutr., April 1, 2004; 134(4): 974S - 979S. [Abstract] [Full Text] [PDF]
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