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Department of Internal Medicine II, Technical University of Munich, D-81675 Munich, Germany
Address all correspondence and requests for reprints to: Dr. Johannes Erdmann, Else-Kröner-Fresenius Center of Nutritional Medicine, Technical University of Munich, Ismaninger Strasse 22, D-81675 Munich, Germany. E-mail: johannes.erdmann{at}lrz.tum.de.
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The volume effect of a meal is supported by the nutrient content obviously decreasing the threshold for distension-induced activation of satiety signals (5). Whereas distension-induced satiety and release of satiating hypothalamic neurotransmitters such as cholecystokinin can be abolished by vagotomy (2, 6), reduction of food intake as a result of gastric nutrient content remains unaffected (7). These findings suggest that apart from a vagal mechanism, other, most likely hormonal, mechanisms contribute to acute feeding regulation. Supportive evidence for a hormonal satiety signal has been obtained from cross-perfusion experiments and from studies in rats with transplanted and accordingly completely denervated stomachs (8, 9, 10).
The recent discovery of ghrelin in rat and human stomach (11, 12) has generated a new aspect in this context with possible implications for new treatment modalities of obesity (13).
The exogenous administration of ghrelin causes a profound stimulation of food intake in rodents and humans (12, 14, 15, 16, 17, 18). In the rat, ghrelin has been shown to induce weight gain and adiposity (12). Furthermore, it has been shown that endogenous ghrelin release is reduced after the ingestion of a meal, returning progressively back to baseline levels toward the late postprandial and interdigestive period (19). This meal-induced reduction of a hormonal gastric feeding drive would support neurally mediated satiety signals. Interestingly, the action of ghrelin on meal intake depends on vagal afferent pathways (20).
The previous studies on ghrelin release in man have already shown that the nutrient content but not the volume of a meal is responsible for the postprandial decrease of plasma ghrelin levels (12, 21, 22).
This concept for ghrelin‘s contribution to the acute regulation of postprandial satiety was based on experiments with carbohydrate-rich test meals. In recent experiments, we were able to confirm the data for carbohydrate ingestion, whereas consumption of a protein-rich meat meal increased postprandial plasma ghrelin levels (22). These findings suggest that the contribution of ghrelin to acute postprandial feeding regulation might differ depending on the predominant macronutrient content of the ingested meal. In these recent experiments, however, the respective meal size was selected rather arbitrarily, and hunger and satiety sensations were not considered. Therefore it was the aim of the present study to examine in healthy volunteers plasma ghrelin levels after the ingestion of a satiating quantity of the respective test meal, parallel to ratings of hunger and satiety. In addition to the three macronutrients, carbohydrate, fat, and protein, fruit and vegetable test meals were examined because both contain a high quantity of indigestible carbohydrate and are widely recommended as energy-poor satiating components of a meal for prevention or treatment of obesity.
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Subjects and Methods |
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Experimental design
All subjects were instructed to consume a weight-maintaining diet containing 50% carbohydrate, 20% protein, and 30% fat at least 2 wk before and throughout the study period. All were nonsmokers and were asked to refrain from alcohol consumption.
All experiments started at 0800 h after a 12-h overnight fast. An indwelling catheter was inserted into a forearm vein for collection of blood samples.
On five separate occasions, each subject received in random order one of the following test meals with at least a 2-d interval. They were asked to eat as much of the meal until feeling comfortably satiated. The quantity of food provided was at least 50% above the ingested quantities. The weight of the offered meal was determined before food intake and after satiation had been reached. The meals offered were as follows: 1) a fat-rich meal consisting of homogenized meat enriched with fat served baked (3.2 kcal/g, 0% carbohydrate, 14.5% protein, and 85.5% fat, energy percent); 2) a protein-rich meal of lean pork meat (1.5 kcal/g, 0% carbohydrate, 83% protein, and 17% fat); 3) a carbohydrate-rich meal consisting of bread (2.2 kcal/g, 79.7% carbohydrate, 12.4% protein, and 7.9% fat); 4) a mixture of freshly sliced fruits containing constant amounts of apple, kiwi, and banana (0.5 kcal/g, 93.3% carbohydrate, 6.7% protein, and 0% fat); and 5) a constant vegetable mix of tomatoes, cucumber, and carrots (0.2 kcal/g, 75% carbohydrate, 25% protein, and 0% fat). Ratings of subjective feelings of hunger and satiety were made on 100-mm visual analog scales before and in 15-min intervals after starting meal consumption as described in detail elsewhere (23, 24). After 240 min, all subjects were given a standard test meal consisting of bread, butter, and ham (2.73 kcal/g, 44.4% carbohydrate, 16.2% protein, and 39.4%fat) that they had to eat until reaching satiety. This second meal was intended to examine subsequent food intake in relation to the preceding degree of hunger and satiety feelings and preprandial plasma ghrelin levels.
Blood samples were taken at –15, 0, 15, 30, 45, 60, 90, 120, 150, 180, 210, and 240 min. After the second meal, samples were taken at 255, 270, 285, and 300 min. The samples were collected into plastic tubes containing 1.2 mg EDTA and 500 kIU Trasylol for hormone analysis and into NaF-containing tubes for the determination of glucose. All samples were kept chilled in an ice bath until centrifugation at 2000 rpm for 15 min at 4 C. The separated plasma was stored at –20 C until the time of assay. All samples of one subject were run in duplicate in the same assay.
Plasma ghrelin levels were determined with a commercial RIA that has been used in several previous studies (19, 22, 25, 26, 27, 28, 29, 30) (Phoenix Pharmaceuticals, Belmont, CA). The assay uses 125I-labeled bioactive ghrelin as a tracer molecule and a polyclonal antibody raised in rabbits against full-length octanylated human ghrelin, which detects both active and inactive ghrelin. The interassay coefficient of variation was 10%. The intraassay coefficient of variation was 4%. No cross-reactivity was observed with gastrin, somatostatin, gastrointestinal peptide, glucagon-like peptide-1(7–36)amide, neuromedin C, cholecystokinin, and insulin, respectively.
Insulin was determined using a RIA from Diagnostic Products Corp. (Los Angeles, CA). Glucose was measured by the hexokinase method (Roche Diagnostics, Mannheim, Germany).
Statistical analysis
All data are expressed as mean ± SEM. Incremental levels were calculated for the four 60-min postprandial intervals as the area under the curve according to the trapezoid rule. For statistical comparison, ANOVA for multiple determinations followed by post hoc Dunn's or Tukey's tests was used, and P values of 0.05 or less were considered to be significant. Linear regression analysis was used to determine the correlation between ghrelin values and satiety ratings, or ghrelin and insulin levels, respectively. All data were analyzed by using a commercially available statistics program (SigmaStat, Jandel GmbH, Erkrath, Germany).
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Results |
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Food and energy intake during the various test meals is summarized in Table 1
. For the three macronutrients, total energy intake was fairly similar despite certain differences in the total amount of ingested food. Total fruit and vegetable consumption until feeling satiated was much greater but because of the low-energy density, caloric intake was significantly less. Subsequent sandwich consumption 240 min after the different test meals revealed the highest intake after the preceding fruit and vegetable meal, whereas the lowest intake was observed after the fat-rich meal.
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Fat-rich meal.
In response to the fat-rich meal, plasma ghrelin concentration rose from a mean baseline of 429 ± 74 pg/ml (130 ± 22.3 pmol/liter) to a maximum of 509 ± 77 pg/ml (154 ± 23.2 pmol/liter) at 45 min (P < 0.05), decreasing thereafter toward baseline levels (Fig. 1). During the first and second hour, incremental ghrelin was significantly elevated (Table 2). There was a small but significant increase of plasma insulin levels from 0.9 ± 0.2 µU/ml (6.5 ± 1.4 pmol/liter) to a maximum of 2.0 ± 0.4 µU/ml (14.4 ± 2.9 pmol/liter) at 60 min (P < 0.05), remaining at this plateau for the ensuing 120 min. Incremental insulin levels were significantly elevated between 60 and 180 min. Plasma glucose levels decreased slightly by 5 mg/dl (0.28 mmol/liter) for the initial 180-min period of the experiment (Fig. 1). The incremental values were significantly decreased during the first three experimental hours (Table 2).
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and Table 2).
The subsequent consumption of standard sandwiches decreased plasma ghrelin moderately from 410 ± 67 pg/ml (124 ± 20.2 pmol/liter) at 240 min to 369 ± 65 pg/ml (112 ± 19.6 pmol/liter) at 300 min (P < 0.05), which was paralleled by an increase of insulin and glucose after this carbohydrate-rich meal (Fig. 1).
Protein-rich meal.
After ingestion of the protein-rich meal, plasma ghrelin levels rose from 443 ± 74 pg/ml (134 ± 22.4 pmol/liter) to a maximum of 550 ± 79 pg/ml (166 ± 23.9 pmol/liter) at 45 min (P < 0.05) and remained at 540 pg/ml (163 pmol/liter) for the next 75 min (Fig. 2). Incremental ghrelin levels were significantly elevated above baseline during the entire study period (Table 2).
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). Incremental glucose was significantly lower during the second and third experimental hour (Table 2). Hunger and satiety ratings were significantly changed during the initial 3 h (Table 2). After sandwich ingestion, ghrelin remained unchanged during 45 min and decreased thereafter significantly from 460 ± 55.6 pg/ml (139 ± 16.8 pmol/liter) at 240 min to 370 ± 48.3 pg/ml (112 ± 14.6 pmol/liter) at 300 min (P < 0.05) (Fig. 2).
Bread.
After the intake of bread, plasma ghrelin levels fell from a baseline of 456 ± 64 pg/ml (138 ± 19.3 pmol/liter) to a minimum of 312 ± 40 pg/ml (94.3 ± 12.1 pmol/liter) at 150 min (P < 0.05), remaining below baseline levels until 240 min (Fig. 3). The incremental ghrelin levels were significantly below baseline between 60 and 240 min (Table 2). Insulin levels rose from a baseline of 0.8 ± 0.2 µU/ml (5.7 ± 1.4 pmol/liter) to a maximum of 52.9 ± 7.4 µU/ml (380 ± 53.1 pmol/liter) at 45 min (P < 0.05) and remained above baseline until 240 min (Table 2 and Fig. 3). Plasma glucose levels were significantly elevated during the first postprandial hour (Fig. 3 and Table 2). Hunger and satiety feelings changed significantly from baseline during the first 3 h after meal ingestion (Table 2).
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). Glucose levels did not change from the level of 90 ± 3.7 mg/dl (5 ± 0.2 mmol/liter) within the first 15 min, increasing slightly thereafter to 94 ± 3.6 mg/dl (5.2 ± 0.2 mmol/liter) at 270 min (Fig. 3). Insulin levels, however, increased from 16 ± 3.0 µU/ml (115 ± 21.5 pmol/liter) at 240 min to a maximum of 41 ± 5.1 µU/ml (294 ± 36.6 pmol/liter) (P < 0.05) at 285 min (Fig. 3).
Fruit.
Fruit intake led to a reduction of basal ghrelin levels from 458 ± 68.9 pg/ml (138 ± 20.8 pmol/liter) to a nadir of 363 ± 52 pg/ml (110 ± 15.7 pmol/liter) at 45 and 60 min (P < 0.05) followed by a steady increase to 522 ± 68.4 pg/ml (158 ± 21.7 pmol/liter) at 240 min (Fig. 4). Incremental plasma ghrelin levels were below baseline during the first 120 min, which, however, did not reach statistical significance. During the fourth experimental hour, incremental ghrelin was significantly elevated (Table 2). Insulin levels rose from 0.8 ± 0.3 µU/ml (5.7 ± 2.1 pmol/liter) to a maximum of 42 ± 8.6 µU/ml (302 ± 61.7 pmol/liter) at 45 min (P < 0.05), returning thereafter rapidly to baseline. Plasma glucose levels increased from 85 ± 2.5 mg/dl (4.7 ± 2.5 mmol/liter) to 111 ± 4.4 mg/dl (6.2 ± 0.24 mmol/liter) and 109 ± 5.0 mg/dl (6.1 ± 0.27 mmol/liter) at 30 and 60 min (P < 0.05), respectively, and were below baseline between 90 and 240 min (Fig. 4 and Table 2). Significant changes of hunger and satiety were observed during the initial 3 h (Table 2).
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Vegetable.
After the ingestion of vegetables, plasma ghrelin levels increased steadily from a baseline of 414 ± 58.3 pg/ml (125 ± 17.6 pmol/liter) to a maximum of 560 ± 84.5 pg/ml (169 ± 25.5 pmol/liter) at 150 min (P < 0.05) and remained at an elevated level of around 530 pg/ml (160 pmol/liter) until 240 min (Fig. 5). Incremental ghrelin levels were significantly elevated from the baseline period during the entire study period (Table 2). Insulin rose within 45 min from 1.3 ± 0.35 µU/ml (9.3 ± 2.5 pmol/liter) to a maximum of 13.2 ± 2.3 µU/ml (94.8 ± 16.5 pmol/liter) returning rapidly to baseline levels at 120 min (Fig. 5). Plasma glucose levels decreased from a baseline of 88 ± 3.5 mg/dl (4.9 ± 0.19 mmol/liter) to 76 ± 1.9 mg/dl (4.2 ± 0.1 mmol/liter) at 90 min, remaining thereafter at 82 mg/dl (4.6 mmol/liter) until 240 min (Fig. 5). Incremental glucose was significantly decreased between 60 and 180 min (Table 2).
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). Sandwich ingestion resulted in a prompt decrease of ghrelin from 521 ± 65.9 pg/ml (157 ± 19.9 pmol/liter) to 373 ± 44.2 pg/ml (113 ± 13.4 pmol/liter) at 300 min (P < 0.05) paralleled by a rapid increase of insulin to 52 ± 7.1 µU/ml (373 ± 50.9 pmol/liter) at 285 min (Fig. 5). |
Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In contrast, the two other macronutrients, fat and protein, had a stimulatory and not an inhibitory effect on plasma ghrelin levels, which implies an augmented feeding drive during these meals. On the other hand, the time course and magnitude of hunger and satiety ratings during the fat and protein meal were not substantially different from those observed after the carbohydrate-rich meal. With regard to the total amount of food consumed during these three meals, the greater quantity of ingested protein-rich meat could have been a result of increased ghrelin. On the other hand, it must be noted that a similar increase of ghrelin was observed during the fat-rich meal, which, however, was associated with a much lower food quantity.
After fruit ingestion, the initial although not significant decrease of ghrelin levels could support early postprandial satiety, although the total amount of ingested fruit was substantially greater, especially when compared with bread ingestion, which led to a comparable first-hour reduction of ghrelin levels. The volume of the ingested meals is rather unlikely to have an effect on plasma ghrelin levels in view of the previously reported gastric distension experiments (12, 21, 22).
Despite a greater first-hour increase of ghrelin levels during the vegetable meal compared with the fruit meal, the ingested quantities were very similar. Hunger and satiety ratings after fruit and vegetable were also not substantially different from the other test meals except that during the fourth hour after vegetable ingestion high ghrelin levels were associated with an already positive hunger rating whereas satiety was completely abolished.
Considering all five meals, there is apparently no strong relationship between the changes of early postprandial plasma ghrelin levels and hunger and satiety scores. Because food consumption is terminated within the initial 30 min, the divergence of plasma ghrelin levels would argue against a role as an important common denominator of the feeding drive. This is supported by a linear regression analysis considering the hourly determined incremental ghrelin values on the one hand and the respective incremental hunger and satiety scores on the other hand (r = 0.05; not significant)
In view of these data, one could argue that the originally proposed role of ghrelin in the regulation of feeding behavior is true for carbohydrate-rich test meals, but it is rather irrelevant during ingestion of fat, protein, and vegetable meals. However, it must be kept in mind that endogenous ghrelin contributes to food intake (31). And in analogy to other modulatory endocrine factors of nutrient homeostasis in the gastrointestinal tract such as somatostatin (32), the amount of ingested meat and vegetable might have been substantially less in the absence of increasing ghrelin levels. The answer to this question has to await the development of ghrelin receptor antagonists that can be used in human studies.
With regard to the second meal consisting of standardized sandwiches, the greater food intake observed after the preceding fruit and vegetable meals in comparison with the other three test meals could at least in part be due to the significant elevation of ghrelin levels during the preceding preprandial fourth experimental hour. The correlation between fourth-hour ghrelin levels and subsequently ingested amount of sandwiches was highly significant (r = 0.44; P < 0.001), which supports the previously suggested concept of preprandial ghrelin and subsequent food intake (19).
The initial studies of ghrelin release with carbohydrate-rich test meals have shown that the decrease of plasma ghrelin levels is paralleled by an increase of plasma insulin (19, 21, 33). Supportive evidence for an inhibitory role of insulin on ghrelin secretion has been obtained in three studies (26, 27, 34), whereas two other showed no effect (35, 36). In vitro in the isolated perfused rat stomach, insulin and also the intestinal insulin stimulating hormone glucagon-like peptide-1(7–)amide are potent inhibitors of ghrelin secretion, and in rats in vivo streptozotocin-induced diabetes is associated with increased ghrelin levels (37, 38), further supporting such an inverse relationship.
The present data demonstrate that an increase of ghrelin levels is associated with only a small or moderate increase of plasma insulin levels as observed during the fat- and protein-rich meat meals, whereas the greater rise of insulin and glucose after bread ingestion is clearly associated with an inhibition of ghrelin. During fruit and vegetable ingestion, there is an inverse relationship between the two hormones in the course of the 4-h experimental period. A linear regression analysis of the hourly incremental insulin and ghrelin levels showed a significant inverse correlation (r = –0.434; P < 0.001).
With regard to the ghrelin response after the sandwich meal, ghrelin fell more rapidly in the fruit and vegetable arm compared with the other preceding meals. One possible reason could be the more rapid and greater rise of insulin in these two feeding modalities.
These data support an inhibitory role of insulin on ghrelin release that might require a certain threshold concentration of insulin and/or glucose to become effective. This would have to be determined in careful dose-response studies with small stepwise increasing insulin infusion rates.
Apart from the relationship between insulin and ghrelin levels, it is noteworthy that the increase of plasma ghrelin levels is associated with a small decrease of plasma glucose concentrations.
It is conceivable that meal ingestion primarily stimulates gastric ghrelin secretion, and only when sufficient amounts of carbohydrate are ingested and absorbed leading to both elevated plasma glucose and insulin levels is ghrelin subsequently suppressed. In the absence of hyperglycemia, the rise of ghrelin could contribute to an attenuation of postprandial insulin release, which is supported by several studies (39, 40, 41).
Thus, ghrelin could be a gastric hormone that contributes to the regulation of nutrient homeostasis not only via its effect on feeding behavior but also by modulating insulin release.
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Acknowledgments |
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Received September 16, 2003.
Accepted March 1, 2004.
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