Eur J Nutr (2014) 53:723–729 DOI 10.1007/s00394-013-0576-9
ORIGINAL CONTRIBUTION
The effect of submicron fat droplets in a drink on satiety, food intake, and cholecystokinin in healthy volunteers Harry P. F. Peters • Elisabeth C. M. Bouwens Ewoud A. H. Schuring • Edward Haddeman • Krassimir P. Velikov • Sergey M. Melnikov
•
Received: 27 May 2013 / Accepted: 2 August 2013 / Published online: 23 August 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose Small fat droplets infused into the gut reduce food intake and hunger more than bigger ones, at levels as low as 6 g, and these effects are hypothesized to occur via satiety hormones such as cholecystokinin. It is, however, unknown whether the effect of droplet size would persist after oral consumption. It is also unknown whether an even smaller droplet size can affect hunger and food intake and at what minimum amount of fat. Therefore, the aim of the study was to test the effect of very fine fat droplets on satiety and food intake in two different quantities. Methods In a balanced-order 4-way crossover design, 24 volunteers consumed a fat-free meal replacement drink with either 5 or 9 g oil (rapeseed) and either 3 or 0.1 lm droplet size. Appetite scores and plasma cholecystokinin levels (in n = 12 subset) were measured for 180 min, when food intake was assessed during an ad libitum meal. Data were analyzed by ANCOVA, followed by Dunnett’s test and paired t test. The behavior of the emulsions was also characterized in a simulated gastrointestinal model. Results Despite faster in vitro lipolysis of the smallest droplets, neither droplet size nor fat amount affected satiety or food intake. From t = 45–150 min, cholecystokinin response was 50 % higher (P \ 0.05) after the 0.1 versus 3 lm, but only with 9 g fat. Conclusion When this particular fat at these amounts is delivered in a meal replacement drink, droplet size does
H. P. F. Peters (&) E. C. M. Bouwens E. A. H. Schuring E. Haddeman K. P. Velikov S. M. Melnikov Unilever Research and Development Vlaardingen, Olivier Van Noortlaan 120, P.O. Box 114, 3130 AC Vlaardingen, The Netherlands e-mail:
[email protected]
not influence appetite or food intake. This effect is independent of the amount of fat or plasma cholecystokinin changes. Keywords Satiety Food intake Cholecystokinin Lipids Droplet size
Introduction Several gastrointestinal (GI) processes affect satiety such as gastric distension, gastric emptying, digestion, and absorption [1]. All these processes are influenced by the physicochemical properties of the nutrients within a meal. The rate of fat digestion partly depends on the chemical structure of fat molecules, fat droplet size, as well as surface properties of fat particles [2]. Lipid droplet size, which determines the total surface area available for enzyme activity, is one of the key parameters that affect lipase activity during lipid digestion [2, 3]. Emulsions with different droplet sizes are digested and thus metabolized differently [4, 5]. All these results indicate possible control of the rate of lipid digestion and satiety through the control of particle size and its associated surface properties. Indeed, Seimon et al. [6] showed that a smaller fat droplet size reduced hunger, but not food intake, in a study using 37 g of fat, and this was associated with increased levels of cholecystokinin (CCK) and peptide YY (PYY), the two important satiety hormones [7]. We have shown recently [8] that duodenal delivery of 6 g of fine fat droplets (about 1 lm) within the context of a meal replacer reduced hunger compared to coarse ones, however, without concomitant changes in CCK or PYY and only a borderline significant decrease in food intake [9]. Even smaller droplets might further enhance this effect.
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In both studies, fat was delivered to the duodenum via intubation. As some studies [4, 5] suggest that fat droplet size distribution changes due to the change in pH and ionic strength, mixing in the stomach and the gastric and pancreatic lipases, it is unknown whether the droplet size effects would persist after oral consumption. It is also unknown if an even smaller droplet size can affect hunger and food intake and at what minimum amount of fat. In a very recent study [10], we have shown that infusion of 6 g of lipids into the small intestine is able to reduce hunger and food intake, whereby food intake was only reduced when fat was delivered to the ileum. We hypothesize that an even smaller droplet, leading to an even larger surface area, would lead to even faster digestion and a burst of free fatty acids at the upper part of the small intestine, and this in turn would increase plasma CCK and satiety. Although we have shown that these small amounts of lipids delivered directly into the small intestine affect ingestive behavior, practical applicability of these small droplets would be much greater when they can be ingested orally. Therefore, the primary objective of this study was to compare the effect of fat droplet size (3 vs. 0.1 lm) of different amounts of fat (5 vs. 9 g) in a meal replacer on satiety and food intake. The secondary objective was to compare the effect of fat droplet size of different amounts of fat on plasma CCK.
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Study design In a fully randomized, four-way, double-blind crossover design, 24 healthy normal-to-overweight volunteers were investigated on four test days. On each test day, subjects consumed, instead of breakfast, 325 ml of 1. 2. 3. 4.
Fat-free Fat-free Fat-free Fat-free
drink drink drink drink
? ? ? ?
5 9 5 9
g g g g
fat, fat, fat, fat,
droplet droplet droplet droplet
size size size size
3 lm (control). 3 lm. 0.1 lm. 0.1 lm.
As blood sampling might interfere with the satiety measurements, two separate groups were tested. One group of 12 subjects was not involved with blood sampling, while in the other group of 12 subjects, blood sampling was performed (although also in this group, satiety was measured). The amount of fat used in the present study was based on the use of meal replacers that regularly contain 6 g fat per portion and has been shown to induce satiety, at least when infused directly into the small intestine [8, 10]. Instructions to volunteers on background diet, physical activity, and dietary restrictions prior to and during the test day and recording of body weight, sleeping time, mode of transportation, menstrual cycle, and incidental lifestyle changes were identical to the previous studies (e.g., [13]). Test products and emulsions
Experimental methods Subjects The volunteers were recruited from Vlaardingen, The Netherlands, and surroundings. Selection criteria were as follows: age 18–60 years, body mass index (BMI, kg/m2) C 21 and B 30.0, apparently healthy (measured by questionnaire) and not using medicines judged likely to influence the study results. Restrained eaters (as assessed by the Dutch Eating Behavior Questionnaire [11]), subjects who reported that they were following either a weightreduction diet or a medically prescribed diet and subjects with tendencies toward diagnosable eating disorders (anorexia nervosa or bulimia), were excluded from participation [12]. Twenty-four volunteers (16 female) completed the protocol. Their mean age was 45.6 (range 20–59) years, and their mean BMI was 24.3 (range 20.8–30.1) kg/m2. This study was conducted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from each individual, and the study protocol was approved by the Medical Ethics Committee at Wageningen University, The Netherlands.
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All treatments consisted of the consumption of a fat-free meal replacer (Slim-Fast Optima Ready-To-Drink chocolate shake, 606 kJ, 10 g protein, 20 g carb, 0 g fat, vitamin/ mineral mix; Unilever, Englewood Cliffs, NJ) to which one out of two emulsions (3 or 0.1 lm) was added manually in different quantities (to obtain 5 or 9 g fat). To accommodate the emulsions and obtain a final volume of 325 ml, the fat-free meal replacement drink contained less water as usual. The composition of the emulsion was identical for the emulsions, and only the droplet size differed. Emulsions were prepared from Canola oil (10 %; high-oleic rapeseed oil) stabilized with polysorbate (Tween 80, 1 %) with intended average diameters of D *0.1 lm (submicron or colloidal emulsion) and D *3 lm (control emulsion). The choice of emulsions stabilizer was based on in vitro experiments (see also below). In vitro characterization of the fat droplets To unravel the effect of droplet size on the extent and rate of gastric and intestinal lipolysis, the emulsions were tested in vitro. This was tested in standard USP dissolution systems and the pH stat.
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For the in vitro experiment, first gastric conditions were applied (incubation of meal replacer with 1 mg/ml R. oryzae lipase pH 6 (from Fluka) for a given time, followed by incubation with 1 mg/ml pepsin at pH 2 (by adjustment with HCl) total gastric time 60 min at 37 °C). After the gastric phase was ended, the pH was adjusted to pH 7.5 for the intestinal conditions and 9 mm bile (from bovine, Sigma USA) was added. The hydrolysis was measured by pH stat during 120 min at pH 7.5 at 37 °C, starting with the addition of pancreatin from porcine pancreas (1 mg/ml, Sigma, P8096) and using 0.1 M NaOH as the titrant. Droplet size was measured before and after the gastric phase using MasterSizer 2000 and Zetasizer Nano ZS (both from Malvern Instr., Malvern, UK). Satiety and food intake Volunteers arrived in the lab at 8.45 in the morning, and at 9.00 h, they received the test products. They were allowed to consume the test food within a maximum of 15 min. Meal duration was recorded. Immediately after, they filled in a post-consumption evaluation with ratings of taste and liking. The volunteers rated their feelings of hunger, satiety, appetite for a meal, fullness, and appetite for a snack by means of a mark on 64-mm line scales using a EVAS (Electronic Visual Analogue Scale, iPAQ) [14]. This scale was anchored at the low end with the most negative or lowest intensity feelings (e.g., ‘‘not at all’’), and with opposing terms at the high end (e.g., ‘‘very high’’) as described by Flint et al. [15]. Subjects’ self-assessments of feelings of hunger/satiety were measured using EVAS every half hour from 09.00 to 14.00 h. Energy intake was measured 180 min (at 12.00 h) after consumption of the meal replacement drink by providing an ad libitum meal consisting of a single dish in very large quantities. Lunch consisted of 1,250 g macaroni Bolognese (per 100 g 439 kJ, 4 g protein, 5 g fat, 9 g carbohydrates). Food intake from this meal was calculated from the difference in the weight of food offered and that remaining. CCK analysis CCK levels were sampled in plasma from 12 out of 24 subjects before ingestion of the meal replacer drink using an intravenous cannula. Blood was obtained at 15-min intervals during the first 90 min, and at 30-min intervals during the remainder of the second, third, and fourth hour after ingestion. For blood sampling, a flexible intravenous cannula was inserted into an antecubital vein of one arm 15 min before blood sampling on each test day. Blood was collected in
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ice-chilled vacutainers containing EDTA. After the last sample was taken, the tubes were centrifuged (3,000 rpm, 15 min at 4 °C). The supernatant plasma was stored at –70 °C until determination. Plasma CCK was measured by radioimmunoassay [16]. The detection limit of the assay is 0.3 pM. The intra-assay variation ranges from 4.6 to 11.5 %, and the inter-assay variation from 11.3 to 26.1 % [16]. Gastrointestinal symptoms Gastrointestinal disturbances (nausea, abdominal pain, bloating, heartburn, and abdominal cramps) and general symptoms (headache, malaise, dizziness, and fatigue) were scored just before breakfast consumption and every 2 h thereafter (from 09.00 h to 14.00 h) on a 4-point scale (0 = not, 1 = mild, 2 = moderate, 3 = severe) using EVAS. Statistical analysis Results are presented as least-squares means (LSmeans) with standard error (SE), unless otherwise specified. Satiety VAS scores were expressed as percentages of the maximal score (0 cm equaled to 0 and 64 mm equaled to 100 %) and as cumulative areas under the curve (AUC). The AUC was calculated using the trapezoid rule. The data were analyzed using analysis of covariance (ANCOVA) with subjects as blocks and droplet size (3 and 0.1 lm) and fat quantity (5 and 9 g) as factors and baseline values (before consumption) as covariates (where appropriate). Differences compared to the control group (5 g and 3 lm) were established using Dunnett’s test. A paired t test was used to compare the AUC of 9 g 3 micron to the 9 g 0.1 micron and to compare the AUC of 5 g 3 micron to 5 g 0.1 micron. A P value \ 0.05 (one-sided) was considered significant. The analysis was done per time point and per AUC. The analysis was done in SAS v9.3 using PROC MIXED. In earlier studies, a within-subject variance of about 85 mm/min for AUC was found. Based on this variance, a confidence limit of 0.05 and a power of 0.8, 18 subjects were required for this experiment. To prevent the presence of period*treatment effect, and to correct for period effects, the experiment design was completely balanced and randomized using a Williams design, which balances the treatments and treatment orders over the periods and subjects. GI disturbances were analyzed using frequency of occurrence per time point and a standard ANOVA with the personal scores corrected for each subject’s overall mean score.
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Results In vitro Figure 1 shows the combined results for the gastric and intestinal phase. After in vitro gastric conditions of the 0.1 lm emulsion, a high amount of fat was hydrolyzed, while lipolysis of the 3.0 lm emulsion after the gastric conditions was very low. As in gastric phase, the rate of lipid digestion of the 0.1 um emulsion was faster during the intestinal phase. The pancreatic lipase was hydrolyzed about 90 % of the lipid within 60 min for submicron emulsion and * 60 % of the bigger sized emulsions. However, it is unknown to what extent the lipase concentration used in this experiment really reflects in vivo conditions. Several papers suggest that the lipase in vivo concentrations is at least 100 times higher than needed for lipolysis of 50 to 100 grams of fat [17, 18]. For the 6 to 9 g of fat used in the current study, excess lipase might be even higher. The intestinal lipolysis of the product containing the emulsions was performed at 30 mg pancreatin (the commonly used amount of pancreatin in these types of in vitro experiments [4, 19]). The results for both gastric and intestinal phase clearly indicate that the finer emulsion is digested faster. The experiments indicated that at very high lipase concentrations (when the surface area to bind lipase is the rate-limiting factor), lipolysis rate of the submicron emulsion is considerably faster during the first 10 min (data not shown). Before gastric conditions, the surface-weighted mean diameter D [3.2] was 3.03 and 0.12 lm for the regular and ultrafine emulsion, respectively, implying a 25 times larger surface area for the small droplets. The volume-weighted
Fig. 1 In vitro lipolysis rate of 0.1 and 3.0 lm 1 % o/w emulsions during simulated gastric and intestinal phase. % lipolysis is defined as % released FFA from total TAG in the emulsion (when 2 FFA are released from 1 TAG). The first hour represents the gastric phase, while the second and third hour represents the intestinal phase
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droplet size D [4.3] was 5.4 and 0.15 for the regular and ultrafine emulsion, respectively. After gastric conditions, the D [3.2] was 5.0 and 0.16 lm, respectively, implying a 31 times larger surface area for the small droplets, and the D [4.3] was 100.1 and 0.37 lm, respectively. It can therefore be concluded that droplet size slightly increased after gastric conditions for both emulsions (by 40 and 27 % for regular and ultrafine emulsions, respectively), while the droplet surface area of the regular emulsion versus submicron emulsion increased too, from 25 to 31. In vivo Palatability of treatments was not statistically significantly different between treatments (data not shown). Satiety results from ANCOVA are shown as absolute values. As the other appetite scores show comparable changes, only scores for hunger are shown (see Fig. 2). AUC of hunger did not differ between treatments (data not shown). Neither fat droplet size nor fat content affected any of the appetite measures. Neither fat droplet size nor fat content affected meal intake during the ad libitum meal (667, 626, 653, and 653 g (SE 47) for the 5 g 3 lm, 9 g 3 lm, 5 g 0.1 lm, and 9 g 0.1 lm treatments, respectively). Visual inspection of the data revealed that plasma CCK peaked after consumption of the drink and decreased again after about 30 min (Fig. 3). However, CCK rose again after about 45 min. CCK level was significantly higher 15 min after consumption of the fat-free drink with 9 g 3 lm fat as compared to 5 g 3 lm fat. The 9 g 0.1 lm fat nor the 5 g 0.1 lm was significantly different from the 5 g 3 lm fat. At 60 min, CCK level was significantly higher for the 9 g 0.1 lm fat (P \ 0.0001) and for the 9 g 3 lm fat (P = 0.005) as compared to the 5 g 3 lm fat. A paired t test showed that the AUC of the CCK response was significantly higher for 0.1 lm fat as compared to 3 lm fat
Fig. 2 Hunger ratings (in mm; LSmeans; n = 24) after consumption of a fat-free meal replacement drink with addition of different amounts of fat (5 g vs. 9 g) varying in droplet size (3 vs. 0.1 lm). For visibility reasons, SE only shown for two treatments
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Fig. 3 Mean plasma CCK concentrations (in pM; LSmeans; n = 11) after consumption of a fat-free meal replacement drink with addition of different amounts of fat (5 g vs. 9 g) varying in droplet size (3 vs. 0.1 lm). For visibility reasons, SE only shown for two treatments CCK level was significantly higher 15 min after consumption of the fat-free drink with 9 g 3 lm fat as compared to 5 g 3 lm fat. The 9 g 0.1 lm fat nor the 5 g 0.1 lm was significantly different from the 5 g 3 lm fat. At 60 min, CCK level was significantly higher for the 9 g 0.1 lm fat (P \ 0.0001) and for the 9 g 3.0 lm fat (P = 0.005) as compared to the 5 g 3 lm fat. AUC of the CCK response was significantly higher for 0.1 lm fat as compared to 3 lm fat when 9 g fat was consumed during t = 45–150 min (P = 0.02), but not when 5 g was consumed
when 9 g fat was consumed during t = 45–150 min (difference 90, SE = 36, P = 0.02), but not when 5 g fat was consumed (difference 31, SE = 31, P = 0.33). Although there were occasional symptoms, most of them were rated ‘‘mild,’’ and some were rated ‘‘moderate’’. Gastrointestinal complaints and general symptoms were not significantly different from control.
Discussion This study clearly indicates that reduction in droplet size from 3 to 0.1 lm, which resulted in a faster rate of in vitro lipolysis and faster release of fatty acids, did not reduce appetite or food intake when droplets were delivered orally within a drink. This was independent of the amount of fat studied. The amount of fat used in the present study was based on the use of meal replacers that regularly contain 6 g fat per portion and has been shown to induce satiety, at least when infused directly into the small intestine [8, 10]. Droplet size affected plasma CCK modestly during the two hours after drink consumption only in 9 g fat. Lipid droplet size is one of the key parameters that affect lipase activity during lipid digestion, most likely via an increased surface area available for the human enzymes to catalyze fat digestion process at the oil–water interface [2, 3]. Emulsions with different droplet sizes are digested and metabolized differently [4, 5]. These results suggested that the rate and extent of lipid digestion (via the control of droplet size and its associated surface properties) could
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affect satiety as well. Indeed, we [8] and others [6] have shown that a smaller fat droplet size, when infused into the duodenum 30 min after consumption of a meal replacer, reduced hunger. We hypothesized that an even smaller droplet, leading to an even larger surface area, would lead to even faster digestion and a burst of free fatty acids at the upper part of the small intestine, and this in turn would increase plasma CCK and satiety [7], but this did not occur. This could be rationalized in several ways, namely that a rapid digestion of lipids is not a sufficient physiological trigger for satiety and release of CCK; the effect is too small and overwhelmed by the background effect of other nutrients in the accompanying drink: it is only effective for satiation (feelings within a meal) and not for satiety (feelings in between meals); the effective physiological response to fat digestion is more likely in the lower part of the small intestine (the ileum) and not in the stomach or upper part of the small intestine, or the very small droplets become unstable and increase in size when passing through mouth and stomach and entering into the duodenum. Indeed, our in vitro experiments showed a faster lipolysis of the smaller droplets. As expected, the extent was related to the amount of lipase present, and part of the effect was already apparent in the stomach and not in the small intestine. We also found an increase in CCK, but this increase was modest when compared to other studies investigating CCK changes after nutritional interventions, while CCK is not always linked to satiety (e.g., [20–25]). Furthermore, this increase was only apparent during the 9 g fat and not during the 5 g fat. In our own research [8], small droplets delivered directly into the duodenum increased satiety by about 10 %, but apparently the surface area/lipase effect was not strong enough in the current study setup. The in vivo lipolysis is a complex process, and other parameters such as concentration and type of stabilizer, protein or mineral content, and type of fatty acids might have been important for the physiological response. The change in lipolysis rate may have been too small to give effective difference between the two sizes. It is difficult (but possible) to further increase the rate of lipid digestion by further decreasing the fat droplet size using co-solvent removal [26]. Another plausible explanation is that there is a small effect, but this is overwhelmed by the background effect of the meal replacement drink, e.g. protein and fiber. The effect of the fat droplets was based on a previous study where we tested it in the context of a meal replacer. A study without this drink might have shown effects of these small droplets. Finally, it is possible that we are still far below the fat concentration threshold for satiety. We found a modest, although statistically significant, effect of small droplets in the 9 g treatment on CCK. It is
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possible that we did not find an effect on satiety because CCK is primarily effective for satiation and not for satiety [7]. This is explained by the fact that CCK triggers satiety much more when during the nutritional intervention, the stomach is distended [27, 28], even though the distension itself does not increase CCK [27, 28]. A drink with 9 g of fat given just before a meal might give a more pronounced effect on subsequent food intake. Another possible reason for the absence of a satiety effect is the location of fat delivery. We have shown that by using intubation, delivery of 6 g fat to the duodenum increased satiety, but not CCK, while delivery to the ileum did not increase satiety, but did decrease food intake and increased CCK [9]. The difference in that study might be related to the timing of infusion. The duodenal infusion started 30 min after the oral ingestion of a fat-free meal replacement drink, and the effect was then associated with gastric distension. The ileal infusion started 105 min after the oral ingestion of the fat-free meal replacement drink, and at that moment, most of the drink had already left the stomach. At that moment, there was no effect of gastric distension, but also the background satiety effect of the drink had disappeared. Another clear difference between the current and previous study is the amount of lipolysis in the stomach. In the current study, part of the fat was already hydrolyzed in the stomach. Although it has been hypothesized that gastric lipolysis facilitates intestinal lipolysis [29], it is unknown how the rate of gastric lipolysis affects satiety. The final explanation for the absence of a satiety/food intake effect is the change in droplet size in the GI tract. Although the in vitro experiments showed only minor changes in droplet size in the stomach, it is possible that in vivo the 0.1 lm droplets, despite their small original size, increased significantly in size in the stomach and duodenum. This hypothesis is based on work from Armand et al. [4]. However, we used much smaller droplets (0.1 lm) and another emulsifier, and these two parameters should make the droplet even more stable against coalescence [26, 30]. Nevertheless, it is possible that the gastric motility, which is difficult to mimic in vitro, changed the droplet size in vivo, resulting in fat droplets of similar size. In conclusion, we have demonstrated that droplet size of fat droplets delivered orally, at least at rapeseed oil levels up to 9 g, did not influence appetite or food intake, independent of plasma cholecystokinin changes. Acknowledgments We thank Henk Husken from Unilever R & D Vlaardingen for assistance in preparing the emulsions. This study was funded by Unilever R & D, Vlaardingen, The Netherlands. All authors are employees of Unilever R & D, Vlaardingen, The Netherlands. None of the authors had a personal or financial conflict of interest.
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