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APPETITE, OBESITY AND METABOLISM
1Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808; and 2Department of Psychiatry, Weill Medical College, Cornell University-Edward W. Bourne Behavioral Research Laboratory, White Plains, New York 10605
Submitted 21 March 2003 ; accepted in final form 21 April 2003
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-casomorphin displaced [3H]L-364,718 from CCK-A receptors
expressed in 3T3 cells or the binding of 125I-CCK-8S from rat brain
sections. The data suggest that both the peripheral and central responses to
enterostatin are mediated through or dependent on peripheral and central CCK-A
receptors. lorglumide; cholecystokinin-A receptor; near-celiac arterial; intracerebroventricular
Like other gut peptides, enterostatin appears to have both a peripheral and
a central site of action. Peripherally, it appears that enterostatin acts
within the gastroduodenal region to activate vagal fibers that communicate
through the brain stem regions to hypothalamic and extrahypothalamic forebrain
regions to effect food intake
(12,
42). Stereotaxic injections
suggest that the amygdala is the central site of action of enterostatin
(17) and that the feeding
response is modulated through a pathway that involves both paraventricular
serotonergic activity in the hypothalamus
(19,
48) and 
-opioid
activity in the nucleus tractus solitarius (NTS)
(48). Despite evidence that
µ-opioids displace enterostatin from binding sites on brain membranes, the
majority of data, using agonists and antagonists, strongly suggests that it is
a -opioid system in the NTS that modulates fat intake and is affected
by enterostatin (16,
30).
The response to enterostatin is dependent on the previous ingestion of dietary fat. Indeed, diet-switch studies suggest that there is an adaptive period of fat ingestion before the response to enterostatin becomes evident (20). The nature of this "fat" signal is unclear at this time. It could be dietary fat itself. Evidence for the presence of signaling systems that are responsive to cis-polyunsaturated fatty acids in both taste buds and the proximal duodenum has come from electrophysiological studies and sham-feeding experiments, respectively (10, 11). Alternatively, it is possible that an endocrine or neuroendocrine response to dietary fat ingestion is a necessary prerequisite for the enterostatin response. CCK is one candidate that could fit this signaling role (35). It has been recognized for many years that dietary fat is a potent signal for CCK secretion (33) and that CCK reduces food intake through effects mediated by the CCK-A receptor subtype (25,35). This anorectic response to peripheral CCK is also modulated through the afferent vagus nerve (38) and reflects a reduction in meal size (44), similar to the response to peripheral enterostatin (21).
In this study, we have investigated the potential role of CCK-activated pathways and CCK-A receptors in the response through which enterostatin reduces the intake of dietary fat. This work was facilitated by the availability of the selective CCK-A receptor subtype antagonist lorglumide and by the use of Otsuka Long Evans Tokushima Fatty (OLETF) rats. These rats have a large base deletion in the CCK-A receptor gene that covers the first two exons and the promoter region and prevents expression of the receptor (9). They are hyperphagic and become obese and develop non-insulin-dependent diabetes mellitus. The hyperphagia is characterized by increased meal size and decreased responsiveness to dietary fat and possibly other nutrients, consistent with the interpretation that the lack of CCK-A receptors results in a satiety deficit (5, 34). The results presented in this manuscript confirm that CCK-A receptor activity is necessary for the feeding response to enterostatin.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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All experiments on Sprague-Dawley (SD) rats (Harlan-Sprague-Dawley, Indianapolis, IN) were performed at the Pennington Center and approved by its Institutional Animal Care and Use Committee (IACUC). These rats, aged 8 wk and weighing 198–236 g on arrival, were housed individually in wire-mesh hanging cages in a light-controlled (lights on 0700–1900) and temperature-controlled (22°C) room. Rats were provided water ad libitum through an automated watering system. Experiments with OLETF (15–18 wk old, 600–700 g body wt) and their lean Long Evans Tokushima Otsuka (LETO) (15–18 wk old, 425–500 g body wt) control rats (Otsuka Pharmaceutical) (9, 36) were performed by Dr. G. Schwartz at Johns Hopkins University and approved by their IACUC. They were obese and suspected to be prediabetic but not diabetic. These rats were housed under similar conditions to those at the Pennington Center.
Diets
Rats either were fed a high-fat (HF) diet or allowed to select from a two-choice HF/low-fat (LF) diet protocol. The composition of these diets has been described previously (14). The HF diet (4.78 kcal/g) consisted of 56% fat energy, 20% carbohydrate energy, and 24% protein energy, and the LF diet (3.66 kcal/g) consisted of 10% fat energy, 66% carbohydrate energy, and 24% protein energy. Each diet was equivalent in its micronutrient content per calorie. The diets were supplied on an ad libitum basis with feeding jars. In two-choice diet selection regimes, the positions of two separate feeding jars were alternated on a daily basis.
Surgery
The surgeries were performed on rats anesthetized by subcutaneous injection of 1.25 ml/kg body wt of the mixture of ketamine (80 mg/ml), acepromazine (1.6 mg/ml), and xylazine (5 mg/ml).
Intracerebraventricular cannulas. Rats were placed in a stereotaxic frame with incisor bar 3.3 mm below the ear bar. Stainless steel guide cannulas (22 gauge, 12 mm long) were implanted with the following coordinates: 1.4 mm lateral to midline, 0.8 mm posterior to bregma, and 3.5 mm ventral to the dura according to the atlas of Paxinos and Watson (31). The cannulas were secured in place with three anchor screws and dental acrylic and occluded with a 26-gauge wire stylet. On test day, the peptide administrations were made through a injector projected 0.5 mm beyond the guide cannula. The placement of each cannula was verified at the end of experiments by injecting blue dye. The brain was removed and cut coronally to view the location of the blue dye. Only the data from rats showing blue dye in the ventricular system were included in the results.
Near-celiac arterial catheter. The left common carotid artery of a
rat was exposed after a midline incision over the neck and dissection of the
overlying fascia and muscles. Polyurethane tubing (ID 0.40 mm, OD 0.76 mm,
PhysioCath, Data Science International, St. Paul, MN), filled with heparinized
saline (30 U/ml), was inserted through the left carotid artery caudally. It
was passed into the aorta until its tip resided 10–15 mm above the
celiac-arterial junction. This required 
70 mm length of tubing inside the
artery. The distal end of the catheter was connected to 20-mm length of
25-gauge stainless steel tubing and tightly covered with a cap made from
polyethylene tubing. The catheter was then exteriorized through the dorsal
skin of the neck and secured to the skull with acrylic dental cement anchored
to three stainless steel screws. The catheter was filled with a solution of
50% polyvinylpyrrolidone (mol wt 40,000, Sigma Chemical, St. Louis, MO) in
saline, containing 1,000 U heparin/ml. This solution prevented occlusion of
the catheter. At the end of the experiments, the patency of catheters for
near-celiac arterial delivery was checked by infusion of 0.1 ml green dye
(McCormick, Adams Extract, Austin, TX) to anesthetized rats after the
abdominal organs were exposed. Only the rats that showed green coloring in the
gastric vasculature within 2 min were included in the results.
All of the animals were allowed at least 7 days to recover from surgery before testing.
Reagents
Enterostatin (APGPR) was synthesized by the Core Laboratory of the
Louisiana State University Medial Center (New Orleans, LA). It was freshly
dissolved in sterile saline (0.9% wt/vol for arterial and
intracerebroventricular injections) on the day of testing. CCK-8S,
-casomorphin-(1–7) (Sigma Chemical), and lorglumide sodium
(Research Biochemical International, Natick, MA) were also dissolved in 0.9%
sterile saline.
Experimental Procedures
Feeding studies in food-deprived rats. Rats were adapted to either HF diet or two-choice HF/LF diet for 14 days before the experiments. All of the studies were conducted on the overnight food-deprived rats with free access to water. Enterostatin, CCK, or lorglumide and their vehicles were administered at various doses according to different injection routes as described below. After injections, rats were returned to their home cage for refeeding where preweighed food jars with fresh diets were provided. The intake of the diet was measured by weighing the food jar and spillage at various time intervals.
PERIPHERAL ENTEROSTATIN IN OLETF RATS. OLETF and control LETO rats were injected intraperitoneally with saline vehicle or enterostatin [300 µg/kg (604 nmol/kg)]. The intake of HF diet was measured at 0.5, 1, 2, and 4 h.
PERIPHERAL CCK INJECTION ON TWO-CHOICE HF/LF DIET IN SD RATS. CCK-8S [0.5 and 1 µg/kg (0.44 and 0.88 nmol/kg, respectively)] and saline vehicle were given intraperitoneally. CCK-8S, the sulfated octapeptide, was used in these studies because it has a more potent effect on feeding than that of nonsulfated CCK-8 when given by the intraperitoneal route (41). The intake of the HF/LF diet was measured at 0.5 and 1 h.
LORGLUMIDE (INTRAPERITONEAL) EFFECT ON THE RESPONSE TO NEAR-CELIAC ARTERIAL AND INTRACEREBROVENTRICULAR ENTEROSTATIN IN SD RATS. The CCK-A receptor antagonist lorglumide [300 µg/kg (623 nmol/kg) ip] was injected to rats 10 min before either near-celiac arterial injection of enterostatin (2 nmol) or saline vehicle (0.5 ml) or intracerebroventricular injection of enterostatin (1 nmol) or saline vehicle (5 µl). After near-celiac arterial injections, food intake was measured at 5, 10, 20, 30, and 60 min, whereas after intracerebroventricular injection, food intake was measured at 0.5, 1, 2, and 4 h, in line with the time courses of response that have previously been reported (12, 16, 30).
INTRACEREBROVENTRICULAR LORGLUMIDE EFFECT ON THE RESPONSE TO INTRACEREBROVENTRICULAR AND NEAR-CELIAC ARTERIAL ENTEROSTATIN. A similar protocol was used to that described in the previous section. Lorglumide (5 nmol icv) or saline vehicle (5 µl) was injected 20 min before either intracerebroventricular (1 nmol) or near-celiac arterial (2 nmol) injection of enterostatin.
Displacement of enterostatin to [3H]L-364,718 binding to
NIH/3T3 cells expressing CCK-A receptors. NIH/3T3 cells expressing the
human CCK-A receptor gene (lot 508–60008; New England Nuclear Life
Science Products, Boston, MA)
(40) were incubated in 500
µl buffer containing 50 mM Tris·HCl, pH 7.4, 5 mM MgCl2,
0.2% bovine serum albumin fraction V, and 0.5 nM
[N-methyl-3H]L-364,718 (CCK-A receptor antagonist;
specific activity 2,863 GBq/mmol; New England Nuclear) with or without excess
either cold CCK-A antagonist lorglumide or the peptides VPDPR and APGPR or
-casomorphin-(1–7) at concentrations from 0 to 500 µM.
Incubation was for 60 min at 4°C. The incubates were filtered over GF/C
filters presoaked in 0.3% polyethylenimine. The filters were washed nine times
with ice-cold 50 mM Tris·HCl buffer, pH 7.4. Membranes were dissolved
in EcoLite(+) (ICN Biomedicals, Costa Mesa, CA) and counted by liquid
scintillation.
Autoradiography of 125I-CCK-8S binding to brain sections. SD rats at 8 wk of age were decapitated, and brains were rapidly dissected and frozen in dry ice. Frozen coronal sections (14 µm) were cut on a cryostat and thaw-mounted onto glass slides. After preincubation in 50 mM Tris, 100 mM NaCl buffer (pH 7.5) for 20 min, they were incubated with 100 pM 125I-Bolton Hunter CCK-8S (Amersham Pharmacia Biotech, NJ), 50 mM Tris·HCl, 10 mM MgCl2, 0.1% bovine serum albumin, and 0.05% bacitracin in a humid chamber at room temperature for 60 min. Competition studies were performed by adding either CCK-8S (0.4 mM) or enterostatin (2 mM) to the adjacent sections. The slides were washed 3 x 5 min with Tris buffer solution and then dipped briefly in ice-cold water to remove buffer salts. After drying at room temperature, the slides were placed in X-ray cassettes and apposed to Biomax-MS film (Amersham) at -70°C. The films were developed automatically (Kodak X-OMAT Processor) after 2-day exposure.
Data Analysis
Cumulative food intake (g) is presented as means ± SE. The intake of two-choice HF/LF diet is shown as kilocalories. Statistical analysis was performed using repeated-measures ANOVA with time as repeated factors. Duncan's adjustment was used in the post hoc analysis to preserve an overall P < 0.05 level.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Effect of enterostatin in OLETF rats. OLETF rats have a mutation in the CCK-A receptor gene that prevents expression of the receptor protein (9). After an overnight fast, the intake of HF diet was significantly increased in OLETF rats compared with their control LETO rats (Fig. 1). Enterostatin given by the intraperitoneal route had no effect in either strain when administered at a dose of 100 µg/kg (data not shown); the higher dose of enterostatin (300 µg/kg) significantly reduced food intake in the control LETO rats during the first 3 h of feeding and with a maximum reduction of 23% at 1 h (saline 8.14 ± 0.39 g vs. enterostatin 6.31 ± 0.47 g, P < 0.05) but had no effect on the food intake of the CCK-A receptor-deficient OLETF rats (saline 8.7 ± 0.52 g vs. enterostatin 8.22 ± 0.83 g, P < 0.05). ANOVA shows significant effects of enterostatin (F1,16 = 5.83, P = 0.03).
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Effect of peripheral CCK in two-choice HF/LF selection. If enterostatin acts through CCK-A receptors, it would be expected that CCK and enterostatin should share similar selective effects on intake of dietary fat. Figure 2 shows the effect of peripherally administered CCK on caloric intake of rats allowed to select between HF and LF diets. The ingestion of HF diet was reduced by 36% at the higher dose of CCK (1 µg/kg) (saline 16.8 ± 1.4 kcal vs. CCK 10.7 ± 2.1 kcal, P < 0.05), but there were no significant effects on the intake of the LF diet. This reflected a decrease in the total weight of food intake eaten in the CCK-treated group at 30 min (saline 7.42 ± 0.37 g vs. CCK 6.22 ± 0.56 g, P < 0.05) but not at 60 min (saline 9.68 ± 0.45 g vs. CCK 9.57 ± 0.50 g).
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Effect of peripheral lorglumide on the response to near-celiac arterial and intracerebroventricular enterostatin. Lorglumide is a selective antagonist of CCK-A receptor subtypes that crosses the blood-brain barrier. At a dose of 1 mg/kg ip, lorglumide has been shown previously to have no effect on feeding behavior (8). In a pilot study, we showed that a lorglumide dose of 300 µg/kg that had no effect on food intake by itself completely reversed the CCK-induced inhibition of feeding (data not shown). Hence we used this dose in the current studies. As shown in Fig. 3, lorglumide (300 µg/kg ip) alone had no effect on food intake. However, it blocked the inhibitory effect of enterostatin given both into the near-celiac artery (Fig. 3A) and into the brain lateral ventricle (Fig. 3B) on intake of the HF diet. A reduction in food intake was observed 5 min after the near-celiac arterial enterostatin injection, and this was maintained for 30 min (P < 0.01 vs. saline control group). Preinjection of lorglumide reversed this feeding suppression. ANOVA indicated a significant effect of arterial enterostatin treatment on feeding over the 60 min (F1,27 = 6.71, P = 0.0153).
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Similarly, a lorglumide inhibitory effect was observed in the rats given intracerebroventricular enterostatin (Fig. 3B). Intracerebroventricular enterostatin decreased the intake of HF diet by 34% at 0.5 h (P < 0.05 vs. saline control). Again, this reduction was reversed by lorglumide. The effects of intracerebroventricular enterostatin (F1,35 = 7.892, P = 0.008) were significant, and there were significant effects of lorglumide or the treatment interaction (Fig. 3B).
Effect of intracerebroventricular lorglumide on the response to
near-celiac arterial and intracerebroventricular enterostatin. When
lorglumide was given intracerebroventricularly before intracerebroventricular
injection of enterostatin, it blocked the enterostatin-induced reduction in
intake of the HF diet. The enterostatin group consumed 25% less diet relative
to saline control at 1 h (P < 0.05)
(Fig. 4B). Overall
ANOVA revealed a significant enterostatin treatment effect
(F1,54 = 8.21, P = 0.006) but nonsignificance for
the effects of lorglumide or for the treatment interaction. In contrast,
intracerebroventricular lorglumide failed to block the rapid inhibitory effect
of near-celiac arterial enterostatin on intake of the HF diet. Both the
enterostatin group and the lorglumide plus enterostatin group ate less than
the control group (50% reduction at 10 min)
(Fig. 4A). ANOVA shows
significant enterostatin effects (F1,26 = 10.55,
P = 0.003) but no effect of lorglumide and/or of the
enterostatin-lorglumide interaction.
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Displacement of enterostatin from [3H]L-364,718 for CCK-A
receptor in 3T3 cells. 3T3 cells transfected with the CCK-A receptor gene
were used to investigate if enterostatin or its analogs could displace ligands
from binding sites on this receptor. Lorglumide displaced the specific CCK-A
ligand [3H]L-364,718 from binding with an approximate half-maximal
displacement at 1.5 µM (Fig.
5). However, neither the rat nor human enterostatin APGPR
(46) nor the enterostatin
analog VPDPR nor the enterostatin antagonist -casomorphin-(1–7)
was able to displace the L-364,718 from binding sites at concentrations up to
500 µM.
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Effect of enterostatin on 125I-CCK binding to brain sections of rat. Autoradiographic analysis of coronal sections of rat brain showed binding of the 125I-CCK-8S to multiple brain sites (amygdala, cortex, hippocampus, hypothalamus, and brain stem). Figure 6 shows an example of the high density of CCK-8S binding in the amygdala (Fig. 6A). This binding was displaced by excess cold CCK in adjacent sections (Fig. 6B) but could not be displaced by addition of higher doses of cold enterostatin (Fig. 6C). Similar effects were seen in the cortex.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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There are multiple questions on the role of CCK-A receptors in modulating the response to enterostatin. The first relates to the site of the CCK-A receptors that modulate the response. After the initial observations that enterostatin given intraperitoneally would inhibit intake of dietary fat (28), localized infusions of enterostatin, initially into the stomach (45) or duodenum (24) and subsequently into the near-celiac artery (12), have suggested that the gastric-proximal duodenum region is a peripheral site of action. Both the procolipase precursor protein and enterostatin have been localized to mucosal layers in this region by using immunohistochemical approaches (23, 39). We have further demonstrated that the feeding response to intraperitoneal and near-celiac arterial enterostatin is mediated through the afferent vagal system because both selective hepatic vagotomy and capsaicin treatment abolish the response (12, 42).
CCK given peripherally or into the near-celiac artery inhibits food intake (3). This response is likewise recognized to result from an activation of afferent vagal neurons from the gastrointestinal tract to the brain stem and higher brain centers (38). Indeed CCK-A receptors are present in afferent vagal neurons to the NTS region of the brain stem (4). Thus it is possible that enterostatin modulates its response from the periphery by activation of a subset of CCK-dependent vagal afferent neurons. Lorglumide, given peripherally, inhibited the response to both near-arterial and intracerebroventricular enterostatin. Because lorglumide can cross the blood-brain barrier, this experiment did not differentiate between peripheral or central CCK-A receptors in modulating these responses to enterostatin. However, the demonstration that intracerebroventricular administration of small amounts of the CCK-A receptor antagonist lorglumide inhibited the response to intracerebroventricular but not to near-celiac arterial enterostatin suggests that central CCK-A receptors are necessary for the response to intracerebroventricular enterostatin, whereas peripheral CCK-A receptors, presumably those in the gastrointestinal tract or afferent vagus, are necessary for the response to near-arterial enterostatin. The location of these central CCK-A receptors is unclear at this time. CCK-A receptors have been localized to afferent vagal fibers (4) and also to the area postrema and NTS regions of the hindbrain (2), as well as to numerous regions within the forebrain, including the nucleus accumbens, and substantia nigra (26).
A second question is whether enterostatin modulates its response by stimulation of CCK release. There are many similarities between the peripheral responses to CCK and enterostatin in that they both activate afferent vagal neurons to the NTS (6, 42), both decrease gastric emptying and meal size (21, 35), both may be mediated by near-celiac arterial injections (3, 12), and both induce c-fos expression in the amygdala, paraventricular nucleus, supraoptic nucleus, and NTS. (6, 42). Furthermore, peripheral CCK had a selective effect in reducing the intake of an HF diet in rats allowed to choose between HF and LF diets, as does enterostatin, confirming some but not all previous reports (1, 43). While the effect of exogenous enterostatin to suppress food intake appears to last longer than that of exogenous CCK, this could be explained by a continued endogenous secretion of CCK in response to enterostatin. These data raise the possibility that enterostatin stimulates CCK secretion and that this action mediates its effects on dietary fat intake. If this were the case, it would suggest that the response to central enterostatin is mediated by central release of CCK to activate CCK-A receptors because intracerebroventricular injection of lorglumide had differential responses to peripheral and intracerebroventricular enterostatin. Thus, although we do not have any direct data on CCK levels after enterostatin treatment, it is possible that stimulation of CCK release, either peripherally or in the central nervous system, is the mechanism through which enterostatin has its effect on feeding behavior.
Another possibility is that enterostatin can compete with CCK for binding to its receptors. Such an effect, limited to those neuronal regions in the central nervous system where procolipase and enterostatin are expressed, could have selective effects on macronutrient selection. However, two pieces of evidence point against this possibility. First, we were unable to show any displacement of the CCK-A ligand L-364,718 from binding sites in NIH/3T3 cells expressing the CCK-A receptor. Second, autoradiographic analysis of 125ICCK-8S binding to brain slices did not show any displacement of the labeled ligand with high concentrations of enterostatin.
The response to enterostatin requires a fat-related signal to be effective. Thus rats fed LF diets do not normally respond to enterostatin (27). Furthermore, when rats are switched to an HF diet from their habitual high-carbohydrate diet, the enterostatin response does not become evident for 7–14 days (20). It is possible that CCK-A receptor function is important for recognition of dietary fat. Its ability to function in this role is evident from the failure of OLETF rats to reduce voluntary food intake in response to gastric preloads of intralipid, whereas they show a normal suppression of feeding to carbohydrate and protein preloads (36) although this finding has not been verified in a subsequent study (5). Duodenal lipids suppress feeding, an effect that is blocked by CCK-A receptor antagonists (11). Furthermore, the recognition of lipoprivic feeding signals is dependent on the afferent vagus (34) as are the responses to both peripheral CCK (38) and enterostatin (12, 42). Thus it is possible that the CCK-A receptor activity is needed for the recognition of dietary fat intake and that this is permissive to the response to enterostatin. However, such an explanation would not provide insight into the requirements for the CCK-A receptor activity to be localized to the same area in which the enterostatin was injected.
There are multiple endocrine and peptidergic systems that effect food intake by actions either in the periphery or in the central nervous system. Little attention has been directed to the interactions between these systems. However, it is clear that CCK has a synergistic interaction with both leptin and insulin to reduce food intake (22, 32). We were unable to show such a synergism between CCK and enterostatin (White and York, unpublished observations) but rather a permissive requirement for CCK-A receptor function for the response to enterostatin. Both CCK and enterostatin are short-term regulators of feeding, affecting the size of the first meal taken but not subsequent meals, whereas leptin and insulin affect multiple meals over the long term. These different relationships might be explained if CCK acts as a neurotransmitter within the pathway that is activated by enterostatin, whereas CCK may independently presynaptically activate neurons that themselves are activated by leptin and/or insulin.
Functional studies using stereotaxic injections of agonists and antagonists
have suggested that enterostatin activates a pathway that includes a
serotonergic system (47,
48) within the paraventricular
nucleus that inhibits fat intake
(37) and a -opioidergic
system within the NTS that promotes fat intake
(47,
48). Previous data have shown
that the µ-opioid agonist -casomorphin-(1–4) did not increase
the intake of HF diet or block the response to enterostatin, whereas
-casomorphin-(1–7) did
(16). In contrast to the
behavior data, all three casomorphins
(1–7,
1–5,
1–4)
were able to displace enterostatin from binding sites on brain membranes
(16). We interpreted these
data as showing the importance of the terminal three carboxyl amino acids for
the biological activity of casomorphins-(1–7) and -(1–5) to block
the enterostatin effects on food intake and that these effects were
independent of the µ-opioid activity that is mainly related to the
casomorphin-(1–4) residues. These results suggested that a µ-opioid
mechanism is not involved in the pathway affected by enterostatin. In
contrast, studies with -opioid agonists and antagonists do suggest the
involvement of a -opioid system that is localized to the NTS region of
the brain stem (47,
48). The relationship of these
systems to the CCK receptor component identified in the current studies awaits
further investigation using both immunohistochemical and behavioral
approaches.
Perspectives
The results of these studies provide further insight into the mechanism through which enterostatin modulates the intake of dietary fat. They suggest the possibility that enterostatin may stimulate CCK secretion both peripherally and within the central nervous system. Recognition that environmental, physiological, and pharmacological factors can influence the ingestion of specific dietary components, such as sodium or fat, emphasizes the complexity of feeding behavior; it suggests that the composition of the diet eaten is probably the result of the integration of multiple independent pathways affecting a spectrum of micro- and macronutrients. Understanding the pathway(s) that regulate fat intake may have significant benefits for the treatment of chronic diseases in which dietary fat is a significant risk factor.
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FOOTNOTES |
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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.
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REFERENCES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-Casomorphins stimulate and enterostatin
inhibits the intake of dietary fat in rats. Peptides
19: 325–331,
1998.[Web of Science][Medline]
-casomorphin attenuates the
suppression of fat intake by enterostatin. Peptides
21: 1377–1381,
2000.[Web of Science][Medline]
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