QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Froetschel, M. A. Articles by Amos, H. E. Search for Related Content PubMed PubMed Citation Articles by Froetschel, M. A. Articles by Amos, H. E.

---

Articles

Opioid and Cholecystokinin Antagonists Alleviate Gastric Inhibition of Food Intake by Premeal Loads of Casein in Meal-Fed Rats¹

M. A. Froetschel², M. J. Azain, G. L. Edwards^*, C. R. Barb and H. E. Amos

Animal and Dairy Science Department, ^* Physiology and Pharmacology Department, The University of Georgia, Athens, GA 30602 and U.S. Department of Agriculture, ARS, R. Russel Research Center, Athens, GA 30602

²To whom correspondence should be addressed. E-mail: markf{at}arches.uga.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
This study was undertaken to determine whether casein, compared with its constituent amino acids, given at the onset of a meal, would influence intake due to cholecystokinin (CCK) or opioid activity. Male Sprague-Dawley rats (n = 80; 225 g) were given either premeal loads of casein or its constituent amino acids and treated with opioid or CCK antagonists in a 2 x 4 factorially designed experiment. During a 21-d period, rats were meal-fed by restricting access to food to 5 h/d. The rats were fed the AIN-93 diet with soy isolate substituted for casein as the dietary protein source. On d 7–21, rats were given oral premeal loads of 5 mL of a 50 g/L casein or constituent amino acid solution before meal-feeding. On d 14–21, 20 rats were injected intraperitoneally with one of the following treatments: saline, naltrexone (l mg/kg), naloxone methiodide (5 mg/kg) or lorglumide (1 mg/kg) before the premeal load and feeding. Antagonist treatments increased intake (P < 0.05) by 15.3% compared with saline treatment (7.82 vs. 9.02 g/d) in rats given premeal loads of casein. Intake of rats given premeal loads of amino acids was not influenced by antagonists. At 2 h after feeding on d 21, the rats were killed, bled and eviscerated. Effects of antagonists on stomach and intestinal mass, digesta contents and fecal output were also dependent on the type of premeal load, indicating that gastric retention of digesta due to casein was mediated by CCK and opioids. Body weight accretion, liver, and epididymal fat mass and blood concentrations of specific amino acids changed in the same manner as intake (P < 0.05). Serum insulin was greater (P < 0.05) in casein-treated rats and reduced (P < 0.01) by opioid antagonists. Satiety associated with premeal loads of casein is related to changes in gastrointestinal function of meal-fed animals and involves both opioid and CCK regulation.

KEY WORDS: • intake • satiety • casein • opioids • cholecystokinin • rats

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Dietary peptides have been identified (1 –3 ) that could provide a peripheral stimulus for premature termination of meal size (4 ). These peptides, known as exorphins, inhibit gastric emptying (5 ), cause distension and may amplify vagally transmitted gastric satiety signals (6 ). Exorphins are opioid peptides that are present within the primary structure of various food proteins (7 ). These peptides are released into the small intestine during protein digestion, resist hydrolysis (7 ) and are absorbed intact depending on mucosal peptidase activities (8 –10 ). Exorphins reduce gastric emptying (5 ) by directly interacting with opioid receptors that control gastrointestinal motility (11 –13 ). In addition, these peptides modulate postprandial levels of metabolic hormones (14 ) involved in satiety and energy homeostasis (15 ,16 ). Milk protein is a source of exorphins (7 ), and a particular class of peptides found in ß-casein known as casomorphins has received considerable research attention in this regard (4 ). Consumption of milk protein immediately before a meal may accelerate the onset of satiety and reduce meal size due to opioid activity. Presumably this effect would be accentuated in animals that have an exaggerated appetite after being conditioned to a meal-feeding regimen. Our objective was to determine whether intake in meal-fed rats would be influenced by an oral dose of casein compared with its constituent amino acids before the meal and whether this effect could be blocked with specific opioid and choleocystokinin (CCK)³ antagonists.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Male Sprague-Dawley rats (n = 80;Harlan Sprague Dawley, Indianapolis, IN), averaging 225 g in body weight initially, were housed individually in an animal room in the University of Georgia Animal Resources Facility at a controlled temperature (21–23°C) and a 12-h light:dark photoperiod. Animal protocols were approved by the University of Georgia Animal Care and Use Committee concerning the ethical treatment of animals. Rats were fed the AIN-93 diet (17 ) with the exception that soy isolate was substituted as the dietary protein source to provide the same concentration of nitrogen as casein. In addition, specific amino acids were added to the experimental diet to have dietary concentrations that would be attained using AIN-93 specifications. The diet contained the following (g/kg): cornstarch, 529.25; soy protein isolate, 193.0 (50% grade I and 50% grade II); sucrose, 100; soybean oil, 68.5; fiber, 50; mineral mixture, 35.0; vitamin mixture, 10.0; L-methionine, 4.0; L-cysteine, 3.0; L-lysine, 1.0;g L-threonine, 1.0; L-tryptophan, 0.75; and choline chloride, 2.5 (all diet ingredients were purchased through United States Biochemical, Amersham Life Sciences, Cleveland, OH). Upon arrival, rats were given 2 d to adjust to the experimental diet and then were started on a daily meal-feeding regimen that was maintained for 21 d. Rats were given 5-h access to their food cups every day from 1300 to 1800 h. Lights were set to turn off at 1700 h to allow rats to have 1 h of their 5-h access to food to occur during the dark period. Continuous access to water was provided throughout the experiment. All the rats were meal-fed experimental diet for 7 d to adjust to the meal feeding regimen, and then randomly divided into two treatment groups. On d 7–21, rats were given an oral load of casein or its constituent amino acids. Premeal loads, consisting of 5 mL of a 50 g/L solution of casein (C-0376, Sigma Chemical, St. Louis, MO) or its amino acids, were given to rats immediately before their meal. The premeal load of constituent amino acids was made according to the amino acid composition of casein as specified by the supplier (Sigma Chemical, St. Louis MO) and contained the following (g/L): arginine, 1.79; glycine, 1.07; serine, 1.23; histidine, 1.42; isoleucine, 2.07; lysine, 4.51; methionine, 1.10; cystine, 0.13; phenylalanine, 3.22; tyrosine, 2.79; threonine, 1.73; tryptophan, 0.50; valine, 3.22; proline, 4.18; aspartic acid, 2.51; and glutamic acid, 9.38. Premeal loads of casein and its constituent amino acids were given using a latex feeding-tube catheter (size 5F x 16; Durr Medical, Atlanta, GA) that was attached to a 25-mL syringe mounted on a laboratory stand.

On d 14–21, four groups of 20 rats, equally representing those receiving premeal loads of casein or its constituent amino acids, were randomly assigned to one of four antagonist treatments. These assignments consisted of a control treatment (saline), an opioid antagonist that blocks both central and peripheral opioid receptors (naltrexone hydochloride, O-004, RBI, Research Biochemicals International, Natick, MA), an opioid antagonist that exclusively blocks peripheral receptors (naloxone methiodide, N-129, RBI, Research Biochemicals) and a CCK A receptor subtype (CCK-A) antagonist (lorglumide sodium, L-109, RBI, Research Biochemicals). Antagonist treatments were administered intraperitoneally, given with 1 mL of saline as a carrier, using a 1-mL syringe to individual rats, each day 15 min before infusion of premeal loads and feeding. Naltrexone (18 ) and lorglumide (19 ) were both administered at a dose of 1 mg/kg body and naloxone methiodide (20 ) was administered at 5 mg/kg body. Dosages were related to the relative potencies of these antagonists (18 ,19 ,20 ).

Food intake and body weight were measured daily throughout the experiment. On d 18–19 of the experiment, all feces were collected at hourly intervals for 24 h from underneath each rat cage. Hourly samples were pooled for five rats within each treatment group. Fecal samples were dried to a constant weight to determine diurnal excretion patterns of dry feces. On d 21, rats were sedated with CO₂ and decapitated 2 h after receiving premeal loads and feeding. Trunk blood was collected, allowed to clot, centrifuged at 1000 x g for 20 min and serum harvested and stored at 4°C before RIA of insulin (ICN Biomedicals, Costa Mesa, CA) and insulin-like growth factor-1 (IGF-I) (21 ), and spectrophotometric determination of glucose (Sigma Chemical). The mass of specific tissues including the liver, pancreas, epididymal fat pad and the soleus and gastrocnemius muscles was measured. The mass of designated portions of the gastrointestinal tract and its contents was measured. The stomach, small intestine and lower digestive tract, posterior to the ileo-cecal junction, were isolated and weighed before and after removal of digesta contents.

The experimental data were analyzed as a randomized complete design with a 2 x 4 factorial arrangement of treatments. All data were statistically analyzed for treatment differences using ANOVA as conducted with the general linear model procedures of SAS (22 ). The main effects undergoing analysis in the statistical model were premeal load (casein vs. amino acids), antagonist treatments (saline-control, naltrexone, naloxone methiodide and lorglumide) and the interaction between premeal load and antagonist treatments. The data tables are arranged to present the interaction between premeal load and antagonist treatments. Treatment differences were tested by orthogonal comparisons between least-squares means. The effect of saline treatment was compared to the mean effect of the antagonist treatments (saline vs. naltrexone + naloxone methiodide + lorglumide); the mean effect of the opioid antagonist treatments was compared with the effect of the CCK antagonist treatment (naltrexone + naloxone methiodide vs. lorglumide); and the effect of the central opioid antagonist was compared with the peripheral opioid antagonist treatment (naltrexone vs. naloxone methiodide). Differences were considered significant at P < 0.05.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
There was an interaction detected for premeal load by antagonist treatment for food intake and body weight during d 14–21 (Table 1 ). The three antagonists, naltrexone, naloxone methiodide and lorglumide, all acted in a similar fashion and increased intake of the rats given premeal loads of casein but did not influence intake of rats given premeal loads of the amino acid solution. In rats given premeal loads of casein, administration of antagonists increased intake (P 0.05) by 15.3% compared with those given saline as a placebo (7.82 vs. 9.02 g/d). Body weight accretion was also influenced by antagonists in rats given premeal loads of casein. The average body weight gain of rats given premeal loads of casein was 35% greater (P < 0.05) when treated with antagonists compared with those given saline (2.47 vs. 1.83 g/d). As with intake, the antagonists did not influence body weight accretion of rats given premeal loads of the amino acid solution.

Fecal output in relation to time after feeding on d 18 of the experiment is shown in Table 4 . An interaction between the premeal load infused and antagonist treatment was observed for the dry fecal output during the first 2–4 h after meal-feeding, when hourly cumulative measurements were expressed as a percentage of total fecal output. Cumulative fecal output 2–4 h after feeding was 87.2% greater (P < 0.05) in rats treated with casein and injected with saline compared with those treated with amino acids and injected with saline. During this time period, 2–4 h after feeding, fecal output decreased 55% (P < 0.05) in rats given premeal loads of casein and injected with lorglumide compared with those rats given premeal loads of casein and injected with saline. In rats given premeal loads of amino acids, fecal output increased 45.2–117.6% (P < 0.05) in rats injected with antagonists compared with those injected with saline. The effects on fecal output were more pronounced in the first 2 h and diminished 2–4 h after feeding and treatment administration. There were no differences in total fecal output of the rats. Fecal output shortly after meal-feeding appeared to be influenced by gastric retention of digesta. The treatments that resulted in greater gastric digesta contents and food intake inhibition also had increased fecal output during the first 2–4 h after meal-feeding. These results suggest that gastric distension due to opioid and CCK activity may have stimulated digesta emptying of the lower portion of the intestinal tract.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

The results of this experiment suggest that premeal loads of intact casein cause premature meal termination in meal-fed rats due to opioid and CCK activities. This was determined by using opioid and CCK antagonists to reverse the inhibitory effect of premeal loads of casein on food intake. This antagonist response was not apparent in rats given premeal loads of free amino acids. The experiment was designed to assess the interaction between the type of premeal load and different antagonists to determine whether opioid and CCK activities were responsible for casein-induced satiety. The opiod antagonists, naltrexone and naxolone methiodide, and the CCK antagonist, lorglumide, all acted in a similar fashion. These antagonists blocked intake inhibition caused by a premeal load of casein but did not influence intake of rats given premeal loads of amino acids. Orthogonal comparisons were used to test the interaction between the type of premeal load and the combined treatment effects of antagonists compared with saline treatment. The interaction does not specifically prove that opioid and CCK activities are responsible for casein-induced satiety. This is because numerical differences in intake response occurred due to the type of premeal load and whether it was given in conjunction with an injection of saline or the antagonists. However, on the basis of other research that demonstrates that premeal loads of protein compared with amino acids result in CCK-induced satiety (24 ,25 ), it is reasonable to suspect that the intake effects were due to casein causing satiety rather than amino acids increasing appetite.

Presumably, endogenous peptides in casein influence motile processes of the digestive tract that increase the retention of chyme in the stomach as observed in nursing rats (5 ). Changes in mass and contents of the intestinal tract 2 h after feeding indicated that a premeal load of casein prematurely terminated meal consumption via a gastric-mediated mechanism in mature rats (225–250 g). The empty stomach mass and its contents were greater in rats given premeal loads of casein and this effect was blocked with the CCK-A antagonist, lorglumide. Changes in empty stomach mass were inversely related to intake responses, and both of these effects may be a consequence of gastric distension. An interaction between the type of premeal load and antagonist was not observed for mass and contents of the lower intestinal tract. However, it appears that the treatments were influencing the lower portion of the digestive tract as shown by changes in fecal output in the initial time period after treatment administration and feeding. Fecal output during the first 2–4 h after feeding increased in rats given premeal loads of casein, and this effect was blocked with lorglumide. Fecal output 2–4 h after feeding was inversely related to the intake response and paralleled changes in stomach mass and contents. Premeal loads of casein stimulated emptying of the lower bowel 2–4 h after feeding, either through a direct action of casein or a more indirect influence of gastric distension. Casein acts as a secretagogue for CCK (26 ) and should affect gastric retention of chyme; however, its effects on the lower digestive tract are less clear. Feeding a 2-g meal containing casein (80 g/kg) increased small intestinal retention of a marker protein as much as 25% compared with a similar meal containing soy protein isolate in rats deprived of food for 24 h (25 ). However, these researchers found only a slight effect of casein diet on increasing gastric retention of the protein marker.

Both CCK-A and opioid antagonists acted similarly in stimulating intake of rats given premeal loads of casein. Other research has demonstrated that exogenous opioid and CCK peptides interact to influence feeding behavior at the level of the central nervous system (26 ). However, based on their effects after central administration, opioids are thought to stimulate and CCK peptides inhibit feeding behavior. Central administration of ß-casomorphins was found to stimulate the intake of dietary fat (27 ). It appears that the central and peripheral effects of casomorphins on intake may be opposite. Opioid antagonists blocked the actions of centrally administered CCK on feeding and gastrointestinal motility of sheep and led to the speculation that effects of CCK are mediated by an opioid system (28 ). In this experiment, the effects of opioid and CCK antagonists appeared to be synergistic. Furthermore, effects of naloxone methiodide and lorglumide, which specifically block peripheral opioid and CCK receptors, respectively, were comparable to the effects of naltrexone, which blocks both peripheral and central opioid receptors. The similar effects of the antagonists, which are incapable of crossing the blood-brain barrier, suggest that intake and digesta retention responses associated with casein ingestion are peripherally mediated in a synergistic fashion involving both opioid and CCK receptors.

Although premeal loads of casein increased insulin compared with amino acids, the effects of the antagonist treatments were similar in rats given either casein or amino acids. Postprandial insulin release in dogs due to dietary casomorphin or a peptic digest of casein was blocked by the opioid antagonist naloxone but not in those fed a liver extract-sucrose meal (14 ). Finding that opioid antagonists lowered insulin in rats treated with premeal loads of amino acids to a similar extent as rats treated with premeal loads of casein indicates that casomorphins are not likely the only stimulus of insulin release after ingestion of milk protein. In the present experiment, naltrexone, which blocks both peripheral and central opioid receptors, had a greater effect at lowering postprandial insulin than naloxone methiodide, which specifically blocks peripheral opioid receptors. This suggests that a central opioid mechanism that is related to dietary amino acids may exist in addition to the peripheral influence of casomorphins that mediates this effect on postprandial insulin. Furthermore, the changes in circulating insulin without corresponding changes in glucose may also contribute to a central effect of insulin on satiety (15 ).

Serum IGF-1 was increased in rats given premeal loads of amino acids and was not influenced by antagonist treatments. Because this growth factor was increased in rats given premeal loads of amino acids, growth promotion associated with casein consumption may be related more to its supply of essential amino acids than to bioactivity of intact protein.

The bioactivity of casein in relation to casomorphins has been demonstrated by the blocking effects of casein with opioid antagonists compared with other protein sources as controls or direct administration of casomorphins (5 ,14 ). The suitability of the amino acid solution as a control can be questioned even though it is devoid of opioid peptides because of its osmotic strength potentially influencing gastric distension. Amino acids from the premeal load of amino acids were absorbed more readily than those from casein, as indicated by increased plasma concentrations of amino acids measured 2 h after their administration. Intragastric infusion of albumen suppressed food intake of rats compared with an intragastric infusion of its amino acids, and this effect was reversed by the CCK-A antagonist, devazepide (24 ,25 ). The lack of an antagonist effect in rats given premeal loads of amino acids compared with casein supports the overall hypothesis that peptide fractions of casein, known as casomorphins, are responsible for a reduction in intake. The only definitive method to determine whether casomorphins are responsible for the intake-suppressive effects of casein is to administer these peptides directly. However, postabsorptive delivery of free peptides and their susceptibility to intestinal hydrolysis may influence their relative activities compared with peptides within intact casein (10 ). Another concern is related to the potential opioid and CCK bioactivity of isolated soy protein, used as the protein source in the basal diet. Pepsin hydrolysates of other protein sources including wheat and bovine serum albumin may contain peptides with opioid activity as indicated by naloxone reversible inhibition of adenylate cyclase activity in cell homogenates (3 ). However, a fraction of soy protein did not exhibit opioid activity with this procedure compared with these other protein sources (3 ). In this experiment, premeal loads of 0.25 g of casein resulted in effects that were reversed by opioid and CCK-A antagonists even though the rats were receiving >1.5 g of isolated soy protein from their diet. Others have found that premeal loads of albumen, another intact protein source, will cause CCK-A antagonist reversible intake suppression compared with premeal loads of amino acids, carbohydrates or fat (24 ,25 ). Comparisons between different protein sources in relation to their effects on CCK or opioid-antagonist reversible-inhibition of intake suppression would help determine whether opioid activity is specific to a few identified protein sources such as casein, albumen or wheat.

These results clarify a potential mechanism to support using a premeal load of casein to elicit a short-term satiety effect and facilitate weight loss. A premeal load of protein decreased energy intake during the subsequent meal 15.9% compared with premeal loads of carbohydrate, fat or alcohol in lean women (31 ). These researchers used a number of protein sources to formulate their protein preload, including nonfat milk. Our research indicates that milk consumption before the meal may reduce meal size and should be investigated. The segment of our population that is most inclined to obesity, persons in adolescence to middle age, is least inclined to consume large quantities of milk. Satiety factors such as CCK and its influence on gastric retention of digesta and satiety are characterized as short-term controls of intake. Recently, short-term regulation of intake has received less attention as a target to control obesity. The lipostatic theory of intake regulation involves a more long-term control of intake and has become a particularly important focus of research (16 ) after the discovery of leptin. Moreover, leptin’s effects on food intake are mediated in part by increased sensitivity to CCK (32 ). On the basis of the above idea, animals with greater adipose mass may be more sensitive to intake suppression after receiving premeal loads of casein.

In summary, the results demonstrate that a premeal load of intact casein promotes premature meal termination in meal-fed rats. Antagonists were used to demonstrate that these effects involved peripheral opioid and CCK receptors. It is important to note that this response was observed in animals with an exaggerated appetite due to a meal-feeding paradigm. Hormonal analysis, digesta passage measurements and compositional analysis of specific organs and tissues tend to support the mechanism for the satiety effect as one related to a gastric distension response during the meal.

	ACKNOWLEDGMENTS

 
The technical service of Patricia G. Smith for performing laboratory assays and managing dosing regimen is acknowledged.

	FOOTNOTES

 
¹ Supported by a grant provided by The National Dairy Council^®.

³ Abbreviations used: CCK, choleocystokinin; CCK-A, choleocystokinin A receptor subtype; IGF-1, insulin-like growth factor-1.

Manuscript received May 15, 2001. Initial review completed June 30, 2001. Revision accepted August 28, 2001.

	LITERATURE CITED

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

1. Brantl, V., Teschemacher, H., Henschen, A. & Lottspeich, F. (1979) Novel opioid peptides derived from casein (ß-casomorphins). I. Isolation from bovine casein peptone. Hoppe-Seyler’s Z. Physiol. Chem. 260:1211-1216.

2. Henschen, A., Lottspeich, F., Brantl, V. & Teschemacher, H. (1979) Novel opioid peptides derived from casein (ß-casomorphins) II. Structure of active components from bovine casein peptone. Hoppe-Seyler’s Z. Physiol. Chem. 360:1217-1222.

3. Zioudrou, C., Streaty, R. A. & Klee, W. A. (1979) Opioid peptides derived from food proteins. J. Biol. Chem 254:2446-2449.[Abstract/Free Full Text]

4. Froetschel, M. A. (1996) Bioactive peptides in digesta that regulate gastrointestinal function and intake. J. Anim. Sci. 74:2500-2508.[Abstract]

5. Daniel, H., Vohwinkel, M. & Rehner, G. (1990) Effect of casein and ß-casomorphins on gastrointestinal motility in rats. J. Nutr. 120:252-257.

6. Ritter, R. C., Brenner, L. & Yox, D. P. (1992) Participation of vagal sensory neurons in putative satiety signals from the upper digestive tract. Ritter, S. Ritter, R. C. Barnes, C. D. eds. Neuroanatomy and Physiology of Abdominal Vagal Afferents 1992:221-248 CRC Press Boca Raton, FL. .

7. Meisel, H. & Schlimme, E. (1990) Milk proteins: pre-cursors of bioactive peptides. Trends Food Sci. Technol. 1:41-43.

8. Gardner, M. G., Lindblad, B. S., Burston, D. & Matthews, D. M. (1983) Trans-mucosal passage of intact peptides in the guinea pig small intestine in vivo: a re-appraisal. Clin. Sci. (Lond.) 64:433-437.[Medline]

9. Tome, D., Mansour, A. B., Hautefeuille, M., Dumontier, A. M. & Desjeux, J. F. (1988) Neuromediated action of ß-caspmorphins on ion transport in rabbit ileum. Reprod. Nutr. Dev. 23:909-918.

10. Tiruppathi, C., Miyamoto, Y., Ganapathy, V. & Leibach, F. H. (1993) Genetic evidence for role of DPP-IV in intestinal hydrolysis and assimilation of prolyl peptides. Am. J. Physiol. 265:G81-G89.[Abstract/Free Full Text]

11. Chang, K. J., Killian, A., Hazum, E. & Cuatrecasas, P. (1981) Morphiceptin (NH₄-Tyr-Pro-Phe-Pro-CON₂): a potent and specific agonist for morphine (u) receptors. Science (Washington, DC) 212:75-77.[Abstract/Free Full Text]

12. Chang, K. J., Cuatrecasas, P., Wei, E. T. & Chang, J. K. (1982) Analgesic activity of intracerebroventricular administration of morphiceptin and ß-casomorphins: correlation with the morphine (u) receptor binding affinity. Life Sci 30:1547-1551.[Medline]

13. Chang, K. J., Su, Y. F., Brent, D. A. & Chang, J. K. (1985) Isolation of a specific u-opiate receptor peptide, morphiceptin, from an enzymatic digest of milk proteins. J. Biol. Chem. 260:9706-9712.[Abstract/Free Full Text]

14. Schusdziarra, V., Schick, R., De La Fuente, A., Specht, J., Klier, J., Brantl, V. & Pfeiffer, E. F. (1983) Effect of ß-casomorphins and analogs on insulin release in dogs. Endocrinology 112:1948-1951.[Abstract/Free Full Text]

15. Schwartz, M. W., Figlewicz, D. P., Baskin, , Woods, S. C. & Porte, D., Jr (1992) Insulin in the brain: a hormonal regulator of energy balance. Endocr. Rev. 13:387-414.[Abstract/Free Full Text]

16. Woods, S. C., Seeley, R. J., Porte, D., Jr & Schwartz, M. (1998) Signals that regulate food intake and energy homeostasis. Science (Washington DC) 280:1378-1382.[Abstract/Free Full Text]

17. Reeves, P. G., Nielson, F. H. & Fahey, G. C., Jr (1993) AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J. Nutr. 123:1939-1951.

18. Gold, M. S., Dackis, C. A., Pottash, A.L.C., Sternbach, H. H. & Annitto, W. J. (1982) Naltrexone, opiate addiction and endorphins. Med. Res. Rev. 2:211-247.[Medline]

19. Makovec, F., Bani, , Cereda, R., Christe, R., Pacini, M. A., Revel, L., Rovati, L. A. & Rovati, L. C. (1987) Pharmacological properties of lorglumide as a member of a new class of cholecystokinin antagonists. Arzneim.-Forsch./Drug Res. 37:1265-1270.

20. Russel, P., Bass, P., Goldberg, L. I., Schuster, C. R. & Merz, H. (1982) Antagonism of gut but not central effects of morphine with quaternary narcotic antagonists. Eur. J. Pharm. 78:255-261.[Medline]

21. Latimer, A. M., Hausman, G. J., McCusker, R. H. & Buonomo, F. C. (1993) The effects of thyroxine on serum and tissue concentrations of insulin-like growth factors (IGF-I & -II) and IGF binding proteins in the fetal pig. Endocrinology 133:1312-1319.[Abstract/Free Full Text]

22. SAS Institute Inc (1990) SAS/STAT User’s Guide version 6 4th ed. 1990 SAS Institute Cary, NC. .

23. Burton-Freeman, B. & Scheeman, B. O. (1996) Lipid infused into the duodenum of rats at varied rates influences food intake and body weight gain. J. Nutr. 126:2934-2939.

24. Liddle, R. A., Green, G. M., Conrad, C. K. & Williams, A. (1986) Proteins not amino acids, carbohydrates, or fats stimulate choleocystokinin secretion in the rat. Am. J. Physiol. 251:G243-G248.[Abstract/Free Full Text]

25. Hiroshi, H., Nishikawa, H. & Kiriyama, S. (1992) Different effects of casein and soyabean protein on gastric emptying of protein and small intestinal transit after spontaneous feeding of diets in rats. Br. J. Nutr. 68:59-66.[Medline]

26. Baile, C. A., McLaughhlin, C. L. & Della-Fera, M. A. (1986) Role of cholecystokinin and opioid peptides in control of food intake. Physiol. Rev. 66:172-234.[Abstract/Free Full Text]

27. Umahara, L. L., York, D. A. & Bray, G. A. (1998) ß-Casomorphins stimulate and enterostatin inhibits the intake of dietary fat in rats. Peptides 19:325-331.[Medline]

28. Bueno, L., Duranton, A. & Ruckebusch, Y. (1983) Antagonistic effects of naloxone on CCK-octapeptide induced satiety and rumino-reticular hypomotility in sheep. Life Sci 32:855-863.[Medline]

29. Trigazis, L., Orttmann, A. & Anderson, G. H. (1997) Effect of a cholecystokinin-A receptor blocker on protein-induced food intake suppression in rats. Am. J. Physiol. 272:R1826-R1833.[Abstract/Free Full Text]

30. Trigazis, L., Vaccarino, F. G., Greenwood, C. E. & Anderson, G. H. (1999) CCK-A receptor antagonists have selective effects on nutrient induced food intake suppression in rats. Am. J. Physiol. 276:R323-R330.[Abstract/Free Full Text]

31. Poppitt, S. D., McCormack, D. & Buffenstein, R. (1998) Short-term effects of macro-nutrient preloads on appetite and energy intake in lean women. Physiol. Behav. 64:279-285.[Medline]

32. Emond, M., Schwartz, G. J., Ladenheim, E. E. & Moran, T. H. (1999) Central leptin modulates behavior and neural responsivity to CCK. Am. J. Physiol. 276:R1545-R1549.

This article has been cited by other articles:

				B. L. Luhovyy, T. Akhavan, and G. H. Anderson Whey Proteins in the Regulation of Food Intake and Satiety J. Am. Coll. Nutr., December 1, 2007; 26(6): 704S - 712S. [Abstract] [Full Text] [PDF]

				A. Aziz, G. H. Anderson, A. Giacca, and F. Cho Hyperglycemia after protein ingestion concurrent with injection of a GLP-1 receptor agonist in rats: a possible role for dietary peptides Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2005; 289(3): R688 - R694. [Abstract] [Full Text] [PDF]

				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]

				L. Lin, S. R. Thomas, G. Kilroy, G. J. Schwartz, and D. A. York Enterostatin inhibition of dietary fat intake is dependent on CCK-A receptors Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R321 - R328. [Abstract] [Full Text] [PDF]

				A. Aziz and G. H. Anderson Exendin-4, a GLP-1 Receptor Agonist, Interacts with Proteins and Their Products of Digestion to Suppress Food Intake in Rats J. Nutr., July 1, 2003; 133(7): 2326 - 2330. [Abstract] [Full Text] [PDF]

				J. Pupovac and G. H. Anderson Dietary Peptides Induce Satiety via Cholecystokinin-A and Peripheral Opioid Receptors in Rats J. Nutr., September 1, 2002; 132(9): 2775 - 2780. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Froetschel, M. A. Articles by Amos, H. E. Search for Related Content PubMed PubMed Citation Articles by Froetschel, M. A. Articles by Amos, H. E.