Effects of peripheral CCK receptor blockade on food intake in rats

Type A cholecystokinin receptor (CCKAR) antagonists differing in blood-brain barrier permeability were used to test the hypothesis that satiety is mediated, in part, by CCK action at CCKARs located peripheral to the blood-brain barrier. At dark onset, non-food-deprived rats received a bolus injection of devazepide (2.5 micromol/kg iv), a 3-h infusion of A-70104 (1 or 3 micromol x kg-1 x h-1 iv), or vehicle either alone or coadministered with a 3-h infusion of CCK-8 (10 nmol x kg-1 x h-1 iv) or a 2-h intragastric infusion of peptone (1 g/h). Food intake was determined from continuous computer recordings of changes in food bowl weight. Devazepide penetrates the blood-brain barrier; A-70104, the dicyclohexylammonium salt of Nalpha-3-quinolinoyl-d-Glu-N,N-dipentylamide (A-65186), does not. CCK-8 inhibited 3-h food intake by more than 50% and both A-70104 and devazepide abolished this response. A-70104 and devazepide stimulated food intake and similarly attenuated the anorexic response to intragastric infusion of peptone. Thus endogenous CCK appears to act, in part, at CCKARs peripheral to the blood-brain barrier to inhibit food intake.     

Synergistic stimulation of food intake by simultaneous insulin and cold

Insulin administered to rats during simultaneous exposure to cold increases food intake by more than the sum of the separate feeding responses and prevents the normal cold-induced loss of body weight. On withdrawal of insulin with cold maintained, all the body weight maintained by insulin is immediately lost and body weight thereafter is identical to that of rats exposed to cold only. Accumulated food intake for the joint treatment and after withdrawal of insulin with cold maintained is greater than for cold exposure only. There is no increase in metabolic cost due to insulin. Energy density of weight gain during insulin treatment is high and of weight loss on withdrawal of insulin with cold maintained is very low. These responses do not conform with commonly proposed models of feeding control.     

Interaction between CCK and a preload on reduction of food intake is mediated by CCK-A receptors in humans

Cholecystokinin (CCK) interacts with neural signals to induce satiety in several species, but the mechanisms are unclear. We therefore tested the hypothesis that alimentary CCK (CCK-A) receptors mediate the interaction of CCK with an appetizer on food intake in humans. CCK octapeptide (CCK-8, 0.75 microgram infused over 10 min) or saline (placebo) with concomitant infusions of saline (placebo) or loxiglumide, a specific CCK-A antagonist, was infused into 16 healthy men with use of a double-blind, four-period design. All subjects received a standard 400-ml appetizer (amounting to 154 kcal) but were free to eat and drink thereafter as much as they wished. The effect of these infusions on feelings of hunger and satiety and on food intake was quantified. CCK-8 induced a reduction in calorie intake (P < 0.05) compared with saline. Furthermore, a decrease in hunger feelings (P < 0.05, saline-CCK-8 vs. all other treatments) and an increase in fullness were observed. These effects were antagonized for hunger and fullness by loxiglumide. We conclude that CCK-8 interacts with an appetizer to modulate satiety in humans. These effects are mediated by CCK-A receptors.     

FoxO1 target Gpr17 activates AgRP neurons to regulate food intake

Hypothalamic neurons expressing Agouti-related peptide (AgRP) are critical for initiating food intake, but druggable biochemical pathways that control this response remain elusive. Thus, genetic ablation of insulin or leptin signaling in AgRP neurons is predicted to reduce satiety but fails to do so. FoxO1 is a shared mediator of both pathways, and its inhibition is required to induce satiety. Accordingly, FoxO1 ablation in AgRP neurons of mice results in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to insulin and leptin. Expression profiling of flow-sorted FoxO1-deficient AgRP neurons identifies G-protein-coupled receptor Gpr17 as a FoxO1 target whose expression is regulated by nutritional status. Intracerebroventricular injection of Gpr17 agonists induces food intake, whereas Gpr17 antagonist cangrelor curtails it. These effects are absent in Agrp-Foxo1 knockouts, suggesting that pharmacological modulation of this pathway has therapeutic potential to treat obesity.     

Regulation of food intake in the goldfish by interaction between ghrelin and orexin

Intracerebroventricular (ICV) administration of ghrelin, orexin and neuropeptide Y (NPY) stimulates food intake in goldfish. Orexin and NPY interact with each other in the regulation of feeding, while ghrelin-induced feeding has also shown to be mediated by NPY in the goldfish model. To investigate the interaction between ghrelin and orexin, we examined the effects of a selective orexin receptor-1 antagonist, SB334867, and a growth hormone secretagogue-receptor antagonist, [D-Lys(3)]-GHRP-6, on ghrelin- and orexin-A-induced feeding. Ghrelin-induced food intake was completely inhibited for 1h following ICV preinjection of SB334867, while [D-Lys(3)]-GHRP-6 attenuated orexin-A stimulated feeding. Furthermore, ICV administration of ghrelin or orexin-A at a dose sufficient to stimulate food intake increased the expression of each other's mRNA in the diencephalon. These results indicate that, in goldfish, ghrelin and orexin-A have interacting orexigenic effects in the central nervous system. This is the first report that orexin-A-induced feeding is mediated by the ghrelin signaling in any animal model.     

Effects of naltrexone and CCK on estrous behavior and food intake in Syrian hamsters

Food deprivation inhibits estrous behavior in several species of rodents, but little is known about the neurotransmitter systems mediating this phenomenon. We determined whether partial blockade of opioid receptors by continuous infusion of naltrexone and/or acute peripheral injection of cholecystokinin (CCK) administration would overcome the suppressive effects of food deprivation on estrous behavior in Syrian hamsters. Contrary to expectation, naltrexone produced a slight suppression of estrous behavior, and systemic CCK administration had no effect. This dose of naltrexone was sufficient to reduce in vivo binding of [(3)H]naloxone in the brain, and both compounds affected other parameters such as food intake and body weight gain. Thus, the doses of CCK and naltrexone that were used were physiologically effective. These findings suggest that neither peripheral CCK nor opioid systems are likely to play a major role in the suppression of hamster estrous behavior by food deprivation.     

Intracerebroventricular leptin administration reduces food intake in pregnant and lactating mice

Leptin acts within the hypothalamus to diminish food intake. During pregnancy and lactation, both circulating leptin concentrations and food intake are elevated, suggesting an ineffectiveness of leptin to reduce food intake in these mice. Thus, this study tested the ability of intracerebroventricular (ICV) leptin administration to alter food intake during pregnancy and lactation. Mice during the first, second, and third trimesters of pregnancy, lactating mice on postpartum Day 7, and age-matched female mice were used. Plasma leptin concentrations averaged 2.9 +/- 0.3 ng/ml in control mice, increased steadily as pregnancy progressed (3.4 +/- 0.7, 29.8 +/- 4.5, and 40.5 +/- 0.7 ng/ml during the first, second, and third trimesters, respectively), and remained elevated on Day 7 postpartum (26.4 +/- 7.8 ng/ml). Mice were food deprived for 4 h, injected ICV with vehicle or leptin (1 micro g), and food intake was subsequently measured hourly for 3 hr, and after 24 hr. Vehicle-treated pregnant mice consumed marginally more food than cycling control mice, whereas nursing dams ate two to three times as much food as controls. As expected, ICV leptin administration reduced 24-hr food intake of control mice by 2 g, or approximately 50%. ICV-administered leptin was as effective in reducing food intake of pregnant and lactating mice as observed in control mice. Thus, the elevated circulating leptin concentrations observed in pregnant and nursing mice did not alter the ability of ICV-administered leptin to diminish food intake. High plasma concentrations of leptin-binding proteins observed during pregnancy, and probably during lactation, may limit the amount of endogenous leptin reaching the hypothalamus, and may consequently enable increases in food intake concomitant with elevated plasma leptin during these nutritionally demanding periods.     

Synergistic interaction between xanthan and guar gum

The non-Newtonian behavior and dynamic viscoelasticity of a series of aqueous mixtures of xanthan and guar gum were measured with a rheogoniometer. At a concentration of 0.2% of total gums, gelation did not occur at room temperature but occurred at a low temperature (0°). A much stronger interaction was observed with a mixture of deacetylated xanthan than that with native xanthan. The maximum dynamic modulus was obtained when the ratio of xanthan to guar gum was 2:1. The transition temperatures of dynamic viscoelasticity for mixtures with native and deacetylated xanthan were observed at 25 and 30°, respectively. It was concluded that the side chains of the guar gum molecular prevent an intermolecular interaction with the side chains of the xanthan molecule. An intermolecular interaction between xanthan and guar gum at low temperature might be promoted between the periphery of the side chains of the xanthan molecule and the backbone of the guar gum molecule and dissociation takes place at the transition temperature.     

Hormonal modulation of food intake in response to low leptin levels induced by hypergravity

A loss in fat mass is a common response to centrifugation and it results in low circulating leptin concentrations. However, rats adapted to hypergravity are euphagic. The focus of this study was to examine leptin and other peripheral signals of energy balance in the presence of a hypergravity-induced loss of fat mass and euphagia. Male Sprague-Dawley rats were centrifuged for 14 days at gravity levels of 1.25, 1.5, or 2 G, or they remained stationary at 1 G. Urinary catecholamines, urinary corticosterone, food intake, and body mass were measured on Days 11 to 14. Plasma hormones and epididymal fat pad mass were measured on Day 14. Mean body mass of the 1.25, 1.5, and 2 G groups were significantly (P < 0.05) lower than controls, and no differences were found in food intake (g/day/100 g body mass) between the hypergravity groups and controls. Epididymal fat mass was 14%, 14%, and 21% lower than controls in the 1.25, 1.5, and 2.0 G groups, respectively. Plasma leptin was significantly reduced from controls by 46%, 45%, and 65% in the 1.25, 1.5, and 2 G groups, respectively. Plasma insulin was significantly lower in the 1.25, 1.5, and 2.0 G groups than controls by 35%, 38%, and 33%. No differences were found between controls and hypergravity groups in urinary corticosterone. Mean urinary epinephrine was significantly higher in the 1.5 and 2.0 G groups than in controls. Mean urinary norepinephrine was significantly higher in the 1.25, 1.5 and 2.0 G groups than in controls. Significant correlations were found between G load and body mass, fat mass, leptin, urinary epinephrine, and norepinephrine. During hypergravity exposure, maintenance of food intake is the result of a complex relationship between multiple pathways, which abates the importance of leptin as a primary signal.     

Time-dependent effects of leptin on food intake and locomotor activity in goldfish

The present study investigates the possible circadian dependence of leptin effects on food intake, locomotor activity, glycemia and plasma cortisol levels in goldfish (Carassius auratus). Fish were maintained under 12L:12D photoperiod and subjected to two different feeding schedules, one group fed during photophase (10:00) and the other one during scotophase (22:00). Leptin or saline were intraperitoneally injected at two different times (10:00 or 22:00), coincident or not with the meal time. To eliminate the entraining effect of the light/dark cycle, goldfish maintained under 24 h light (LL) were fed and leptin-injected at 10:00. A reduction in food intake and locomotor activity and an increase in glycemia were found in goldfish fed and leptin-injected at 10:00. No significant changes in circulating cortisol were observed. Those effects were not observed when leptin was administered during the scotophase, regardless the feeding schedule; neither in fish maintained under LL, suggesting that a day/night cycle would be necessary to observe the actions of leptin administered during the photophase. Changes in locomotor activity and glycemia were only observed in goldfish when leptin was injected at daytime, coincident with the feeding schedule, suggesting that these leptin actions could be dependent on the feeding time as zeitgeber. In view of these results it appears that the circadian dependence of leptin actions in goldfish can be determined by the combination of both zeitgebers, light/dark cycle and food. Our results point out the relevance of the administration time when investigating regulatory functions of hormones.     

Role of leptin in the regulation of food intake in fasted mice

Leptin is well acknowledged as an anorexigenic hormone that plays an important role in feeding control. Hypothalamic GABA system plays a significant role in leptin regulation on feeding and metabolism control. However, the pharmacological relationship of leptin and GABA receptor is still obscure. Therefore, we investigated the effect of leptin or combined with baclofen on the food intake in fasted mice. We detected the changes in hypothalamic c‐Fos expression, hypothalamic TH, POMC and GAD67 expression, plasma insulin, POMC and GABA levels to demonstrate the mechanisms. We found that leptin inhibit fasting‐induced increased food intake and activated hypothalamic neurons. The inhibitory effect on food intake induced by leptin in fasted mice can be reversed by pretreatment with baclofen. Baclofen reversed leptin's inhibition on c‐Fos expression of PAMM in fasted mice. Therefore, these results indicate that leptin might inhibit fasting‐triggered activation of PVN neurons via presynaptic GABA synaptic functions which might be partially blocked by pharmacological activating GABA‐B. Our findings identify the role of leptin in the regulation of food intake.     

CCK and 5-HT act synergistically to suppress food intake through simultaneous activation of CCK-1 and 5-HT3 receptors

Cholecystokinin (CCK) and serotonin (5-HT) systems have been shown to cooperate interdependently in control of food intake. To assess mechanisms by which CCK and 5-HT systems interact in control of food intake we examined: (1) participation of CCK-1 and 5-HT3 receptors in 5-HT-induced suppression of sucrose intake; (2) the interaction between CCK and 5-HT in suppression of food intake; (3) the role of CCK-1 and 5-HT3 receptors in mediating this interaction. Intraperitoneal administration of 5-HT (0.25, 0.5 and 1.0 mg/kg) significantly reduced intake compared to control in a dose responsive fashion (r2=0.989). Suppression of food intake by 5-HT was significantly attenuated by prior treatment with the 5-HT3 receptor antagonist ondansetron at each 5-HT dose tested (P<0.05), while blockade of CCK-1 receptors by lorglumide had no effect on 5-HT-induced suppression of intake. Administration of CCK-8 (0.5 microg/kg) or 5-HT (0.5 mg/kg) alone significantly reduced sucrose intake by 22.9 and 22.2% respectively, compared to control (P<0.0001). Co-administration of CCK and 5-HT resulted in a synergistic suppression of intake leading to an overall 48.4% reduction in sucrose intake compared to saline (P<0.0001). Concomitant CCK-1 and 5-HT3 receptor blockade by lorglumide and ondansetron respectively, resulted in a complete reversal of the combined CCK and 5-HT-induced suppression of intake. Independent administration of lorglumide or ondansetron did not alter intake compared to control. These studies provide evidence that 5-HT causes suppression in food intake by acting at 5-HT3, not CCK-1 receptors. Furthermore, CCK and 5-HT interact to produce an enhanced suppression of food intake, an effect mediated through concomitant activation of CCK-1 and 5-HT3 receptors.     

Serum leptin concentration in pigs selected for high or low daily food intake

Selection for high or low daily food intake (DFI) in Large White pigs resulted in higher serum leptin concentration, fat deposition and food intake in the high DFI line. The response in serum leptin concentration indicated that the higher fat deposition of the high DFI line was not due to insufficient leptin production, as in the Lepob/Lepob mouse. Serum leptin was more highly correlated with fat deposition than with food intake indicating that the response in serum leptin was primarily due to increased fat deposition rather than to higher energy intake per se. The low correlations between serum leptin measured at 30 kg and performance test traits indicate that serum leptin would not be efficient for selection of animals prior to performance test. However, the consistent positive correlations between serum leptin and a measure of fat deposition suggest that serum leptin could usefully be incorporated in selection criteria for genetic improvement of carcass lean content in pigs.     

Interoceptive "satiety" signals produced by leptin and CCK

The present studies assessed the extent to which the adiposity signal leptin and the brain-gut hormone cholecystokinin (CCK), administered alone or in combination, give rise to interoceptive sensory cues like those that are produced by a low (1h) level of food deprivation. Rats were trained with cues arising from 1 to 24-h food deprivation as discriminative stimuli. For one group, 24-h food deprivation predicted the delivery of sucrose pellets, whereas 1-h food deprivation did not. Another group received the reversed deprivation level-sucrose contingency. After asymptotic performance was achieved, the effects of leptin and CCK on food intake and on discrimination performance were tested under 24-h food deprivation. In Experiment 1a, leptin administered into the third cerebroventricle (i3vt) at 3.5 or 7.0 microg doses had little effect, compared to saline on food intake or discriminative responding. In Experiment 1b, leptin (7.0 microg, i3vt) combined with CCK-8 (2 microg/kg, i.p.) reduced food intake significantly, but the findings indicated that CCK-8 alone produces interoceptive discriminative cues more like those produced by 1- than 24-h food deprivation. Experiment 2a tested rats with i.p. leptin (0.3 and 0.5mg/kg). Although neither dose suppressed intake, the 0.3mg/kg dose produced interoceptive cues like 1-h food deprivation. Experiment 2b tested two doses of CCK-8 (2 and 4 mg/kg, i.p.) and found significant intake suppression and generalization of discrimination with both doses of CCK-8. These findings suggest a role for both leptin and CCK in the production of sensory consequences that correspond to "satiety".