Oxytocin and an oxytocin agonist administered centrally decrease food intake in rats.

Intracerebroventricular administration of oxytocin (OT) and an OT agonist significantly decreased food intake in a dose-related manner in fasted rats. Central administration of an OT antagonist by itself (up to doses of 8 nmol) did not potentiate deprivation-induced food intake, but pretreatment with the OT receptor antagonist prevented the expected inhibition of food intake produced by OT and the OT agonist. Once-daily ICV injections of OT led to the development of tolerance to the inhibitory effects on food intake by the third day of treatment, but daily pretreatment with the OT antagonist prevented the development of this tolerance. In addition to causing decreased food intake, ICV administration of OT significantly increased grooming behavior but produced no dyskinesias. The inhibitory effect of OT on food intake was characterized by decreased amounts of food intake but a normal pattern of ingestion. The anorexia produced was central in nature and was not associated with altered plasma levels of hormones involved in caloric homeostasis or with changes in blood glucose. The OT agonist had relatively little effect on water intake when given in doses that significantly inhibited food intake. These results support the hypothesis that specific OT receptors within the central nervous system participate in the inhibition of feeding under certain conditions in rats.     

Voluntary food consumption and gastric emptying in rats given intravenous Triton WR-1339

Intravenously administered Triton WR-1339, a nonionic surface active agent, has been used as an endogenous hyperlipemic agent since 1951. We expected Triton to increase food consumption to supply, at least partially, the energy and acetyl groups necessary for producing the hyperlipemic state. In this study, however, we observed that the rats injected intravenously with various dose levels of Triton decreased their voluntary food intake in a dose-related manner. Two other nonionic surface active agents, Tween 20 and Tween 80, given intravenously did not alter food intake. Further studies revealed that Triton WR-1339 administered intravenously 30 min before feeding by stomach tube resulted in a marked delay in the rate of gastric emptying which was also dose related. A delay in gastric emptying has previously been suggested as one mechanism that controls food intake. Tween 20 and Tween 80 did not alter the rate of gastric emptying. We suggest that the mechanism responsible for the decrease in voluntary food consumption in Triton WR-1339 injected rats may be due to the delay of gastric emptying in these animals.     

Effect of cholecystokinin on feeding is attenuated in monosodium glutamate obese mice

Treatment of newborn mice with monosodium glutamate (MSG) is neurotoxic for hypothalamic arcuate nucleus (ARC) and causes obesity. In the MSG-treated 16-week-old NMRI mice, we detected specific ablation of ARC neuronal cells, 8 times higher fat to body mass ratio but unchanged body mass compared to controls, advanced hyperglycemia and hyperinsulinemia--both more pronounced in males, and hyperleptinemia--more severe in females. After fasting, the MSG-treated mice showed attenuated food intake compared to controls. Cholecystokinin octapeptide, which decreased food intake in a dose-dependent manner in 24 h fasted controls, did not significantly affect food intake in the MSG-treated animals. We propose that the obesity-related changes in the feeding behavior of the MSG-treated obese mice were the result of missing leptin and insulin receptors in ARC and consequent altered neuropeptide signaling. This makes the MSG model suitable for clarifying generally the central control of food intake.     

Effects of excess biotin administration on the growth and urinary excretion of water-soluble vitamins in young rats

To determine the effects of excess biotin administration on growth and water-soluble vitamin metabolism, weaning rats were fed on a 20% casein diet containing 0.00002% biotin, or same diet with 0.04, 0.08, 0.10, 0.20, 0.50, 0.80 or 1.0% added biotin for 28 days. More than 0.08% biotin administration decreased the food intake and body weight gain compared with the levels in control rats. An accumulation of biotin in such tissues as the liver, brain and kidney increased in a dose-dependent manner, and the both bound and free biotin contents in the liver also increased in a dose-dependent manner. An excess administration of biotin did not affect the urinary excretion of other water-soluble vitamins, suggesting no effect on the metabolism of other water-soluble vitamins. The results of the food intake and body weight gain indicated that the lowest observed adverse effect level for young rats was 79.2 mg/kg body weight/day, while the no observed adverse effect level was 38.4 mg/kg/day. These results suggested immediately setting a tolerable upper intake level for biotin.     

Diurnal variations in food intake and in lipogenesis in mammary gland and liver of lactating rats.

Despite the hyperphagia, the food intake of the lactating rat showed marked diurnal changes which paralleled those of virgin rats. The major difference was that lactating rats consumed a higher proportion (35%) of their diet during the light period than did virgin rats (14%). The peak rate of lipogenesis in the lactating mammary gland occurred around midnight, and this decreased by 67% to reach a nadir around mid-afternoon; this corresponded with the period of lowest food intake. The diurnal variations in hepatic lipogenesis in lactating rats were much less marked. The changes in hepatic glycogen over 24 h suggest that it acts to supply carbon for lipogenesis during the period of decreased food intake. The activation state of acetyl-CoA carboxylase in mammary gland altered during 24 h, but the changes did not always correlate with alterations in the rate of lipogenesis. The changes in plasma insulin concentration tended to parallel the food intake in the lactating rats, but they did not appear to be sufficient to explain the large alterations in lipogenic rate in the mammary gland.     

Albutensin A and complement C3a decrease food intake in mice

Albutensin A (Ala-Phe-Lys-Ala-Trp-Ala-Val-Ala-Arg) derived from serum albumin dose-dependently decreased food intake after intracerebroventricular (10-50 nmol/mouse) or peripheral (0.3-1.0 micromol/mouse) administration in fasted conscious ddY mice. Albutensin A delayed gastric emptying and elevated blood glucose levels. Although albutensin A showed low affinity for bombesin receptor, it decreased food intake in bombesin receptor knockout mice, indicating that its inhibitory effect on feeding was not mediated through bombesin receptor. Then, we investigated whether the albutensin A-induced decrease in food intake was mediated by complement C3a and C5a receptors, because albutensin A had affinities for these receptors. Des-Arg-albutensin A, lacking affinity for C3a and C5a receptors, did not inhibit food intake. We found for the first time that centrally administered C3a (10-100 pmol/mouse) by itself decreased food intake in fasted mice. In contrast, C5a increased food intake after central injection. Based on these results, we conclude that the inhibitory effect of albutensin A on food intake is mediated through the C3a receptor.     

The sterol composition of Trypanosoma cruzi changes after growth in different culture media and results in different sensitivity to digitonin-permeabilization

Respiration, oxidative phosphorylation. and the corresponding changes in membrane potential (deltapsi) of Trypanosoma cruzi epimastigotes grown either in liver infusion-tryptose (LIT) or brain heart infusion (BHI) culture medium were assayed in situ using digitonin to render their plasma membrane permeable to succinate, ADP, safranine O, and other small molecules. When the cells were permeabilized with 64 microM digitonin, a concentration previously used with epimastigotes, the ability of the cells grown in LIT medium to sustain oxidative phosphorylation was demonstrated by the detection of an oligomycin-sensitive decrease in mitochondrial membrane potential induced by ADP. In contrast, the cells grown in BHI medium were not able to sustain a stable membrane potential and did not respond to ADP addition. Analyses of oxygen consumption by these permeabilized cells indicated that the rate of basal respiration, which was similar in both cell types, was significantly decreased by 64 microM digitonin. Addition of ADP to the permeabilized cells grown in LIT medium promoted an oligomycin-sensitive transition from resting to phosphorylating respiration in contrast to the cells grown in BHI medium, whose respiration decreased steadily and did not respond either to ADP or CCCP. Titration of the cells grown in BHI medium with different digitonin concentrations indicated that their mitochondria have higher sensitivity to digitonin than those grown in LIT medium. Analysis of the sterol composition of epimastigotes grown in the two different media showed a higher percentage of cholesterol in total and mitochondrial extracts of epimastigotes grown in BHI medium as compared to those grown in LIT medium, suggesting the involvement of this sterol in their increased sensitivity to digitonin-permeabilization.     

Effects of ovarian hormones on eating behaviors, body weight, and glucoregulation in rhesus monkeys

The influences of ovarian hormones on food intake, taste preferences, and glucoregulation were examined in intact and ovariectomized rhesus monkeys. Intake of intact monkeys was lowest in the preovulatory stage of the cycle, when estrogen levels are elevated, and exogenous estradiol transiently suppressed food intake of ovariectomized monkeys in a dose-related manner, confirming previous observations. Progesterone treatment did not affect food intake when given alone, but it did attenuate the effect of estradiol when both hormones were given concurrently. Preferences for sweet solutions were not detectably influenced by chronic treatment with estradiol or progesterone, and compensatory responses to ingestion of sugar were unaltered by hormone treatment. Glucose tolerance tests did not reveal significant influences of ovarian hormones on glycemia, but insulin levels were elevated during periods of progesterone treatment. These results do not support the suggestion that fluctuations in caloric intake during the menstrual cycle are secondary to changes in taste preference or glucoregulation. However, possible changes in sweet preference and glucoregulation shortly after initiation of estrogen treatment, i.e., during the time of suppressed food intake, remain to be examined.     

Endogenous opioid peptides in the control of food intake in cats

In this report, we investigated the role of exogenous and endogenous enkephalins on food intake in the cat, using, respectively, exogenous [D-Ala2-Met5]-enkephalin (DAME) and acetorphan (Ac) in order to inhibit the degradation of endogenous enkephalins. In addition, the selective peripheral antagonist naltrexone methylbromide (NTxMB) and the nonselective antagonist naloxone (Nx) were used in an attempt to discriminate central and peripheral opioid receptors. In 18-hours food-deprived animals, Ac (5 mg/kg IV) increased milk intake during sham feeding (+18%, p less than 0.05), but did not modify it in feeding conditions. Nx (1 mg/kg SC) reduced milk intake in sham-feeding experiments (-67%, p less than 0.01) more than in milk-feeding conditions (-30%, p less than 0.01). NTxMB (1 mg/kg SC) did not modify milk intake in sham-feeding but decreased it in feeding experiments. In nonfasted animals, Ac did not modify food intake. IV infusion of DAME (50 micrograms/kg) resulted in a reduction of daily food intake (-32%, p less than 0.01). Nx (1 mg/kg SC) decreased the earlier 30 min intake followed by reduction of daily intake (-30%, p less than 0.01). NTxMB (1 and 4 mg/kg SC) increased the 30-min intake dose dependently, without significant change in daily intake. In conclusion, Ac increases food intake in sham-feeding conditions, suggesting that endogenous enkephalins are likely to be involved in the stimulation of food intake. The effects of Nx and NTxMB furthermore suggest both a central activation, and a peripheral inhibition of food intake by opiates when food is allowed to proceed normally through the digestive tract.     

The effect of peripheral administration of peptides on food intake, glucose and insulin in wolf pups

In the studies reported here we demonstrate that bombesin decreases food intake in wolf (Canis lupus) pups without altering glucose or insulin levels. A high dose of cholecystokinin-octapeptide (CCK, 5 μg/kg) decreased food intake. CCK produced a transient increase in insulin, without altering glucose. Glucagon (0.5 mg/kg) failed to decrease food intake despite producing a marked hyperglycemia and hyperinsulinemia. Calcitonin was ineffective at decreasing food intake, although it did decrease the time spent feeding. These studies suggest a potential role for peripheral peptides in food regulation in the wolf.     

Food intake in rhesus monkeys following central administration of orexins

Orexin A has been reported to stimulate food intake in rats while orexin B does not. The purpose of this study was to determine the role of orexin A or orexin B administration on food intake in adult, male rhesus monkeys. Food intake was measured at 2 and 8 h after the morning feeding following central injections of vehicle, orexin A (10, or 20 microg) or orexin B (10, 30, or 100 microg). When compared to vehicle injections, the 10 and 20 microg doses of orexin A decreased food intake at 2 h post-dose by 45% and 64%, respectively. Eight-hour food intake was decreased at only the 20 microg orexin A dose. Orexin B at all doses and time points did not alter food intake when compared to vehicle. These results indicate that orexin A exhibits anorectic activity while orexin B does not affect food intake in the rhesus monkey.     

Effects of somatostatin on food intake in rats

We examined the possibility that somatostatin, a tetradecapeptide distributed in the gut and the central nervous system, may influence food intake and behavior in rats. Although intravenously infused somatostatin did not alter food intake in 8 hour fasted rats, intracerebroventricularly infused somatostatin resulted in a biphasic response, first increasing then decreasing food intake. We also observed that the effects of somatostatin vary depending upon whether animals are fed or fasted. In fed rats, food intake was decreased, while in fasted rats food intake was increased. These results suggest that somatostatin can act in the central nervous system to stimulate appetite; but that other factors, possibly related to gut motility or clearance, may inhibit further feeding once the stomach is full.     

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.     

Effects of corticocerebellar lesions on taste preferences, body weight gain, food and fluid intake in the rat.

The experiments reported here attempted to examine in two groups of rats the effects on the taste preferences, food and fluid intake, energy balance and body weight gain of corticocerebellar lesions involving, primarily, the Lobulus VI (LVI) or the Lobulus Paramedianus (LP). The results showed that the lesions of LVI or LP did not affect the daily intake of total fluid and salty solution. The intake of sweet solution increased in both groups of lesioned rats, while the intake of deionized water and acid and bitter solutions decreased only in the LVI lesioned rats. Food intake decreased in the LVI-lesioned rats but not in the LP-lesioned animals. Body weight gain, efficiency of food utilization, caloric intake and body surface gain decreased in both groups. It seems therefore that the cerebellar cortex, which probably receives taste fibers, somehow influences taste preferences and water intake, and that it may be involved in the mechanisms of food intake, its utilization and body energy balance.     

Centrally and peripherally administered bombesin decreases food intake in turkeys

The effects of intracerebroventricular (ICV) and intravenous injections of bombesin (BBS) on food intake were investigated in turkeys. Adult turkey hens were injected ICV with 50 to 1000 ng of BBS. In addition, the effect of pretreatment with the BBS antagonist [d-Arg1, D-Phe5, D-Trp7,9, Leu11]-substance P was investigated. To determine if BBS also had a peripheral site of action, 0.5 to 8 micrograms/kg body weight of BBS was injected IV into turkey poults. The ICV and IV injections of BBS decreased food and water intake in a dose-dependent manner. The most efficacious doses when injected ICV for decreasing food and water intake were 1000 and 500 ng, respectively, whereas 8 micrograms/kg was most efficacious in decreasing food intake when administered IV. The satiating effect of ICV-injected BBS could be attenuated with pretreatment with the BBS antagonist. The results of these studies suggest that BBS acts to decrease food and water intake in both the periphery and the central nervous systems of turkeys.     

Decreased behavioral effects of daily intracerebroventricular bombesin

Intracerebroventricular (ICV) bombesin increases grooming and decreases food intake in rats. We examined tolerance to these effects by administering a daily injection of either saline or 25 ng bombesin to rats for 8 days via lateral ventricular cannulas. Food intake and grooming were monitored. After 8 days bombesin no longer increased grooming or decreased food intake in bombesin-treated rats, but did increase grooming and decrease food intake in saline-treated rats. This development of behavioral tolerance conflicts with previous reports using larger doses and demonstrates that repeated small doses of ICV bombesin produce different effects from larger doses.     

Lithium Chloride SCN Injection Alters the Orcadian Rhythm of Food Intake

Effect of lithium injections through chronically implanted cannulae into the bilateral suprachiasmatic nuclei (SCN) on the circadian rhythm of food intake was investigated in the rat. It was observed that the circadian rhythm was disrupted by injections of lithium at the beginning of the light as well as the dark phase of the LD cycle. In either case the percentage of the food consumed during the 12-hr light period increased while that during the dark period decreased without any significant change in the total daily intake. Disruptions in the circadian rhythm of food intake failed to show any dose-response relation. Injections of saline into the SCN or lithium into the nearby SCN area did not produce a disruption of the circadian rhythm of food intake.     

Inhibitory effect of ghrelin on food intake is mediated by the corticotropin-releasing factor system in neonatal chicks

It is known that, in rats, central and peripheral ghrelin increases food intake mainly through activation of neuropeptide Y (NPY) neurons. In contrast, intracerebroventricular (ICV) injection of ghrelin inhibits food intake in neonatal chicks. We examined the mechanism governing this inhibitory effect in chicks. The ICV injection of ghrelin or corticotropin-releasing factor (CRF), which also inhibits feeding and causes hyperactivity in chicks. Thus, we examined the interaction of ghrelin with CRF and the hypothalamo-pituitary-adrenal (HPA) axis. The ICV injection of ghrelin increased plasma corticosterone levels in a dose-dependent or a time-dependent manner. Co-injection of a CRF receptor antagonist, astressin, attenuated ghrelin-induced plasma corticosterone increase and anorexia. In addition, we also investigated the effect of ghrelin on NPY-induced food intake and on expression of hypothalamic NPY mRNA. Co-injection of ghrelin with NPY inhibited NPY-induced increase in food intake, and the ICV injection of ghrelin did not change NPY mRNA expression. These results indicate that central ghrelin does not interact with NPY as seen in rodents, but instead inhibits food intake by interacting with the endogenous CRF and its receptor.     

A sex difference in the effect of CCK-8 on food and water intake in obese (ob/ob) and lean (+/+) mice

Male and female ob/ob and +/+ mice were tested with CCK-8 (1, 2, 4 and 8 micrograms/kg) administered 15 min prior to 30-min access to solid food after 17.5 hr food deprivation and 15 min prior to 30-min access to water after 17.5 hr water deprivation. The threshold dose for suppressing 30-min food intake was 2 micrograms/kg for all mice. Larger doses of CCK-8 inhibited food intake in male obese and lean mice in a linear fashion. The dose-response relationship for female mice, however, was not linear: lean females failed to suppress food intake following 4 or 8 micrograms/kg and obese females did not suppress food intake at 4 micrograms/kg. There was also a sex difference in the effect on water intake. No dose of CCK-8 changed water intake in lean males and only the 8 micrograms/kg dose decreased water intake in obese males. In contrast CCK-8 (1, 4 and 8 micrograms/kg) increased water intake in obese females, CCK-8 (1 and 8 micrograms/kg) increased water intake in lean females and no dose of CCK-8 decreased water intake in females. These data demonstrate significant sex differences in the effect of CCK-8 on food and water intake in mice.     

Signals from intra-abdominal fat modulate insulin and leptin sensitivity through different mechanisms: neuronal involvement in food-intake regulation

Intra-abdominal fat accumulation is involved in development of the metabolic syndrome, which is associated with insulin and leptin resistance. We show here that ectopic expression of very low levels of uncoupling protein 1 (UCP1) in epididymal fat (Epi) reverses both insulin and leptin resistance. UCP1 expression in Epi improved glucose tolerance and decreased food intake in both diet-induced and genetically obese mouse models. In contrast, UCP1 expression in Epi of leptin-receptor mutant mice did not alter food intake, though it significantly decreased blood glucose and insulin levels. Thus, hypophagia induction requires a leptin signal, while the improved insulin sensitivity appears to be leptin independent. In wild-type mice, local-nerve dissection in the epididymis or pharmacological afferent blockade blunted the decrease in food intake, suggesting that afferent-nerve signals from intra-abdominal fat tissue regulate food intake by modulating hypothalamic leptin sensitivity. These novel signals are potential therapeutic targets for the metabolic syndrome.