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Am J Physiol Regul Integr Comp Physiol 290: R208-R218, 2006. First published August 11, 2005; doi:10.1152/ajpregu.00379.2005
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APPETITE, OBESITY, DIGESTION, AND METABOLISM

Independent ingestion and microstructure of feeding patterns in infant rats lacking CCK-1 receptors

S. Blumberg,1 D. Haba,1 M. Schroeder,1 G. P. Smith,2 and A. Weller1

1Developmental Psychobiology Laboratory, Department of Psychology and the Gonda (Goldschmeid) Brain Research Center, Bar Ilan University, Ramat-Gan, Israel; and 2Department of Psychiatry, Joan and Sanford I. Weill Medical College of Cornell University and New York-Presbyterian Hospital, Westchester Division, White Plains, New York

Submitted 31 May 2005 ; accepted in final form 26 July 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Otsuka Long-Evans Tokushima fatty (OLETF) rats are a strain of Long-Evans Tokushima Otsuka (LETO) rats that do not express CCK-1 receptors, developing in adulthood, hyperphagia, obesity, and non-insulin-dependent diabetes mellitus (NIDDM). We examined weight gain and meal patterns during a 30-min independent ingestion test on postnatal days 2–4 and again on days 9–11 in OLETF and LETO rat pups. OLETF pups were significantly heavier compared with their LETO controls at both ages, and they consumed significantly more of the sweet milk diet. The difference in intake can be attributed to a significant increase in meal size and duration. Number of clusters and bursts of licking within a meal were greater in OLETF rat pups, with no difference between strains in burst and cluster size. Interlick interval (ILI) was not significantly different between OLETF and LETO pups. This measure decreased on days 9–11 compared with days 2–4 in both strains. Latency to start feeding was significantly shorter on days 2–4 in OLETF vs. LETO pups, but this difference disappeared at the second test at the older age. Two- to four-day-old OLETF pups consumed a larger volume of milk during the first minute of feeding, and their initial lick rate and decay of lick rate were significantly larger compared with their LETO controls. Lack of CCK-1 receptors, or other OLETF-related abnormalities, therefore, resulted in a satiation deficit, leading to increased meal size, hyperphagia, and increased weight gain as early as 2–4 postnatal days.

cholecystokinin; obesity; independent ingestion; meal-patterns; Otsuka Long-Evans Tokushima fatty rats; infant rats

THE BRAIN-GUT PEPTIDE CHOLECYSTOKININ (CCK) has been demonstrated to reduce food intake in a dose-related manner in different species and experimental designs (3, 29, 35). Entry of food into the intestine triggers the release of endogenous CCK by the intestinal mucosa, thereby activating CCK-1 receptors located in the periphery to transmit through the vagus nerve a neural signal to the brain, which subsequently terminates feeding and initiates the sequence of behaviors associated with satiety (4, 60).

CCK was found to reduce meal size and duration (29, 38) and to induce an earlier appearance of behavioral satiety. The satiety produced by endogenous or exogenous administration of the peptide is mediated via interaction with CCK-1 receptors rather than CCK-2 receptors (5, 44). CCK-1 receptors are abundant in peripheral organs and in a few discrete brain regions (33, 45).

Exogenous and endogenous CCK, through receptors of CCK-1, have been shown to reduce feeding in newborn and infant rats independently ingesting their first meal away from the dam (53, 61, 68). Furthermore, CCK-1 receptors appear to mediate a portion of the reduction of intake produced by a preload of corn oil (but not by mineral oil, glucose, 2-deoxy-D-glucose, maltose, or peptone) in infant rats (66–69). These findings suggest that the CCK system can function selectively at a preweanling age, mediating the emerging feeding-regulatory system.

Otsuka Long-Evans Tokushima fatty (OLETF) rats are a strain of Long-Evans rats demonstrated to lack any production or expression of functional CCK-1 receptors in pancreas or brain, as a result of a congenital lack of a 6-kb segment including the promoter region of the gene encoding the CCK-1 receptor (63). The OLETF rat has been used as a model for examining physiological and behavioral roles of CCK. Adult OLETF rats are hyperphagic, become obese, and develop non-insulin-dependent diabetes mellitus (NIDDM) at ~18 wk of age (35), which later converts to insulin-dependent diabetes mellitus after 65 wk of age. Moran et al. (47) examined body weights of OLETF and Long-Evans Tokushima Otsuka (LETO) rats from the age of 6 wk onwards and reported a significantly heavier weight of the OLETF rats starting at 9 wk of age. Moran et al. (47) also characterized the microstructure of 30-min glucose intake, reporting an increased volume of intake by the OLETF rats, characterized by an increased number of licks in the OLETF compared with the LETO rats. They also found that OLETF rats maintained a higher initial licking rate, which declined slower than in the LETO. Analysis of licking behavior of an Ensure diet through the first 6-h period of the dark cycle further revealed that mean burst number was significantly different between the LETO and OLETF rats, but burst size, cluster size, and cluster number were not. Spontaneous food intake of chow pellets revealed that total daily intake, or intake in both the dark and the light cycle, was significantly greater in OLETF than in LETO rats. That increase was a result of a significant increase in meal size. The increase in meal size in OLETF rats lacking CCK-1 receptors resembles similar results after administration of a CCK-1 receptor antagonist in lean Zucker mice (62) and in Rhesus monkeys (46).

The aim of the current study was to characterize differences in body weight, intake, and patterns of feeding episodes as early as postnatal days 2–4 and 9–11 in OLETF and LETO rat pups.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Subjects. Fifteen pregnant female OLETF and 15 LETO control rats were obtained as a generous gift from Tokushima Research Institute, Otsuka Pharmaceutical, Tokushima, Japan. Females were housed separately. Pups were born to 10 OLETF and 14 LETO dams and were kept in polycarbonate cages with stainless steel wire lids and with wood shavings as bedding material. Lights were on from 0500 to 1900, and temperature was maintained between 21 and 25°C. Chow and water were continuously available in the top of the cage. No more than two siblings from a litter were allocated for this experiment. Subjects were studied on postnatal days 2–4 and again a week later. Seventeen OLETF and 21 LETO pups were studied from all the participating litters. Data were available for analysis from the first week for 15 OLETF pups (for technical reasons, 2 pups that ate the test meal were not observed) and for all 21 LETO controls. In the second week, data were collected from all 17 OLETF pups and from 14 LETO controls (a sibling was selected randomly from all 14 participating LETO litters; the remaining controls were not included because of technical limitations). The research was approved by the Institutional Animal Care and Use Committee and adhered to the ethical guidelines of the American Physiological Society and the Society for Neuroscience.

Test procedure. Four pups from each litter were separated from nest and dam and were placed in a small container in a humid and warm (33°C) incubator. After 3 h, two pups from each litter were marked and then weighed with a Mettler precision scale accurate to 0.01 g, averaging body weight over 9 s, and excretion was stimulated with a cotton swab. Each pup was then reweighed. Next, each pup was placed in a separate beaker that had 2 ml of high-fat milk (UHT Longlife cream, 10% fat; Tnuva Dairy, Rehovot, Israel), sweetened with the addition of sucrose to make a 10% solution, warmed to 38°C, and spread equally over heavy tissue paper cut to fit the bottom of the beaker. The beaker was allocated in a humid incubator maintained at 33°C. Two experimenters, blinded to the pup's genotype, participated in each experiment. Pup behavior was observed visually and noted by pressing the appropriate keyboard button or the button of a mouse connected to a computer. A program noted the time at which a button was touched. Special attention was given to feeding behavior: the ingestive act of rats ingesting liquids is composed of a rhythmic cycle of tongue extensions and retractions directed at the tissue paper saturated with sweetened milk. On postnatal days 2–4, the experimenter pressed the appropriate mouse button whenever the pup's tongue made contact with the tissue paper. Bouts of lickings were interrupted by pauses. Pup behavior during these intermissions was noted as well. At postnatal days 9–11, licking rate increased significantly up to a point where the experimenter was not able to press the buttons for each lick that occurred. Instead, the experimenter pressed the button at the onset and offset of each continuous, uninterrupted series of lickings. In addition, animal behavior was filmed with a video camera for later analysis. After 30 min, each pup was removed from the incubator, wiped dry with tissue paper, and weighed. Intake was measured as the change in body weight that occurred during the 30-min test and is reported as percent body weight gain.

Microstructure of meals. At the microstructural level, licking behavior of rats is characterized by bouts of licking at a relatively constant rate, interrupted by pauses of various length (18). The licking rate of the pups was slower than that of the mature rats; therefore, we could not use their criteria for microstructure analysis.

Following the conceptual framework of Davis and Smith (18), we drew a distribution curve of all interlick intervals (ILI) for all LETO and OLETF pups participating in this experiment at the first test (Fig. 1). The distribution of ILI in the range of 0.1–1.2 s for all LETO and for all OLETF rat pups is symmetrical with very little variability. Despite the difference in ranges, the steepness of the distribution and the flat tail to its right are consistent with frequency distributions of mature rats reported by Davis and Smith (18). We chose an ILI criterion of 1.1 s for use as the ILI threshold, or bout criterion interval (BCI). This value represents the point from which the distribution curve was skewed to the right.



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  		Fig. 1. Frequency distribution of the interlick intervals in the range of 0.1 to 6 s. A: all Long-Evans Tokushima Otsuka (LETO) rat pups participating in the independent ingestion test. B: all Otsuka Long-Evans Tokushima fatty (OLETF) rat pups participating in the independent ingestion test.

 
Intervals shorter than or equal to 1.1 s were interpreted to be within a licking burst. Pauses longer than 1.1 s but shorter than 2.5 s were defined to be interburst intervals. A longer pause, >2.5 s, during which different behaviors that are not typical of ingestive behavior occurred, was assigned to the category of intercluster interval. Licks were divided into meals by using the criteria of three licks with an ILI <1.1 s (i.e., licks occurring within a burst) to initiate a meal (17). The intermeal interval was defined as 5 min without licking, as previously validated (47, 54–55). Meals were defined as beginning when at least three licks occurred, separated by ILI of <1.1 s and followed by 5 min or longer until the animal broke contact with the wet paper and was engaged in behaviors other than licking. Ten of the OLETF and 12 of the LETO pups started a second meal.

To quantify the changes in rate of licking during the test, we calculated the number of licks during successive minutes of the independent ingestion test for each of the pups in 1-min bins. Lick rate for each individual animal was fit to an exponential function, y = A x (–t)B (19, 20). The parameter A represents the initial rate of licking, and parameter B is the slope of the decline.

For meal pattern analysis of 9- to 11-day-old pups, tapes of 3 min of continuous feeding, 10–15 min after the experiment onset, from three different LETO pups and five different OLETF pups were analyzed frame by frame. ILI was measured, and a frequency distribution of ILI was drawn, as described above. At this age, threshold for a burst (BCI) was determined to be 0.7 s; ILI values ≤ 0.7 s were defined as being within a burst of licking.

To eliminate sporadic lickings from being interpreted as licking behavior for bout analysis, we defined a minimum burst size as three consecutive licks with ILI values <1.1 s for pups 2–4 days old and <0.7 s for 9–11 days old.

Summary of measures analyzed. Gross feeding parameters in the first test (days 2–4) included latency to onset of feeding, duration of feeding (in s), percent body weight gain, ILI, number of licks counted, and two calculated variables: efficiency of licking, defined as weight gain of each pup divided by the total number of licks during the 30-min observation, and orosensory stimulation, defined as the volume of milk consumed by the pups during the first minute of feeding. For this, licking efficiency (average volume of milk consumed per lick) was multiplied by the number of licks during the first minute of feeding for each pup. For the second test, only the first four of these variables were available for analysis.

Microstructure parameters derived from the first test, separately for the first and second meals within that day's session, included the number of bursts, number of clusters, mean duration of bursts and of clusters (in s), and mean number of licks counted in bursts and in clusters. In addition, a satiety ratio was defined as the duration of the intermeal interval divided by the preceding meal size. For the second test (days 9–11), only four of the above variables were available: number of bursts, number of clusters, and mean duration of bursts and of clusters (in s).

Statistical analysis. Data were analyzed using multivariate analyses of variance (MANOVA), with strain (LETO-OLETF) as the independent factor. These analyses were performed separately for the gross feeding parameters of the first (days 2–4) and second test days (days 9–11) and for the microstructure data on feeding patterns from the first and second meals on the first test day and from the first meal on the second test day. The MANOVAs were followed by post hoc univariate ANOVAs on each dependent measure. For some analyses, a few variables could not be included in the MANOVA. Specifically, when two variables were expected to be highly correlated because they measured the same thing in different ways (e.g., cluster size as measured in seconds and as measured by number of licks), only one of the two variables was included in the MANOVA to avoid violating statistical assumptions. For similar reasons, when a ratio variable was calculated based totally on variables included in the MANOVA, it was not included in the MANOVA for degree-of-freedom considerations. Strain differences on these variables were assessed using independent t-tests. Finally, strain differences on the variable with a very small sample size (ILI on second test day) were assessed using a nonparametric Mann-Whitney U-test.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Body weight and percent body weight gain. At postnatal days 2–4 and 9–11, OLETF pups weighed significantly more than LETO pups at the study onset (P < 0.001; Fig. 2, A and B). At both postnatal ages, OLETF pups ingested significantly more milk during the test session, as indicated by their percent body weight gain compared with LETO controls [P < 0.05 (first test), P < 0.001 (second test); Fig. 2, C and D].



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  		Fig. 2. A: body weight of 2- to 4-day-old OLETF and LETO pups. B: body weight of 9- to 11-day-old OLETF and LETO pups. C: percent body weight gain of 2- to 4-day-old OLETF and LETO pups after the 30-min independent ingestion test. D: percent body weight gain of 9- to 11-day-old OLETF and LETO pups after the 30-min independent ingestion test. Values are means ± SE. *Significant difference between OLETF and LETO values.

 
Total time spent feeding. Time spent feeding during the independent ingestion test as assessed by the number of licks observed was significantly longer in OLETF pups at both ages tested (P < 0.05; Fig. 3, A and B). When this variable was assessed by duration of observation in seconds, the difference approached, but did not reach significance in the 2- to 4-day-old pups (P < 0.07, two-tailed analysis) and was significant in the 9- to 1-day-old pups (P < 0.01; Fig. 3C).



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  		Fig. 3. A: total time spent feeding during the 30-min independent ingestion test at the age of 2–4 postnatal days. B: total time spent feeding during the 30-min independent ingestion test at the age of 9–11 postnatal days. C: time spent feeding, expressed as number of licks at the age of 2–4 postnatal days. *Significant difference between OLETF and LETO values.

 
Interlick interval. Pups at both ages examined had longer mean ILI values (0.57 s at postnatal days 2–4, 0.37 s at postnatal days 9–11; Fig. 4) compared with mature rats whose microstructure of ingestive behavior was analyzed by Davis and Smith (18), who reported mean ILI values of 0.135 s with a standard deviation of 0.013 s for a rat that licks rapidly and 0.162 s with a standard deviation of 0.014 s for one that licks slowly (18). There was no significant difference between the mean ILI values in OLETF and LETO pups at both ages.



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  		Fig. 4. A: interlick interval (ILI) at 2–4 postnatal days. B: ILI at 9–11 postnatal days. Values are means ± SE.

 
Latency to start feeding. OLETF pups exhibited a significantly shorter latency to start feeding at the age of 2–4 days (P < 0.001) compared with LETO controls. This was not evident a week later (Fig. 5).



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  		Fig. 5. A: latency to start feeding in OLETF and LETO pups at 2–4 postnatal days. B: latency to start feeding in OLETF and LETO pups at 9–11 postnatal days. Values are means ± SE. *Significant difference between OLETF and LETO values.

 
Both strains exhibited a significant decrease in latency at the age of 9–11 postnatal days compared with their latency at the age of 2–4 days. LETO pups decreased their latency by an average of 81% compared with a 36% decrease in latency of the OLETF pups.

Efficiency of licking and orosensory stimulation, postnatal days 2–4. These two variables were calculated from the data as described above. No significant difference in efficiency of licking was revealed between both strains (Fig. 6). Orosensory stimulation was significantly greater in OLETF pups compared with their LETO controls (P < 0.01; Fig. 7).



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  		Fig. 6. Average volume of milk per lick consumed by OLETF and LETO pups. Values are means ± SE.

 


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  		Fig. 7. Volume of milk consumed during first minute of feeding by OLETF and LETO rat pups. Values are means ± SE. *Significant difference between OLETF and LETO values.

 
Microstructure of a first meal, postnatal days 2–4. All 15 OLETF and 21 LETO pups completed their first meal (after 3 h of deprivation) and provided data for this analysis. Analysis of microstructure variables revealed that the increased weight gain of OLETF pups compared with their LETO controls during the 30-min independent ingestion test was exclusively the outcome of a larger first meal following deprivation (Table 1). When OLETF and LETO microstructure variables were compared in a time frame limited to an average LETO size meal, no significant difference was revealed between groups for any of the meal parameters analyzed (Table 1).


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  		Table 1. First meal parameters in OLETF and LETO rat pups

 
Although burst size and cluster size were not significantly different, the numbers of bursts and clusters in OLETF pups were significantly elevated compared with their LETO controls (P < 0.05, number of clusters; P < 0.01, number of bursts). As a result, the total time pups were engaged in feeding behavior as well as the total number of licks was significantly higher in OLETF compared with LETO pups (Fig. 3, A and C). The elevated numbers of bursts and clusters in the OLETF's meal are consequent to the extended meal duration or size. Intercluster interval duration appeared shorter in OLETF rat pups compared with LETO controls, also when the time frame was limited to an average LETO meal duration, but this difference was not significant (Table 1).

Lick rate decay, postnatal days 2–4. Figures 8 and 9 provide plots of lick rate for the two strains of animals during 30-min observation, whereas Fig. 10 represents their lick rate during the first 10 min of feeding. Initial licking rate was significantly different between the two strains, as expressed by the difference in intercept (Tables 2 and 3, P < 0.05). Rate of licking declined significantly faster in OLETF rats compared with their LETO controls, as expressed by the significant difference in slopes in both overall feeding time observation (P < 0.05) and during the first 10 min of observation (P < 0.05; Tables 2 and 3). Despite the significantly higher slope function for OLETF pups, rate of licking was maintained higher for a longer period in OLETF pups as a result of their initial rate of licking (Fig. 10).



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  		Fig. 8. Decay of lick rate over time during the 30-min independent ingestion test. Values represent mean ± SE lick number for each minute. Data are included from the whole 30-min observation time.

 


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  		Fig. 9. Decay of lick rate over time, starting from the minute each pup began licking up to the point where it stopped. Values represent mean ± SE lick number for each minute.

 


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  		Fig. 10. Decay of lick rate over first the 10 min of feeding, starting from the minute each pup began licking. Values represent mean ± SE lick number for each minute.

 

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  		Table 2. Decay-of-feeding function analysis

 

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  		Table 3. Decay-of-feeding function during first 10 min

 
Satiety ratio, postnatal days 2–4. Satiety ratio was defined as the duration of the intermeal interval divided by the preceding meal size. The difference between the two strains was not found to be significant (Table 1). We note that the variability was rather high in this variable for reasons unclear to us. Satiety ratio was calculated solely for pups that completed two meals.

Second meal, postnatal days 2–4. Ten OLETF pups and 12 LETO pups clearly started a second meal. Only seven OLETF and nine LETO pups completed this meal (i.e., for 3 OLETF pups and 1 LETO pup, observation time concluded before the meal did). Data from noncompleted meals were not included in the analyses. Meal parameters of the second meal are presented in Table 4. No significant difference was revealed between groups for any of the meal parameters studied, including those that were significantly different during the first meal (meal duration and size, total number of bursts and clusters).


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  		Table 4. Second meal parameters in OLETF and LETO rat pups

 
Second test, postnatal days 9–11. Data are summarized in Table 5. Analysis of data on meal patterns revealed that at the age of 9–11 postnatal days, meal duration (P < 0.05) was increased in OLETF rat pups compared with their LETO controls. In accordance with the data from the younger age group, the numbers of bursts (P < 0.05) and clusters (P < 0.05) were significantly elevated in OLETF rats compared with their LETO controls.


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  		Table 5. First meal parameters in OLETF and LETO rat pups, second test, on postnatal days 9–11

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Using the advantage of a genetic model, we were able to examine the part played by the CCK-1 receptor when it is absent, due to mutation, in development of hyperphagia in preobese OLETF pups.

Independent ingestion of OLETF and LETO pups: weight, percent weight gain, and time devoted to feeding. According to Moran et al. (47), OLETF rats became significantly heavier than LETO rats only from 9 wk of age onwards. In our experiment, differences in weight were already substantial on postnatal days 2–4. If indeed OLETF rats are continuously heavier than LETO pups from an early age and onward (a topic currently investigated in our laboratory), the results of Moran's study may reflect transport conditions (from Japan to the US) affecting the weight of the young adult males at the beginning of their measurements (5 wk) up to the age of 9 wk. In contrast, rat pups participating in our experiments were born in the colony and did not experience postnatal traveling. Weight differences later in development, however, cannot be accounted for solely by initial neonatal weight differences. We found that percent weight gain during 30-min independent ingestion tests with high fat milk in OLETF pups' was higher than in control pups at both ages tested.

The results raise questions regarding differences in pup weight at birth, maternal weight and nursing behavior, and milk content and its effect on weight and weight gain during infancy. We are following up on these issues. Previous findings suggested that adult OLETF rats have decreased responsiveness to dietary fat (68). Adult OLETF rats did not compensate when switched to a high-fat diet, leading to hyperphagia. Unlike LETO rats, a gastric preload of fat suppressed intake to less than equicaloric protein or carbohydrate intake in OLETF rats (68). Therefore, our findings with independent ingestion of high-fat milk might raise the possibility that the decreased response of OLETF rats to fat is pronounced already at the early age of 2–4 days.

Interlick interval. In the current study, licking occurred at the same rate in OLETF and LETO pups, which suggests that this rhythmic movement, which is under the control of a central pattern generator located in the brain stem (30), is unaffected by the lack of CCK-1 receptors. Nuclei of the brain stem, the nucleus of the solitary tract (NTS) and the parabranchial nucleus (32, 57), receive sensory signaling from the oral cavity and gastrointestinal tract. Rhythm-generating neurons project to motor nuclei and neurons that drive the firing pattern and are located at the medullary reticular formation (64, 70). Our results might indicate a lack of difference in neurons functioning as the central pattern generator (CPG) between the two strains. When differences in rate are found, they typically derive from neural networks that mediate the CPG (59). We found that the ILI becomes shorter as the pups grow. This developmental pattern might suggest a maturation process of the system generating and organizing rhythmic movements of licking. In mature rats, rate of licking is fixed at a frequency of 5–7 licks per second. Lack of CCK-1 receptors appears to have no effect on CPG, whereas when cocaine- and amphetamine-regulated transcript (CART) is administrated, an increase in ILI and slowing of licking rate is pronounced (1, 2).

Latency to start feeding. The current study reveals that 2- to 4-day-old OLETF pups started feeding earlier than their LETO controls. A relationship between CCK and latency to start feeding was previously established: a long-lasting CCK analog, U-67827E, produced dose-dependent increases in onset of feeding in adult male baboons (27). Decerebration at the level of the superior colliculus permits normal swallowing until satiation when liquid food is infused into the mouth through chronic oral catheters, but a decerebrated rat would not initiate eating unless liquid food was infused directly into its mouth (30). Speculatively, our results might suggest a difference in maturation or essence of connections between the forebrain and hindbrain between newborn OLETF and LETO pups. The lack of difference between lines in feeding initiation at postnatal days 9–11 may suggest that the finding is limited to neonatal period, transient immaturity in feeding controls, or age-dependent anxiety control in the test arena.

Another explanation for the decrease in latency to start feeding on postnatal days 9–11 is that at this age, pups were familiar with the test of independent feeding from tissue paper, experienced earlier at postnatal days 2–4. LETO pups exhibited a pronounced decrease in their latency to start feeding compared with their OLETF controls, which might suggest better learning or memory skills. It was previously established that adult OLETF rats have impaired learning and memory compared with their LETO controls (50). Another way of explaining this is that OLETF rats expressed the quickest response to food at the younger age, whereas LETO pups were able to demonstrate this ability only in a later stage/developmental age.

Peptides that regulate food intake, other than CCK, also exert an effect on initiation of a meal: neuropeptide Y (NPY) injected into the pernifornical hypothalamus of satiated male rats decreased latency to eat the first meal (40). Adult OLETF rats demonstrated overexpression of NPY in the dorsomedial hypothalamus before their development of obesity. It was suggested that NPY overexpression is a direct result of lack of CCK-1 receptors (9, 10, 48), because CCK-1 receptors are normally coexpressed with NPY in the hypothalamus (49). Indeed, OLETF rats show greater sensitivity to the effect of lateral ventricular infusions of NPY on food intake compared with LETO controls (49). Furthermore, CCK has been shown to inhibit the effects of the peptide hormone ghrelin; ghrelin promotes initiation and increases meal size (21, 37).

Meal parameters. Analysis of lick rate data revealed that OLETF and LETO rat pups differed in both their initial lick rate as well as rate of decay of licking across time. According to Davis and Smith (18, also see Ref. 11), initial lick rate is modulated by the oropharyngeal stimulatory properties of food. Our current results indicate that OLETF and LETO pups significantly differ in this parameter, i.e., orosensory stimulation was significantly greater in OLETF pups compared with their LETO controls. The stronger oropharyngeal stimulation of food is also demonstrated by the significantly larger volume of milk consumed by OLETF pups during the first minute of feeding. More data provide evidence of altered (increased) preference for glucose following a short-access, two-bottle test and a sham feeding preparation (22). This suggests that OLETF rats might have secondary abnormalities beyond the lack of CCK-1 receptors, such as those involved in the dopaminergic system and in reward processes.

The slope of lick rate over time has been suggested to be under the control of preabsorptive postingestive stimulation that develops as ingestion continues and fluid accumulates in the stomach and small intestine (18–20). The larger slope value of the OLETF pups suggests increased negative feedback compared with their LETO controls. Nevertheless, because their initial lick rate was significantly larger, OLETF pups maintained a faster lick rate throughout the first meal. Moran et al. (47) revealed that adult OLETF and LETO rats that consumed a glucose solution had similar initial lick rates, but OLETF rats had a slower rate of decay over time compared with their LETO controls. The discrepancy in results between adults and neonates might derive from differences in response mechanisms to orosensory and preabsorptive postingestive stimulation following maturation, as well as differences in OLETF and LETO responses to glucose (milk used for independent ingestion was sweetened with sugar, and 10% fat milk was used for the independent ingestion test) and different macronutrients and chemosensory cues included in milk.

Previous pharmacological evidence demonstrated the role of the CCK-1 receptor in control of food intake by intestinal nutrients that do not elevate plasma CCK concentrations (7) as well as by those that stimulate CCK secretion (7, 34, 55). Studies of CCK-1 receptor-deficient rats (OLETF) and their LETO controls (14) indicate that the absence of CCK-1 receptors might result in reduced sensitivity to nutrient-induced intestinal satiety signals, thereby leading to hyperphagia and obesity.

Our results are consistent with findings from other experimental settings, demonstrating increased food intake after administration of CCK-1 receptor antagonists in both pups and mature rats (23, 46, 52–64, 68). CCK-1 receptor blockade produced an increase in both meal size and duration (46). Vagal deafferentation alters meal patterns in rats maintained on liquid diet (55); they consume larger meals than sham-operated controls. Our results for meal patterns in OLETF rat pups lacking CCK-1 receptor resemble those results. These data demonstrate that affecting a major neural afferent pathway by eliminating a major peptide receptor pathway produced a major alternation in feeding behavior.

It should be noted that OLETF rats might have genetic deficits other than the gene for the CCK-1 receptor and may have developmental abnormalities as a result of the receptor absence, which might contribute to their obesity and pattern of food intake. Previous evidence suggests that CCK might modify dopamine transmission in the brain (15). In the OLETF rat, baseline extracellular dopamine levels were significantly elevated in caudate-putamen compared with LETO controls, whereas CART administration exhibited a greater dopamine response in the nucleus accumbens, which is involved in the expression of stimulant-induced dopamine-related behavior (26).

Nevertheless, OLETF rats lacking CCK-1 satiety signaling pathway are a unique model demonstrating how a deficit within the satiety system can result in long-term changes in food intake and body weight. The possible long-term effect of CCK on body weight might occur via its interactions with other peptides: it was suggested that the feeding inhibitory system of leptin depends in part on a functional within-meal CCK satiation pathway (6, 25, 41–43). Studies have shown an interaction between the serotonergic and cholecystokininergic systems in control of food intake: the satiation effect of CCK has been shown to be amplified by 5-hydroxytryptamine (13, 51, 31). Data reported by Watanabe et al. (65) further indicate that CCK-1 is probably not the only receptor disrupted in the OLETF strain, given that the GPR10 receptor is mutated in this strain. Integration of data from congenic lines may clarify the role of CCK-1 receptors and their interactions with the other mutated receptor, GPR10, and its effect on control of food intake and weight regulation.

Perspectives

OLETF rats represent a unique model in which a deficit in a meal-related satiation signal may contribute to deregulation of energy balance over life span, expressed as obesity. Our data support the hypothesis that a deficit in CCK negative feedback may promote the trend toward obesity even at the young age of 2–4 days.

Besides activating vagal afferent nerve fibers, CCK released in the plasma also may act on CCK-1 receptors in the area postrema, being a circumventricular area, and through its monosynaptic connection to the nucleus of the NTS. Studies investigating the role of CCK-1 receptors in activation of the NTS using selective receptor agonist and antagonist have yielded conflicting data (12, 28, 71). Also, lesions of the NTS block or attenuate the satiety effect of CCK (24). Transaction of the ascending fibers from the NTS or lesions in the paraventricular nucleus resulted in blockade of the feeding inhibitory effects of CCK (16). Therefore, further research is needed to examine differences between OLETF and LETO in hindbrain and forebrain satiation signals and the emergence of these signals at a young age.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This research was supported by a grant from the U.S.-Israel Binational Science Foundation.


   ACKNOWLEDGMENTS
 
We thank Gil Geva, Lily Benyamini, and Adi and Nitzan Weller for assistance in the behavioral observations. OLETF and LETO rats were generously provided by Dr. Kawano, Tokushima Research Institute, Otsuka, Japan.


   FOOTNOTES
 

Address for reprint requests and other correspondence: A. Weller, Dept. of Psychology, Bar Ilan Univ., Ramat-Gan 52900, Israel (e-mail: weller{at}mail.biu.ac.il)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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