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Program in Nutritional Sciences (J.E.M.) and Department of Medicine (D.K.S., M.W.S.), University of Washington, Seattle, Washington 98195; and Department of Nutrition (P.J.H.), University of California at Davis, Davis, California 95616
Address all correspondence and requests for reprints to: Michael W. Schwartz, M.D., Division of Metabolism, Endocrinology and Nutrition, University of Washington and Harborview Medical Center (359757), 325 Ninth Avenue, Seattle, Washington 98104-2499. E-mail: mschwart{at}u.washington.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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During a meal, neural and humoral signals are generated in response to nutrient ingestion that induce satiety and meal termination. Among these stimuli are satiety factors, one of which is cholecystokinin (CCK). CCK was first isolated in 1964 (6) and has since been extensively studied for its role in ingestive behavior (for a review, see 7). CCK reduces food intake, within minutes after its release from the upper duodenum and jejunum (8), by binding to CCK-A receptors on afferent fibers of the vagus nerve. The vagus nerve transmits ingestive information to brainstem areas implicated in satiety, including the nucleus of the solitary tract (NTS), which, in turn, projects fibers to the brainstem’s lateral parabrachial nucleus (L-PBN) and the hypothalamic paraventricular nucleus (PVN) (9, 10, 11). Thus, systemic CCK administration to rats rapidly inhibits food intake and activates neurons (as measured by c-Fos induction) in brain stem and hypothalamic areas.
Coadministration of CCK with leptin potentiates its ability to reduce food intake (12, 13, 14, 15) and to activate neurons in the NTS (13, 14, 16). These findings support a model in which leptin’s anorectic effects are mediated, at least in part, by enhancing the response of brainstem neurons to CCK. We therefore hypothesized that reduced leptin signaling, induced by fasting, attenuates the response to satiety signals, which, in turn, increases food intake. To test this hypothesis, we first measured the effect of fasting on the satiety response to ip CCK. To explore the specific role of leptin deficiency in the effect of food deprivation, we performed a second experiment in which fasted animals were infused systemically with a dose of leptin intended to maintain circulating leptin at nonfasted levels, and the satiety response to CCK was compared with that of fasted animals receiving no leptin replacement.
One mechanism by which decreased leptin signaling may increase food intake is via increased synthesis of hypothalamic peptides that stimulate feeding, such as neuropeptide Y (NPY). We therefore hypothesized that NPY increases food intake, at least in part, by attenuating the response of neurons in the brainstem, to satiety signals such as CCK. This hypothesis was investigated by determining the effect of intracerebroventricular (icv) NPY pretreatment on both CCK-induced satiety and on the ability of CCK to induce c-Fos expression in areas of the brain that regulate food intake.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Exp 1: Effect of fasting on CCK-induced satiety
Forty-five rats were weighed and handled daily and habituated to
ip saline vehicle injections 1 week before the beginning of the
experiments.
Ad libitum fed protocol. Food hoppers were removed from cages at 1500 h and weighed. Animals were weight-matched into treatment groups and injected ip between 1745 h and 1800 h, in randomized order, with sulfated CCK octapeptide (Peninsula Laboratories, Inc., Belmont, CA), at doses of 0.5, 0.8, and 3.0 µg/kg, diluted up to 2 ml in 0.9% saline solution, or saline for control. Each rat was allowed access to chow immediately after the injection, at a time corresponding to the beginning of the dark cycle (1815 h). Food consumption was measured 30 min, 90 min, and 4 h after CCK administration.
Fasted protocol. Food hoppers were removed from cages, at 1500 h, 2 days before the feeding experiment. On the day of the experiment, fasted animals were weight-matched into treatment groups, injected ip in randomized order with either saline or CCK, and monitored for intake of chow as described above.
Half of the animals were divided into four groups and received one of the three doses of CCK or vehicle in the fed condition, followed by the same treatment in the fasted condition 10 days later. The remaining animals received the same injection treatments in the fasted condition first; and 10 days later, they were injected in the fed condition. This cross-over design was repeated after 10 days recovery, and the results were analyzed together.
Exp 2: Effect of leptin replacement on the response to
fasting
Intrajugular catheter placement. Rats were habituated with
daily handling for 8 weeks before surgery. After anesthesia, induced by
ip injection of ketamine/xylazine (60 mg/kg ketamine and 8 mg/kg
xylazine), a sterile silicon catheter (ID, 0.020; OD, 0.037 inches) was
placed into the right jugular vein using the method of Steffens
(17). Two weeks of surgical recovery were allowed before
performing the experiment, during which time rats were weighed daily
and habituated to the blood sampling procedure.
Study protocol. Delivery of infusate via minipump was achieved by attaching a polyethylene Lynch coil (18), filled with a precise volume of either vehicle or peptide. Twenty-three jugular-catheterized animals were weight-matched into three groups (average BW = 406.4 ± 7.0 g): vehicle/fed, vehicle/fasted, and leptin/fasted. After anesthesia, induced by ip injection of ketamine/xylazine, all rats were implanted with sc minipumps with attached Lynch coils that delivered 0.9% saline for the first 48 h after minipump placement, so that infusion of test substances did not commence until after this postsurgical recovery period. After this initial 48-h period, food was removed for 48 h from the vehicle/fasted (n = 8) and leptin/fasted (n = 7) groups, during which time the vehicle/fed group (n = 8) was allowed free access to food. Minipumps delivered either 5 mM sodium citrate vehicle sc, or 100 µg/kg·day sc of murine leptin (Peprotech, Inc., Rocky Hill, NJ) dissolved in sodium citrate vehicle at pH 4.0, a rate chosen according to a protocol used previously (19). A jugular vein blood sample was collected from each rat, 44 h into the fast, to measure plasma leptin levels.
The infusions of leptin or vehicle were designed to finish just before the beginning of the dark cycle (1715 h) on the second day of the fast and were followed by a 0.9% saline infusion delivered by the minipumps for the remainder of the study. At 1400 h, food was removed from the cages of the vehicle/fed group. All animals were injected, in randomized order, with 3 µg/kg ip CCK, between 1645 h and 1655 h, and food was immediately returned to all cages. Food intake was measured at 30 min, 90 min, 4 h, and 24 h after injection.
To determine the effect of the leptin replacement protocol on food intake in the absence of CCK, the experiment was repeated after 1 month recovery, using ip saline instead of CCK, in a subset of these animals (n = 17, average BW = 425.3 ± 8.1 g). Each animal was maintained in its previous treatment group.
Exp 3: Effect of icv NPY on CCK-induced satiety and c-Fos
induction
Cannula placement. Rats were habituated with daily handling
for 1 week before surgery. After anesthesia, induced by ip injection of
ketamine/xylazine, a 21-gauge cannula (Plastics One, Roanoke, VA) was
placed stereotaxically into the third ventricle using a previously
described method (20, 21). Cannula placement was verified,
1 week after surgery, by icv injection of 10 ng angiotensin II
(American Peptide Co., Sunnyvale, CA) diluted in 1 µl
cerebrospinal fluid (CSF). Animals not consuming at least 5 ml water
within 30 min post injection were excluded as cannulation failures (4%
of all rats).
Exp 3.1. To determine the effect of icv NPY pretreatment on CCK-induced inhibition of food intake, 19 rats were weight-matched to 4 groups, 3 weeks after cannula placement in the third ventricle. The 4 groups studied were: icv CSF/ip saline treatment (n = 4), icv CSF/ip CCK (n = 5), icv NPY/ip saline (n = 5), and icv NPY/ip CCK (n = 5). At 1400–1500 h, each animal received an icv injection of 3.5-µl vol of either synthetic CSF or 7.5 µg NPY in the same volume of CSF, and food was removed from the cages. At approximately 1745–1755 h, either ip saline or 3.0 µg/kg ip CCK was administered in randomized order, and food was immediately returned to the cages. Food intakes were collected 30 min, 90 min, 4 h, and 24 h after returning food to the cages. After a 10-day recovery period, the same animals were reassigned to groups such that those that had previously received an ip saline treatment now received ip CCK and vice versa, while the icv treatment groups remained as before. In this way, each animal served as its own control for the ip treatments. The results of the 2 trials were similar, and the data were therefore analyzed together.
Exp 3.2. To determine the effect of icv NPY pretreatment on CCK-induced c-Fos staining, a different group of 29 rats was habituated to ip injections and weight-matched into the following 4 groups after cannulation of the third ventricle: icv CSF/ip saline (n = 8), icv CSF/ip CCK (n = 7), icv NPY/ip saline (n = 7), and icv NPY/ip CCK (n = 7). Third-ventricle injections of either 3.5 µl CSF or 7.5 µg NPY, in an equal volume of CSF, were administered to all rats, followed 1 h later by an ip injection of either ip saline or 3 µg/kg ip CCK. Immediately afterwards, each animal was returned to its home cage with food hoppers and water bottles removed. After 110 min, rats were anesthetized with ketamine/xylazine and transcardially perfused with PBS of neutral pH, followed by a 4% paraformaldehyde solution. Brains were removed immediately and postfixed in paraformaldehyde, for 1 week, before assay for c-Fos-like-immunoreactivity (cFLI).
Assays and data analyses
Leptin assay. Plasma leptin levels were determined by RIA
using an antibody with 100% cross-reactivity for both rat and murine
leptin (Linco Research, Inc., St. Louis, MO)
(22).
cFLI. Each postfixed brain was rinsed 2–3 times in PBS and sectioned, at 50 µm, on an oscillating tissue slicer in a PBS bath. Coronal sections were taken from the forebrain (PVN) and from the hindbrain (L-PBN, NTS, and area postrema, AP) and were processed for cFLI as described in detail elsewhere (23). Sections were mounted on slides, and the number of cFLI-positive cell nuclei was quantified in selected brain areas by an investigator blinded to the treatment groups. Quantification was performed using the MCID computer grain counting system (Imaging Research, Inc., St. Catherine’s, Ontario, Canada).
Statistical analyses. All statistical analyses were carried out using Prism 2.01 (GraphPad Software, Inc., San Diego, CA) statistical software. Data are presented as group mean values (±SEM). For experiments with greater than two study groups, comparisons were performed with one-way ANOVA and Neuman-Keuls post hoc test. A paired, two-tailed Student’s t test was used for two-group comparisons in Exp 1. A P value = 0.05 between group mean values was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, P <
0.05 for percent saline control-fed vs. percent saline
control-fasted).
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). Food consumed after 3.0 µg/kg ip
CCK was greater in vehicle/fasted, compared with vehicle/fed, rats
(30-min food intake: vehicle/fasted, 1.7 ± 0.4 g,
P < 0.01; vehicle/fed, 0.3 ± 0.1 g), in
agreement with Exp 1, and this increase was markedly attenuated in
leptin/fasted rats (0.7 ± 0.2 g, P < 0.05
vs. vehicle/fasted; P = not significant
vs. vehicle/fed, Fig. 2). This pattern persisted over the
24-h refeeding period (data not shown).
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).
In the absence of CCK, 30-min food intake in the two groups of fasted
animals was greater than that of fed rats, and leptin replacement did
not significantly affect this response (30-min food intake: 4.7 ±
0.3 and 4.2 ± 0.6 g in vehicle/fasted and leptin/fasted
groups vs. 1.9 ± 0.4 g in vehicle/fed animals,
P < 0.01 for both fasted vs. fed groups)
(Fig. 3). This pattern persisted over the 24-h refeeding period (data
not shown).
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). Similar to previous experiments, CCK
reduced 30-min food intake to 0.2 ± 0.04 g
(P < 0.01 vs. vehicle) in rats receiving
icv CSF vehicle. By comparison, food intake of rats receiving 7.5 µg
icv NPY and ip saline was increased to 5.2 ± 0.5 g
(P < 0.001 vs. vehicle), whereas food
intake of icv NPY/ip CCK-treated rats was similar to that of icv CSF/ip
saline-treated rats (1.9 ± 0.4 g). The relative reduction of
30-min food intake induced by CCK in the icv CSF group was therefore
greater than in the group receiving icv NPY (92 vs. 63%;
P < 0.001).
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. The mean
number of cFLI-positive nuclei in the NTS increased by 960% after
treatment with ip CCK, compared with ip saline, among icv CSF-treated
animals (101.8 ± 10.2 vs. 9.6 ± 2.5
cFLI-positive nuclei, P < 0.001), and this response
was lowered by 35% in rats pretreated with icv NPY (65.9 ± 11.9
cFLI-positive nuclei, P < 0.01 vs. icv
CSF/ip CCK-treated animals) (Fig. 5B). cFLI-positive nuclei
were also markedly increased in the AP after ip CCK, compared with ip
saline, in the icv CSF group (153.0 ± 6.3 vs. 9.6
± 2.7 cFLI-positive nuclei, P < 0.001), and this
effect was attenuated by 28% in animals pretreated with icv NPY
(110.2 ± 21.3 cFLI-positive nuclei, P < 0.05).
In contrast, NPY pretreatment did not attenuate CCK-induced c-Fos
expression in the PVN or the L-PBN, brain areas in which icv NPY and ip
CCK elicited similar cFLI patterns (Fig. 5, A and B). NPY given in the
absence of CCK also increased for staining in the NTS, L-PBN, and PVN,
in relation to icv vehicle.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To test this hypothesis, we first confirmed the ability of a 48-h fast to attenuate CCK-induced satiety in rats. We then demonstrated, in a second experiment, that this effect of fasting was prevented by infusion of leptin at a dose that achieved plasma levels comparable with those of ad libitum-fed animals. Thus, leptin deficiency seems to play a key role in the effect of fasting to reduce the response to exogenous CCK. In addition, we showed that the suppression of food intake elicited by CCK was attenuated by pretreatment with icv NPY, an intervention that also reduced the number of c-Fos-positive nuclei induced by CCK in hindbrain areas strongly implicated in CCK-induced satiety. Taken together, these findings support the hypothesis that the decrease in leptin signaling, induced by fasting, blunts the satiety response to CCK and that fasting-induced increases of NPY may contribute to this response.
Our results are consistent with several previous studies showing that CCK-induced food intake suppression is reduced when animals are fasted (26, 27, 28, 29, 30, 31). Leptin replacement reversed the effect of fasting to attenuate the response to CCK, amounting to a recovery of 59% of the response measured in rats fed ad libitum (P < 0.05 vs. fasted animals receiving vehicle). The fact that CCK suppression of food intake was incompletely restored by leptin replacement in fasted animals raises the possibility that another circulating factor, such as insulin, may also enhance CCK-induced satiety. This possibility is supported by the observations that, like leptin, insulin levels are markedly decreased by fasting, and icv insulin infusion synergistically reduces food intake when coadministered with systemic CCK (32).
The interaction between leptin infusion and CCK was transient, however. Food intake increased in the leptin-replaced group such that, by 4 h, the fasted groups were no longer significantly different from one another, and the recovery of lost weight after 24 h of refeeding did not differ among leptin- and vehicle-treated groups (data not shown). The latter finding is discordant with the results of two previous studies in which coadministration of leptin with CCK elicited a synergistic suppression of food intake and body weight in lean rats that lasted for 2 days (15, 33), but it is in agreement with a more recent study that did not detect this interaction (34). Our study differs from all three of these previous studies, however, in that we sought to achieve physiological leptin replacement during a fast rather than to administer leptin at supraphysiological doses in ad libitum-fed animals.
Conversely, when saline was given instead of ip CCK, food intake in fasted, saline-treated animals was not significantly attenuated by leptin replacement at any time point. Thus, the restoration of the CCK response seen in fasted, leptin-replaced animals in the first trial was not attributable to an independent effect of leptin on food intake. Moreover, it seems that leptin replacement in fasted animals does not reduce fasting-induced hyperphagia. Preventing the decline in plasma leptin levels may therefore be insufficient, in and of itself, to attenuate hyperphagia in response to fasting, and additional studies are warranted to address this possibility. One potential explanation for this outcome is that fasting lowers basal plasma and duodenal levels of satiety factors such as CCK (35, 36, 37, 38), gastrin (35), secretin (36), and glucagon-like-peptide-1 (36). By giving CCK, we may have overridden a fasting-induced reduction of satiety signals, thereby permitting the interaction between leptin and CCK to be detected. In fasted rats that did not receive CCK, however, levels of satiety signals during refeeding may have been too low to interact effectively with leptin.
Several possible mechanisms may be considered to explain an effect of leptin deficiency to inhibit the satiety effect of CCK. The ability of ip CCK to activate NTS neurons is well-documented and is believed to involve stimulation of vagal afferent fibers from the gut that synapse in this brain area (7, 9). Because leptin receptors are present in caudal brainstem areas, such as the NTS (39), the possibility of a local interaction of leptin with CCK at this site may be considered. In this scenario, leptin is proposed to act locally in the NTS to potentiate the activation of hindbrain neurons by CCK or other satiety signals. Alternatively, leptin could act indirectly to influence the response of hindbrain neurons to CCK or other satiety signals. For example, many leptin-sensitive neurons of the ARC project, either directly or indirectly, to the hindbrain, where they may influence the response to CCK and other vagally mediated stimuli (40).
NPY neurons of the ARC provide one example of a pathway downstream of leptin signaling with the potential to mediate some of the effects of leptin deficiency on the response to CCK. Hypothalamic NPY synthesis and release increase during fasting (20, 41, 42), and this response is suppressed by leptin (43). Leptin receptors are present on ARC NPY neurons, especially those that are upregulated with fasting (44), and elevated ARC NPY biosynthesis is implicated in the hyperphagia of leptin-deficient, ob/ob mice (45, 46). ARC NPY neurons project to the PVN and other hypothalamic areas with well-defined projections to the NTS (40).
In the current studies, we found that, when rats were pretreated with third ventricular NPY or CSF vehicle 1–2 h before administering ip CCK or saline vehicle, the feeding effects of NPY and CCK offset one another. Thus, NPY/CCK-treated animals ate the same amount of food as vehicle/vehicle-treated animals in the first 30 min after ip injection, in agreement with the hypothesis that NPY blocked CCK-induced satiety. The results of our study, however, could also be explained by an effect of CCK to interfere with the orexigenic actions of NPY, or by independent effects of NPY and CCK on neuronal circuits that control food intake. To investigate whether the response of key hindbrain nuclei to CCK is also attenuated by icv NPY pretreatment, we measured cFLI in key brain areas as an index of regional neuronal activation. The key finding of this experiment was that third-ventricular NPY injection significantly reduced the number of cFLI-positive nuclei induced by CCK throughout the AP and medial NTS. This finding supports the hypothesis that CCK-induced activation of key hindbrain neurons is attenuated by icv NPY administration.
The site of the NPY receptor population where NPY inhibited the response of NTS and AP neurons to CCK cannot be ascertained from this study. It is conceivable that third-ventricular NPY entered CSF in the 4th ventricle, from where it was able to exert inhibitory effects directly on CCK-sensitive hindbrain neurons containing NPY receptors. Alternatively, NPY may have acted upon forebrain sites involved in food intake regulation, such as the PVN. This brain area contains NPY receptors (47), is richly supplied with NPY-containing fibers emanating from the ARC (48, 49), and is highly sensitive to NPY’s orexigenic effects (50). Because PVN neurons are located adjacent to the third ventricle and project directly to the NTS (reviewed in 40), NPY inhibition of CCK-responsive neurons could have occurred indirectly via this highly integrative hypothalamic nucleus. The role of the PVN and other neuronal subsets, as mediators of the inhibitory effect of NPY on brainstem responses to CCK, warrants additional study.
In conclusion, our findings support the hypothesis that fasting attenuates the satiety response to CCK via a mechanism involving decreased leptin signaling. These findings support a model in which CCK’s satiety effects are modulated in proportion to changes in energy balance, and that leptin signaling plays a key role in this process. In addition, our data suggest that the opposing effects of NPY and CCK on food intake involve interactions with specific subsets of neurons in the brain stem and provide a novel mechanism whereby NPY may increase food intake. Thus, the ability of reduced leptin signaling to attenuate the response to exogenous CCK may involve hypothalamic mediators such as NPY. Because sc leptin injections are limited in their ability to reduce body weight in humans (51), our findings suggest a potential application for drugs targeting the control of short-term food intake, given in combination with those that regulate long-term energy balance, as an approach to obesity treatment.
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Acknowledgments |
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Footnotes |
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Received June 21, 2000.
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References |
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, P < 0.05 vs. icv
vehicle/ip CCK.