Leptin fails to reduce ethanol intake in Marchigian Sardinian alcohol-preferring rats

Leptin, a hormone secreted by the adipocytes and involved in feeding and energy balance control, has been proposed to modulate alcohol craving in mice and humans. This study evaluated whether leptin modulates alcohol intake in Marchigian Sardinian alcohol-preferring (msP) rats. Rats were offered 10% ethanol either 2h per day at the beginning of dark period of the 12:12h light/dark cycle, or 24h per day. Leptin was injected into the lateral ventricle (LV), the third ventricle (3V), or intraperitoneally (IP) once a day, 1h before the onset of the dark period. Neither acute nor chronic (9 days) leptin injections (1 or 8microg per rat) into the LV or 3V modified ethanol intake in male msP rats, offered ethanol 2h per day. Chronic LV injection of leptin (8 or 32 microg per rat in male rats and 8 or 16 microg per rat in female rats for 7 days), or chronic IP injections of leptin (1mg/kg in male rats for 5 days) failed to modify the intake of ethanol, offered 24h per day. Finally, chronic LV leptin injections (8 or 32 microg per rat for 12 days) did not modify ethanol intake in male msP rats, adapted to ad libitum access to ethanol and then tested after a 6-day period of ethanol deprivation. In contrast, in most of these conditions leptin significantly reduced food intake. These data do not support a role for leptin in alcohol intake, preference, or craving in msP rats.     

Effect of the melanocortin receptor stimulation or inhibition on ethanol intake in alcohol-preferring rats

It has been recently reported that acute intracerebroventricular injection of 1 nmol/rat of the non-selective melanocortin 3 and 4 receptor (MC3/4) agonist MTII reduces ethanol intake in female AA alcohol-preferring rats and alters opioid peptide levels in the ventral tegmental area of rats. To better understand the role of the MC system in the control of ethanol intake, we tested the acute and chronic effects of lateral ventricular (LV) injections of 0.01-1 nmol MTII, of 0.1-1 nmol of the MC3/4R receptor antagonist agouti related peptide (AgRP), and 0.1-0.5 nmol of the MC3/4R receptor antagonist SHU9119 on food, water, and 10% ethanol intake in Marchigian-Sardinian alcohol-preferring (msP) rats, which spontaneously ingest pharmacologically relevant quantities of ethanol both under short and long term access conditions. The data showed that with 2h/day ethanol access, LV MTII injections reduced intake of food and ethanol intakes. When food, water, and ethanol were available ad libitum and 0.01 nmol MTII was given by daily LV injection, however, ethanol intake was reduced for only the first 2 days, whereas food intake was reduced for all 5 days of treatment. Finally, acute LV injection of neither AgRP nor SHU9119 affected ethanol intake under ad libitum conditions, although both antagonists significantly increased food and water intake. In conclusion, these data fail to support a role for endogenous MC3/4R in the control of spontaneous ethanol intake in the msP rat. MC3/4R agonism, however, reduced ethanol intake in association with reduced food intake, suggesting that MTII might reduce nutrient-related controls of ethanol intake rather than, or in addition to, reward-related controls of ethanol intake.     

Chronic intracerebroventricular infusion of nociceptin/orphanin FQ increases food and ethanol intake in alcohol-preferring rats

Central administration of low doses of nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the opioid-like orphan receptor NOP, have been shown to reduce ethanol consumption, ethanol-induced conditioned place preference and stress-induced reinstatement of alcohol-seeking behavior in alcohol preferring rats. The present study evaluated the effect of continuous (7 days) lateral brain ventricle infusions of N/OFQ (0, 0.25, 1, 4, and 8 microg/h), by means of osmotic mini-pumps, on 10% ethanol intake in Marchigian-Sardinian alcohol-preferring (msP) rats provided 2h or 24h access to it. N/OFQ dose-dependently increased food intake in msP rats. On the other hand, in contrast to previous studies with acute injections, continuous lateral brain ventricle infusion of high doses of N/OFQ increased ethanol consumption when the ethanol solution was available for 24h/day or 2h/day. The present study demonstrates that continuous activation of the opioidergic N/OFQ receptor does not blunt the reinforcing effects of ethanol. Moreover, the data suggest that continuous activation of the opioidergic N/OFQ receptor is not a suitable way to reduce alcohol abuse.     

The H3 receptor is involved in cholecystokinin inhibition of food intake in rats.

We investigated the peripheral effects of an H3-receptor agonist and an H3-receptor antagonist (R)alpha-methylhistamine (Ralpha-MeHA) and thioperamide, respectively, on basal feeding and the CCK8-induced inhibition of food intake in rat. Intraperitoneal injection of thioperamide reduced food intake in a dose-dependent manner with maximal inhibition (35%, P<0.01 vs saline) at 3 mg/kg. (R)alpha-MeHA (0.3-3 mg/kg i.p.), an H3-receptor agonist alone had no effect on feeding but reversed the thioperamide-induced inhibition of food intake in a dose-dependent manner. The maximal feeding inhibitory dose of thioperamide (3 mg.kg i.p) increased by 40% and 22 % (P<0.01 vs saline) brain and stomach histamine contents, respectively. Histamine (0.3 - 6 mg/kg i.p.) and CCK-8 (3 - 30 microg/kg i.p) also inhibited food intake in a dose-dependent manner. Inhibition was 20% to 40% for histamine and 40% to 80% (P<0.01 vs saline) for CCK8. CCK-8 inhibition of feeding was increased by thioperamide and prevented by (R)alpha-MeHA in a dose-dependent way. In addition, CCK-8 did not reduce food intake if rats were pretreated with pyrilamine or ranitidine postsynaptic H1- and H2-receptor antagonists respectively. Our data suggest that the H3-receptor is involved in basal feeding. They also suggest that CCK satiety depends upon the release of histamine which acts on the H2- and H1-receptors, the final mediators of this effect.     

Proglumide fails to increase food intake after an ingested preload

Proglumide, a selective antagonist of exogenous cholecystokinin in vitro, also inhibits the reduction of food intake induced by the systemic administration of cholecystokinin octapeptide (CCK-8) in food deprived rats. On the basis of an increase in the size of a brief test meal which followed an oral preload and treatment with a single dose of proglumide, it was suggested that a role for endogenous cholecystokinin in satiety had been demonstrated. We attempted to replicate this finding and could not under very similar experimental conditions. Subsequently, we tested whether other proglumide doses would antagonize the satiating effect of a larger oral preload on test meal intake. When these results were also found to be negative, we confirmed that proglumide (at several doses) significantly antagonized the reduction in food intake induced by exogenous CCK-8 under our conditions. Since proglumide antagonized the satiating effect of exogenous CCK-8, but did not increase food intake after oral preloads that were presumed to release endogenous CCK, we conclude that a reliable satiating effect of endogenous CCK remains to be demonstrated.     

Pharmacological characterization of the nociceptin receptor which mediates reduction of alcohol drinking in rats

Chronic intracerebroventricular (ICV) treatment with nociceptin/orphanin FQ (NC), the endogenous ligand for the opioid receptor-like 1 (ORL1) receptor, reduces ethanol intake in alcohol-preferring rats and abolishes the rewarding properties of ethanol in the place conditioning paradigm. To pharmacologically characterize the receptor involved, the present study evaluated the effect on ethanol drinking in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats of ICV injections for 8 days of NC or of the NC analogs NC(1-17)NH(2), NC(1-13)NH(2), NC(1-12)NH(2) and [Nphe(1)]NC(1-13)NH(2). In vitro studies indicate that NC, NC(1-17)NH(2), NC(1-13)NH(2) and NC(1-12)NH(2) are agonists, while [Nphe(1)]NC(1-13)NH(2) is a selective antagonist at the ORL1 receptor. Freely feeding and drinking rats were offered 10% ethanol 30 min/day at the beginning of the dark phase of the light cycle. NC significantly attenuated ethanol intake at 500 or 1000 ng/rat (210 or 420 pmol/rat). NC(1-17)NH(2), markedly reduced ethanol intake, but its effect was statistically significant at 1000 (420 pmol/rat), not at 500 ng/rat (210 pmol/rat). After the end of treatment ethanol drinking promptly came back to baseline level. Ethanol consumption was also reduced by NC(1-13)NH(2); however, its effect was less potent and pronounced. NC(1-12)NH(2) did not modify ethanol intake at doses up to 4000 ng/rat (2339 pmol/rat). Water and food consumption were not modified. Treatment with [Nphe(1)]NC(1-13)NH(2), 66 or 99 microg/rat, did not modify ethanol intake; however, [Nphe(1)]NC(1-13)NH(2), 66 microg/rat, given just before 1000 ng/rat of NC(1-17)NH(2), abolished the effect of the agonist. The present results show that the 13 amino acid N-terminal sequence of NC is essential for the effect on ethanol intake and indicate that [Nphe(1)]NC(1-13)NH(2) acts as an antagonist to block the effect of NC. These findings provide further evidence that selective agonists at the ORL-1 receptor attenuate ethanol intake in alcohol-preferring rats and suggest that the NC/ORL1 system may represent an interesting target for treatment of alcohol abuse.     

Cholecystokinin, behavioral tolerance and tumor-induced anorexia

Cholecystokinin octapeptide (CCK-8, 5 micrograms/kg, IP) was injected daily, for two 4-day periods, into rats bearing the Walker 256 carcinosarcoma (TB) and non-tumor bearing (NTB) control animals. All animals were on a 20 hr food and water deprivation schedule and monitored for food and water intake and bodyweight for 4 hr daily. Food intake was significantly reduced by the daily administration of CCK. Behavioral tolerance to CCK was not observed in either the NTB or TB rats. These results indicate that the parameters describing the phenomenon of behavioral tolerance to CCK are yet to be clearly defined and that peptides other than CCK may underlie the mechanism primarily responsible for producing anorexia associated with cancer.     

Effect of spontaneous ingestion of ethanol on brain dopamine metabolism

The effect of ethanol, either administered by gavage or voluntarily ingested, on brain dopamine (DA) metabolism was studied in alcohol-preferring and alcohol non-preferring rats. In alcohol non-preferring rats ethanol administration (2 g/kg) increased 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and reduced DA levels in the caudate nucleus and olfactory tubercle but was ineffective in the medial prefrontal cortex. In alcohol-preferring rats ethanol effect was greater than in non-preferring animals and ethanol influenced DA metabolism also in the medial prefrontal cortex. The effect of voluntary ethanol ingestion was studied in alcohol-preferring rats trained to consume their daily fluid intake within 2 hrs. Voluntary ingestion of ethanol (3.1 +/- 0.7 g/kg in 1 hr) increased DA metabolites and reduced DA levels in the caudate nucleus, olfactory tubercle and medial prefrontal cortex. The results suggest that voluntary ethanol ingestion increases the release of DA from nigro-striatal and meso-limbic DA neurons.     

Endogenous cholecystokinin reduces food intake and increases Fos-like immunoreactivity in the dorsal vagal complex but not in the myenteric plexus by CCK1 receptor in the adult rat

We hypothesized that endogenous CCK reduces food intake by activating the dorsal vagal complex (DVC) and the myenteric neurons of the gut. To test this hypothesis, adult rats were given camostat mesilate; a nonnutrient releaser of endogenous CCK, by orogastric gavage, and Fos-like immunoreactivity (Fos-LI) was quantified in the DVC and the myenteric plexus. The results for endogenous CCK were compared with those for exogenous CCK-8. Exogenous CCK-8 reduced food intake and stimulated Fos-LI in the DVC and in myenteric neurons of the duodenum and jejunum. In comparison, endogenous CCK reduced food intake and increased DVC Fos-LI but did not increase Fos-LI in the myenteric plexus. Similar to CCK-8, devazepide, a specific CCK(1) receptor antagonist, and not L365,260, a specific CCK(2) receptor antagonist, attenuated the reduction of food intake by camostat. In addition, Fos-LI in the DVC in response to both exogenous CCK-8 and camostat administration was significantly attenuated by vagotomy, as well as by blocking CCK(1) receptors. These results demonstrate for the first time that reduction of food intake in adult rats by endogenous CCK released by a nonnutrient mechanism requires CCK(1) receptors, the vagus nerve, and activation of the DVC, but not the myenteric plexus.     

Gastroprotection and control of food intake by leptin. Comparison with cholecystokinin and prostaglandins.

Circulating peptide leptin which is the product of the ob gene is known to provide feedback information on the size of fat stores to central OB-receptors that control food intake. Recently, leptin messenger RNA and leptin protein have been detected in gastric epithelium and leptin was found to be released by CCK into circulation but the physiological role of this gastric leptin remains unknown. As CCK has been reported to protect gastric mucosa against various noxious agents, we designed the study to determine the influence of leptin and CCK on the gastroprotection and the control of food intake and to compare them with classic gastroprotective substance, prostaglandin E2, in rats with acute gastric mucosal lesions induced by topical application of 75% ethanol. Four series of Wistar rats (A, B, C and D) were used to determine; A) the effects of various doses of leptin (0.1-10 microg/kg) given intraperitoneally (i.p.) on ethanol-induced gastric lesions, gastric blood flow (GBF) and plasma levels of immunoreactive leptin; B) the effects of various doses of CCK-8 (0.1-10 microg/kg i.p.) on ethanol-induced gastric lesions, GBF and plasma levels of leptin; C) the effects of various doses of PGE2 (12.5--100 microg/kg) given intragastrically (i.g.) on ethanol-induced gastric lesions and GBF and D) the influence of leptin, CCK and PGE2 on the intake of liquid meal in rats. Rats were anesthetized with ether 1 h after i.g. administration of 75% ethanol to measure the GBF using H2-gas clearance technique and blood samples were withdrawn for the measurement of plasma leptin levels by radioimmunoassay (RIA). Food intake was assessed in separate group of rats fasted 18 h and then fed with liquid caloric meal. Leptin, CCK and PGE2 reduced dose-dependently gastric lesions induced by 75% ethanol, the dose reducing these lesions by 50% (ED50) being, respectively, 1 microg/kg, 5 microg/kg and 20 microg/kg. The protective effects of leptin, CCK-8 and PGE2 were accompanied by significant attenuation of the fall of the GBF caused by ethanol. Leptin and CCK reduced also dose-dependently the food intake while PGE2 was not effective. Leptin and CCK resulted a dose-dependent increment in the plasma leptin levels. We conclude that: 1) exogenous leptin and CCK, causing similar increments in plasma immunoreactive leptin levels, protect dose-dependently gastric mucosa against the damage provoked by 75% ethanol; 2) Leptin and CCK afford similar gastroprotective activity to that attained with PGE2 but unlike PGE2 were highly effective in the reduction in food intake and 3) the protective effects of leptin, CCK and PGE2 were accompanied by significant increase of GBF suggesting that the protection afforded by these substances are mediated, at least in part, by gastric hyperemia.     

Endogenous amylin contributes to the anorectic effects of cholecystokinin and bombesin

Previous studies indicated that amylin contributes to the anorectic effects of cholecystokinin (CCK) and bombesin (BBS), possibly by enhancing the release of pancreatic amylin or by modulating their anorectic actions within the central nervous system (CNS). To elucidate the interaction between amylin and CCK or BBS, respectively, we investigated the influence of an IP injection of CCK or BBS on feeding in amylin-deficient mice (IAPP(-/-)). The anorectic effects of CCK and BBS were nearly abolished in IAPP(-/-) mice compared to wildtype (WT) mice (e.g. 20 microg/kg CCK, 1-h food intake: WT/NaCl 0.53 +/- 0.03 g; WT/CCK 0.16 +/- 0.03 g (P < 0.001); IAPP(-/-)/NaCl 0.49 +/- 0.05 g; IAPP(-/-)/CCK 0.39 +/- 0.04 g). Acute amylin replacement restored the anorectic effect of CCK in IAPP(-/-) mice.To find out whether CCK or BBS enhance the feeding-induced release of pancreatic amylin, we injected rats with CCK-8 (0.5-50 microg/kg) or BBS (5 microg/kg) and measured plasma amylin levels after injections. Neither CCK nor BBS increased the plasma amylin level in rats. We suggest that the mediation of the anorectic effects of CCK and BBS by amylin is not dependent on a CCK- or BBS-induced release of pancreatic amylin, but may rather be due to a modulation of their effects by amylin within the CNS.     

The inhibition of tail-pinch-induced food intake by cholecystokinin octapeptides and their fragments

The effects of intraperitoneally (ip.) and intracerebroventricularly (icv.) administered sulfated and nonsulfated cholecystokinin octapeptide (CCK-8-SE and CCK-8-NS) and their N- and C-terminal fragments on the tail-pinch-induced feeding behavior of rats were investigated. After ip. administration, only CCK-8-SE inhibited tail-pinch-induced food intake. After icv. administration, both CCK-8-SE and CCK-8-NS, in doses of 800 pmole/rat, reduced the amount of food eaten. Of the CCK fragments tested icv., the sulfated N-terminal fragments, the middle portion of the CCK-8-sequence (the CCK-3-6 fragment), and the C-terminal tetrapeptide depressed the food intake of rats during tail-pinch, whereas the C-terminal tripeptide significantly increased it. The results suggest that CCK peptides inhibit tail-pinch-induced feeding by separate mechanisms, depending on the route of administration.     

Interaction of apolipoprotein AIV with cholecystokinin on the control of food intake

Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are peptides that act both peripherally and centrally to reduce food intake by decreasing meal size. The present study examined the effects of intraperitoneally administered bolus doses of recombinant apo AIV, CCK-8, and a combination of subthreshold doses of apo AIV and CCK on 4-h food intake in rats that were fasted overnight. Apo AIV at 100 microg/kg reduced food intake significantly relative to the saline control for 1 h, as did doses of CCK-8 at or above 0.125 microg/kg. Doses of apo AIV (50 microg/kg) or CCK (0.06 microg/kg) alone had no effect on food intake. However, when these subthreshold doses of apo AIV and CCK were administered together, the combination produced a significant inhibition of food intake relative to saline controls (P < 0.001), and the duration of the effect was longer than that caused by the administration of either apo AIV or CCK alone. The satiation effect produced by CCK-8 + apo AIV was attenuated by lorglumide, a CCK1 receptor antagonist. We conclude that, whereas the intraperitoneal administration of doses of either recombinant apo AIV or CCK at or above threshold levels reduces food intake, the coadministration of subthreshold doses of the two peptides is highly satiating and works via CCK1 receptor.     

In vitro, release of cholecystokinin from hypothalamus and frontal cortex of Sprague-Dawley, Zucker lean (Fa/-) and obese (fa/fa) rats

Cholecystokinin (CCK) has been suggested as a putative satiety factor, whose site of action is in the hypothalamus. The genetically obese (fa/fa) Zucker rat has been proposed as a model of human obesity. Though hypothalamic tissue levels of CCK did not vary between the fa/fa rat and age-matched lean littermates (25.5 +/- 5.7 vs. 27.6 +/- 5.2 pmoles/g tissue) we sought to determine if the releasability of hypothalamic and cortical CCK was the same in lean and obese rats. The in vitro superfusion paradigm was used to study the release of CCK and substance P (sP) from hypothalamus, and CCK and vasoactive intestinal polypeptide (VIP) from frontal cortex. The potassium stimulated release of CCK from obese rat hypothalamic tissue was significantly higher than from lean rat hypothalamus (3.62 +/- 0.3 vs. 1.91 +/- 0.3 fmole equivalents CCK-8/mg tissue/10 min). Similarly, sP release was exaggerated in obese rats in a parallel fashion (5.56 +/- 0.44 vs. 2.761 +/- 0.46 fmoles/mg tissue/10 min). However, the potassium stimulated release of CCK and VIP from cortical tissue was the same in all three groups of rats. The obese Zucker rat thus, may have an anomalous release of CCK and sP from the hypothalamus, but not from the frontal cortex, an area not presumably associated with satiety.     

Anti-inflammatory effects of leptin and cholecystokinin on acetic acid-induced colitis in rats: role of capsaicin-sensitive vagal afferent fibers

Leptin and cholecystokinin (CCK) have a synergistic interaction in the suppression of food intake, and afford similar gastroprotective activity. The present study was designed to investigate the putative protective effects of CCK and leptin on acute colonic inflammation. Leptin or CCK-8s was injected to rats intraperitoneally immediately before and 6 h after the induction of colitis with acetic acid. CCK-A receptor antagonist (L-364,718) or CCK-B receptor antagonist (L-365,260) was injected intraperitoneally 15 min before leptin or CCK treatments. In a group of rats, vagal afferent fibers were denervated by topical application of capsaicin on the cervical vagi. Rats were decapitated at 24 h, and the distal 8 cm of the colon were removed for macroscopic scoring, determination of tissue wet weight index (WWI), histologic assessment and tissue myeloperoxidase (MPO) activity. All inflammation parameters were increased by acetic acid-induced colitis compared to control group. Leptin or CCK-8s treatment reduced these parameters in a similar manner, while co-administration of leptin and CCK was found to be more effective in reducing the macroscopic score and WWI. CCK-8s-induced reduction in the score and WWI was prevented by CCK-A, but not by CCK-B receptor antagonist, whereas neither antagonist altered the inhibitory effect of leptin on colitis-induced injury. On the other hand, perivagal capsaicin prevented the protective effects of both CCK-8s and leptin on colitis. Our results indicate that leptin and CCK have anti-inflammatory effects on acetic acid-induced colitis in rats, which appear to be mediated by capsaicin-sensitive vagal afferent fibers involving the reduction in colonic neutrophil infiltration.     

Effects of cholecystokinin octapeptide (CCK-8) on food intake in adult and aged rats under different feeding conditions

The effects of CCK on food intake were investigated under fixed feeding conditions in comparison to a test meal taken after 16 h of food deprivation. The experiments were performed on young adult rats (8 weeks old) as well on aged rats (23 months old). Intraperitoneal CCK-8 (8 and 40 μg/kg) significantly reduced the size of a test meal following 16-h food deprivation. This effect was independent of the age of the rats. However, under fixed feeding conditions neither of the doses used in this study reduced food intake in the young adult rats, whereas the highest dose of 40 μg/kg did so in the aged rats. These results suggest that the hypophagic effect of exogenous CCK-8 depends on experimental conditions, food intake being reduced after a period of food deprivation but not under a fixed feeding regimen in adult animals. Furthermore, the data suggest that age is a factor contributing to the complex behavioral actions of CCK, because only old animals were more susceptible to an anorectic action of CCK under the fixed feeding schedule. An explanation may lie in an interaction of other known behavioral effects of CCK (e.g., anxiogenic, mnemonic action) with its effects under the different feeding schedules.     

Hyperphagia and obesity in OLETF rats lacking CCK-1 receptors

The brain-gut peptide cholecystokinin (CCK) inhibits food intake following peripheral or site directed central administration. Peripheral exogenous CCK inhibits food intake by reducing the size and duration of a meal. Antagonist studies have demonstrated that the actions of the exogenous peptide mimic those of endogenous CCK. Antagonist administration results in increased meal size and meal duration. The feeding inhibitory actions of CCK are mediated through interactions with CCK-1 receptors. The recent identification of the Otsuka-Long-Evans-Tokushima Fatty (OLETF) rat as a spontaneous CCK-1 receptor knockout model has allowed a more comprehensive evaluation of the feeding actions of CCK. OLETF rats become obese and develop non-insulin dependent diabetes mellitus (NIDDM). Consistent with the absence of CCK-1 receptors, OLETF rats do not respond to exogenous CCK. OLETF rats are hyperphagic and their increased food intake is characterized by a large increase in meal size with a decrease in meal frequency that is not sufficient to compensate for the meal size increase. Deficits in meal size control are evident in OLETF rats as young as 2 days of age. OLETF obesity is secondary to the increased food intake. Pair feeding to amounts consumed by intact control rats normalizes body weight, body fat and elevated insulin and glucose levels. Hypothalamic arcuate nucleus peptide mRNA expression in OLETF rats is appropriate to their obesity and is normalized by pair feeding. In contrast, pair fed and young pre-obese OLETF rats have greatly elevated dorsomedial hypothalamic (DMH) neuropeptide Y (NPY) mRNA expression. Elevated DMH NPY in OLETF rats appears to be a consequence of the absence of CCK-1 receptors. In intact rats NPY and CCK-1 receptors colocalize to neurons within the compact subregion of the DMH and local CCK administration reduces food intake and decreases DMH NPY mRNA expression. We have proposed that the absence of DMH CCK-1 receptors significantly contributes to the OLETF's inability to compensate for their meal size control deficit leading to their overall hyperphagia. Access to a running wheel and the resulting exercise normalizes food intake and body weight in OLETF rats. When given access to running wheels for 6 weeks shortly after weaning, OLETF rats do not gain weight to the same degree as sedentary OLETF rats and do not develop NIDDM. Exercise also prevents elevated levels of DMH NPY mRNA expression, suggesting that exercise exerts an alternative, non-CCK mediated, control on DMH NPY. The OLETF rat is a valuable model for characterizing actions of CCK in energy balance and has provided novel insights into interactions between exercise and food intake.     

Reduced CCK signaling in obese-prone rats fed a high fat diet

Deficits in satiation signaling during obesogenic feeding have been proposed to play a role in hyperphagia and weight gain in animals prone to become obese. However, whether this impaired signaling is due to high fat (HF) feeding or to their obese phenotype is still unknown. Therefore, in the current study, we examined the effects of CCK-8 (0.5, 1.0, 2.0, and 4.0 μg/kg) on suppression of food intake of HF-fed obese prone (OP) and resistant (OR) rats. Additionally, we determined the role of endogenous CCK in lipid-induced satiation by measuring plasma CCK levels following a lipid gavage, and tested the effect of pretreatment with devazepide, a CCK-1R antagonist on intragastric lipid-induced satiation. Finally, we examined CCK-1R mRNA levels in the nodose ganglia. We show that OP rats have reduced feeding responses to the low doses of exogenous CCK-8 compared to OR rats. Furthermore, OP rats exhibit deficits in endogenous CCK signaling, as pretreatment with devazepide failed to abolish the reduction in food intake following lipid gavage. These effects were associated with reduced plasma CCK after intragastric lipid in OP but not OR rats. Furthermore, HF feeding resulted in downregulation of CCK-1Rs in the nodose ganglia of OP rats. Collectively, these results demonstrate that HF feeding leads to impairments in lipid-induced CCK satiation signaling in obese-prone rats, potentially contributing to hyperphagia and weight gain.     

Feeding-suppressive mechanism of sulfated cholecystokinin (26-33) in chicks

The anorexigenic effect of cholecystokinin (CCK) is well documented in mammals, but documentation in neonatal chicks is limited. Thus, the present study investigated the mechanism underlying the anorexigenic effect of CCK in neonatal chicks. Intraperitoneal (IP) injection of sulfated CCK(26-33) (CCK8S) significantly decreased food intake in chicks at 60 and 300 nmol/kg. Non-sulfated CCK(26-33) (CCK8) also significantly decreased food intake, but its anorexigenic effect was observed only at the highest dose (300 nmol/kg) and short-lived. However, CCK(30-33) (CCK4) had no effect on food intake. Also, the intracerebroventricular (ICV) injection of CCK8S (0.2 and 1 nmol) significantly decreased food intake in chicks. Similar to IP administration, the anorexigenic effect of CCK8 was weak and CCK4 did not affect food intake. IP and ICV injections of CCK8S caused conditioned aversion and increased plasma corticosterone concentrations, suggesting that their anorexigenic effects might be related to stress and/or malaise. This might be true in ICV-injected CCK8S because co-injection of astressin, a corticotropin-releasing hormone receptor antagonist, tended to attenuate the effect of CCK8S. The present study revealed that N-terminal amino acids and the sulfation of Tyr are important for the anorexigenic effect of CCK8S after IP and ICV administered in chicks. Additionally, the effect of central CCK8S might be related to stress and/or malaise.     

The effect of cholecystokinin, bombesin and calcitonin on food intake in virgin, lactating and postweaning female rats

During lactation food intake increases greatly without an accompanying large increase in body weight; therefore, this physiological state is an excellent example of non-obese hyperphagia. In the present study, we found that cholecystokinin (CCK-8) decreased food intake in lactating and virgin female rats. However, female rats were more resistant to the effect of CCK on eating following weaning of the pups. Bombesin (BB) suppressed food intake in virgin female rats and in lactating rats during early and mid lactation. Rats were resistant to its satiating effect during late lactation and during the postweaning period. Calcitonin potently suppressed food intake in virgin, lactating and postweaning rats. The present findings suggest that CCK and bombesin decrease food intake more effectively in virgin female rats and during earlier phases of lactation than during late lactation or postweaning.