Responses of hepatic and celiac vagal afferents to intraportal mercaptoacetate in rats fed a high-fat or low-fat diet

Responses of either hepatic or celiac vagal afferents to intraportal hepatic vein administration of 2-mercaptoacetate (MA) were examined in rats maintained on either a high-fat or low-fat diet. Afferent activity in both hepatic and celiac vagal afferents significantly increased after administration of MA, but the magnitude of these increases did not differ as a function of either diet. Responses of hepatic vagal afferents were highly variable across individual rats, whereas those of celiac vagal afferents were remarkably consistent across individual rats. These data suggest that MA-induced enhanced feeding in rats given a fat-enriched diet does not depend on a stronger hepatic and/or celiac vagal afferent response than that of rats given a low-fat diet.     

Interleukin-18 null mutation increases weight and food intake and reduces energy expenditure and lipid substrate utilization in high-fat diet fed mice

ObjectiveThe proinflammatory cytokine interleukin-18 (IL-18) putatively modulates food intake and energy metabolism, but the effects of IL-18 in high-fat diet fed animals are unknown. Whether IL-18 alters basal metabolic rate or metabolic processes of living is unknown. Here, we tested the hypothesis that IL-18 modulates weight gain, energy intake, whole-body energy expenditure, and utilization of lipid as a fuel substrate in high-fat diet fed mice.MethodsFood intake, whole-body metabolism, and motor activity of IL-18 knockout mice were compared to those of wildtype littermates; anorectic effects of intracerebroventricular IL-18 administration were compared between IL-18 receptor knockout, IL-18/IL-18R knockout and wildtype mice.ResultsChow-reared IL-18 knockout mice were overweight at 6 months of age and then gained excess weight on both low-fat and high-fat diets, ate more high-fat diet, and showed reduced whole-body energy expenditure and increased respiratory exchange ratios. Reductions in energy expenditure of IL-18 knockout mice were seen across fasting vs. feeding conditions, low- vs. high-fat diets, high vs. low levels of physical activity and times of day, suggesting actions on basal metabolic rate. The circadian amplitude of energy expenditure, but not respiratory exchange ratio, food intake, or motor activity, also was blunted in IL-18 knockout mice. Central IL-18 administration reduced high-fat diet intake in wildtype mice, but not in mice lacking the IL-18 receptor.ConclusionThe loss-of-function results support the hypothesis that endogenous IL-18 suppresses appetite and promote energy expenditure and lipid fuel substrate utilization not only during sickness, but also in healthy adults consuming high-fat diets.     

Internal signals cause large changes in food intake in one-way crossed intestines rats

Fifteen pairs of parabiotic rats had either a surgical operation in which a 15 or 30 cm segment of upper small intestine was disconnected from the digestive tract of one rat in the pair and reconnected to the transected duodenum of its partner or had control surgery. Food eaten by one rat in the pair went to the rat's own stomach, traveled through 5 cm of its upper duodenum and then crossed into the isolated segment of the partner's small intestine. After traversing the 15 or 30 cm isolated segment, the remaining unabsorbed food crossed back into the lower duodenum of the rat that fed. Food eaten by the partner went through its own digestive tract, but bypassed the isolated segment of its own upper small intestine. The operation produced a large and sustained change in food intake of both rats in a pair. For the rats with 30 cm crossed segments, the rat that lost intestinal chyme into its partner ate 3.6 times as much food as did its partner for a period of many months. At sacrifice, the rats that ate more, weighed less and had less body fat. These large changes in food intake may be caused by internal changes associated with changes in the amount of food absorbed into each rat or by differential stimulation of the lower digestive tracts. The results clearly show that there is a major internal control mechanism for the amount of food eaten.     

Nocistatin inhibits food intake in rats

Nocistatin, a product of the same precursor as nociceptin/orphanin FQ (N/OFQ), has been shown to antagonize effects of N/OFQ. N/OFQ stimulates feeding, most probably by inhibiting activation of neurons containing oxytocin (OT) and vasopressin (VP), peptides considered as satiety factors, and implicated in the development of conditioned taste aversion (CTA). The present study was designed to investigate whether intracerebroventricularly (ICV) injected nocistatin (a) affects deprivation- and N/OFQ-induced feeding, (b) causes CTA, and (c) induces activation of hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei, as well as OT and VP neurons present in these regions. C-Fos immunohistochemistry was used as a marker of cellular activation. Nocistatin (1-3 nmol) significantly reduced food intake in deprived rats during the first and second hour post-injection. Doses of 1-3 nmol suppressed N/OFQ-induced feeding. Nocistatin at the highest (3 nmol) dose did not cause CTA. It also did not affect activation of the PVN or SON. In nocistatin-treated animals, the percentage of Fos-positive OT and VP neurons was similar to controls. We conclude that nocistatin antagonizes the influence of N/OFQ on feeding and suppresses deprivation-induced food consumption through mechanisms other than aversion. Nocistatin does not, however, activate the PVN or SON. It does not exert its effects via VP or OT neurons.     

Corticotropin inhibits food intake in rats

The synthetic corticotropin ACTH (1-24) (tetracosactide), injected into a brain lateral ventricle after a 24h starvation period or into the ventromedial hypothalamus during the nocturnal feeding phase, markedly inhibited food intake, in rats. In starved rats, the dose of 4 micrograms/rat was maximally effective and reduced food intake by 76.6% during the first hour after treatment. The same dose, injected into the ventromedial hypothalamus, significantly inhibited food intake also in normally fed rats during the nocturnal phase (58.6% reduction during the 90 minutes of observation). These findings suggest that corticotropin may play a role in the central control of appetite.     

Histidyl-proline diketopiperazine decreases food intake in rats

Histidyl-proline diketopiperazine was found to suppress food intake during stress-induced eating (10⁻⁶–10⁻⁸ mol), starvation-induced eating (10⁻⁸ mol) and over an 8 h period of spontaneous eating (10⁻⁸ mol). In contrast, other cyclic piperzines failed to alter food ingestion. The suppressive effect of histidyl-proline diketopiperazine was antagonized by the enkephalin analogue, d-Ala-Met-enkephalin, in equimolar concentrations.     

Short day-length increases sucrose consumption and adiposity in rats fed a high-fat diet

BACKGROUND: Photoperiod, i.e., the relative day-length per 24h, may modulate the metabolic responses to high-fat diet (HFD) and sucrose consumption. METHODS: To test this hypothesis, hormonal changes, fat accretion and sucrose intake were measured in rats exposed to short- or long-day for 4 weeks and fed with a standard high-carbohydrate low-fat pelleted diet (high-carbohydrate diet (HCD)) or a high-fat, medium-carbohydrate pelleted diet (HFD), with or without free access to 10% sucrose solution in addition to water available ad libitum. RESULTS: Plasma leptin and adiposity index, defined as epididymal white fat expressed as percentage of body mass, were markedly increased only in HFD-fed animals drinking sucrose under short, but not long, photoperiods. Voluntary ingestion of sucrose under short days was greater in HFD rats compared with HCD animals over the experiment, while a trend for the opposite effect was visible under long days. Total energy intake was not changed overall, as rats proportionally decreased chow intake when they drank sucrose. A noteworthy exception was the HFD group with sucrose access under short days that significantly increased their total calorie intake. Fasting blood glucose was generally unaltered, except for an increase in HFD-fed animals drinking sucrose under long days compared to control animals, suggesting a decrease in glucose tolerance. Insulin resistance was not yet affected by nutritional or photoperiodic conditions after 4 experimental weeks. CONCLUSIONS: Even if photoperiod cannot be considered as an obesogenic environmental factor per se, the metabolic effects resulting from the combination of high-fat feeding and voluntary intake of sucrose were dependent on day-length. Exposure to short days triggers a larger increase of sucrose ingestion and hyperleptinemia in rats fed with HFD compared to the control diet. Considering that the cardinal symptoms of winter depression include carbohydrate craving and increased adiposity, the present data provide an experimental basis for developing new animal models of seasonal affective disorder.     

Xenin-a novel suppressor of food intake in rats

Peptides related to the amphibian octapeptide xenopsin are present in various locations in mammalians, such as the gastrointestinal mucosa or brain tissue. In the gastrointestinal tract, xenopsin-related peptides induce partially neurogenic contractions of the colon in humans. In brain, however, their function is not known. Structural similarities of xenopsin-related peptides with neurotensin, a known modulator of ingestive behavior, suggest a possible role in feeding regulation. Therefore, we examined the effect of xenin, a recently identified xenopsin-related pentacosa peptide, on feeding behavior of fasted rats. Male Wistar rats (n=12) were intracerebroventricularly (i.c.v.) injected with either saline (10 μl) or xenin at 0.5, 1.5, 5 or 15 μg dissolved in an identical volume of 10 μl, respectively. In further experiments, xenin 15 μg/0.5 μl or 0.5 μl saline were injected into the lateral hypothalamus (LH). After injections, food intake (g), percentage of time spent with feeding (%) and prandial water intake (ml) were subsequently recorded for 2 h. After i.c.v. injection of 15 μg of xenin 1-h food intake was significantly reduced by 42% and 2-h food intake was diminished by 25%, respectively, compared to saline injection (p<0.01). This reduction of food intake was paralleled by a significant decrease of time spent with feeding by 41% (after 1 h) or 23% (after 2 h). The xenin-induced suppression of feeding behavior was dose-dependent. Thus, the minimal effective dose of xenin was 1.5 μg, while the dose of 0.5 μg was ineffective. Prandial water intake was significantly reduced only by the highest dose of xenin. Following injection of 15 μg of xenin into the lateral hypothalamus food intake was not different from control experiments. These data demonstrate a potent feeding suppressive action of xenin following intracerebroventricularly injection but not injection into the lateral hypothalamus suggesting a possible role of xenin in the central control of feeding termination and satiety.     

Corticotropin-releasing factor receptor type 1 mediates emotional stress-induced inhibition of food intake and behavioral changes in rats

We investigated whether corticotropin-releasing factor (CRF) receptor type 1 (CRFR1) is involved in emotional stress-induced inhibition of food intake and behavioral changes in rats. The inhibition of food intake and increase in locomotor activity induced by emotional stress using a communication box were reversed by both intracerebroventricular injection of alpha-helical CRF (9-41), a non-selective CRF receptor antagonist, and intraperitoneal injection of a selective non-peptidic CRFR1 antagonist. These results suggest that CRFR1 mediates at least in part the emotional stress-induced inhibition of feeding behavior and increase in locomotor activity.     

Selective opioid receptor antagonist effects upon intake of a high-fat diet in rats

Short-term (2 h) intake of a high-fat diet in rats was significantly inhibited by intravenous (0.1-10 mg/kg: 39-67%) and central (1-5 micrograms, i.c.v.: 51%) naloxone. The irreversible mu opioid antagonist, beta-funaltrexamine (10 micrograms, i.c.v.: 37%), but not the irreversible mu 1 antagonist, naloxonazine (10 mg/kg, i.v.) inhibited intake, suggesting mu 2 receptor mediation. The delta antagonist, ICI 174864 (1-10 micrograms, i.c.v.: 41%) inhibited high-fat diet intake only at doses that also produced motor dysfunction.     

Hypothalamic control of seasonal changes in food intake and body weight

Seasonal cycles of fattening and body weight reflecting changes in both food intake and energy expenditure are a core aspect of the biology of mammals that have evolved in temperate and arctic latitudes. Identifying the neuroendocrine mechanisms that underlie these cycles has provided new insights into the hypothalamic control of appetite and fuel oxidation. Surprisingly, seasonal cycles do not result from changes in the leptin-responsive and homeostatic pathways located in the mediobasal and lateral hypothalamus that regulate meal timing and compensatory responses to starvation or caloric restriction. Rather, they result from changes in tanycyte function, which locally regulates transport and metabolism of thyroid hormone and retinoic acid. These signals are crucial for the initial development of the brain, so it is hypothesized that seasonal neuroendocrine cycles reflect developmental mechanisms in the adult hypothalamus, manifest as changes in neurogenesis and plasticity of connections.     

The regulation of seasonal changes in food intake and body weight

Seasonal rhythms of body weight, reflecting altered food intake, energy storage and expenditure, are a common feature of mammals inhabiting temperate and arctic latitudes. They have evolved so that predictable annual changes in the external environment can be anticipated and animals can adjust their physiology and behaviour in preparation for the changing demands of the seasons. These long-term changes in energy balance are not simply effected by the brain centres and peptidergic pathways known to underlie short-term homeostatic regulation. Screens of altered gene expression in Siberian hamsters comparing the anabolic summer state in long photoperiods and the catabolic 'winter' state in short photoperiods have identified differential gene expression in the hypothalamus. The majority of gene expression changes are confined to two restricted areas: the dorsomedial posterior arcuate nucleus, and the ventral ependymal layer of the third ventricle. Functions encoded by these 'seasonal' genes include thyroid hormone metabolism, retinoic acid and histaminergic signalling, and VGF and secretogranin production. The changes in thyroid hormone availability that are brought about by differential activity of deiodinase enzymes are of particular importance because experimental manipulation of central thyroid levels can prevent seasonal cyclicity. Given the importance of thyroid hormone in the initial development of the brain, we hypothesise that thyroid hormone-dependent plasticity of hypothalamic connections and neurogenesis underlie seasonal cycles of food intake and body weight.     

Neuronal histamine in the hypothalamus suppresses food intake in rats

Using probes to manipulate hypothalamic neuronal histamine, we report here that changes in neuronal histamine modulate physiological feeding behavior in rats. Infusion of α-fluoromethylhistidine (FMH), a “suicide” inhibitor of histidine decar☐ylase (HDC), into the third cerebroventricular induced feeding in the early light phase when the histamine synthesis was most accelerated. FMH at an optimum 2.24 μmol dose elicited feeding in 100% of rats. Treatment of FMH specifically and selectively decreased concentration of histamine without affecting concentrations of catecholamines in the hypothalamus. Immediately before the dark phase, when the histamine synthesis was normally lower, FMH infusion did not affect feeding-related parameters such as meal size, meal duration or latency to eat. Conversely, thioperamide, which facilitates both synthesis and release of neuronal histamine by blocking presynaptic autoinhibitory H₃ receptors, significantly decreased food intake after infusion of a 100-nmol dose into the third cerebroventricle. The effect of thioperamide was abolished with i.p. injection of 26 μmol/kg chlorpheniramine, an H₁ antagonist. FMH at 224 nmol was microinfused bilaterally into the feeding-related nuclei in the hypothalamus. The ventromedial nucleus (VMH) and the paraventricular nucleus (PVN), but not the lateral hypothalamus, the dorsomedial hypothalamus or the preoptic anterior hypothalamus were identified as the active sites for the modulation. Neuronal histamine may convey suppressive signals of food intake through H₁ receptors in the VMH and the PVN with diurnal fluctuation.     

Fluoxetine disrupts food intake and estrous cyclicity in Fischer female rats

Adult, regularly cycling female Fischer rats were injected daily with 10 mg/kg fluoxetine for 12-23 days. In the first experiment, body weight and vaginal smears were monitored daily. Fluoxetine treatment reduced body weight within the first 24 h of treatment. Fluoxetine treatment also elongated the estrous cycle, reduced blood levels of progesterone, and eliminated lordosis behavior. In the second experiment, body weight and food intake were examined and a pair-fed group was included to determine if fluoxetine-induced anorexia contributed to the disturbance of the estrous cycle. In pair-fed rats, effects similar to fluoxetine treatment were present. These results lead to the suggestion that fluoxetine's anorectic properties could disrupt the female's normal endocrine cyclicity and that this disruption could be relevant to the reduction in sexual behavior and motivation. However, when the duration of fluoxetine treatment was extended beyond 16 to 17 days, fluoxetine-treated female rats reinitiated vaginal cyclicity and showed evidence of normal sexual receptivity. In contrast, the estrous cycles of their pair-fed counterparts remained disrupted. Thus, restricted food intake appears to contribute to the disruption of the estrous cycle and elimination of sexual receptivity during fluoxetine treatment. However, compensatory changes in the serotonergic system that are associated with chronic fluoxetine administration may contribute to the gradual recovery of estrous cyclicity and sexual receptivity of the fluoxetine-treated animals.     

Lateral hypothalamic injection of bombesin decreases food intake in rats

STUCKEY, J. A. AND J. GIBBS. Lateral hypothalamic injection of bombesin decreases food intake in rats. BRAIN RES. BULL. 8(6)617–621, 1982.—The effect of lateral hypothalamic injections of bombesin on feeding behavior was examined. Rats equipped with stainless steel cannulas directed toward the lateral hypothalamus received bilateral injections of bombesin prior to access to a liquid test diet after a 3 hr food deprivation. Bombesin in doses of 5 ng, 50 ng and 100 ng produced significant reductions in the size of the first meal. Injection of 50 ng of the biologically weak analogue [D-Trp⁸] bombesin had no effect. Injection of 5 ng or 50 ng of bombesin had no effect on deprivation-induced water intake, and injection of 50 ng of bombesin had no effect on body temperature. The food and water intake data and direct quantitative behavioral measures indicated that lateral hypothalamic injections of bombesin specifically reduced food intake. The structure-activity relationship for this effect was similar to those for other actions of bombesin. A bombesin-like peptide in the lateral hypothalamus or its receptors may play a role in postprandial satiety.     

The evaluation of antimuscarinic-induced convulsions in fasted rats after food intake

The present study was performed to evaluate convulsions after food intake in fasted rats pretreated with scopolamine or atropine and to determine whether these convulsions respond to drugs found effective in fasted mice. Scopolamine (2.4 mg/kg) and atropine (2.4 mg/kg) were given intraperitoneally (i.p.) to rats fasted for 52 h. Both drugs induced convulsions after animals were allowed to eat ad lib. Another group of fasted rats pretreated with saline, MK-801 (0.1 mg/kg), clonidine (0.1 mg/kg), chlorpromazine (2 and 4 mg/kg), valproate (200 mg/kg), diazepam (1.5 and 2 mg/kg) or gabapentin (50 mg/kg) were treated i.p. with saline or scopolamine (2.4 mg/kg) and were allowed to eat ad lib. Clonidine, MK-801, chlorpromazine (4 mg/kg) and diazepam (2 mg/kg) reduced the incidence of scopolamine-induced convulsions in fasted rats. Gabapentin could only prolong the onset of convulsions. Neither treatment was effective against myoclonus of hindlimbs. Present results showed that fasted rats also develop antimuscarinic-induced convulsions which do not completely respond to treatments found effective in convulsions of fasted mice.     

The evaluation of antimuscarinic-induced convulsions in fasted rats after food intake

The present study was performed to evaluate convulsions after food intake in fasted rats pretreated with scopolamine or atropine and to determine whether these convulsions respond to drugs found effective in fasted mice. Scopolamine (2.4 mg/kg) and atropine (2.4 mg/kg) were given intraperitoneally (i.p.) to rats fasted for 52h. Both drugs induced convulsions after animals were allowed to eat ad lib. Another group of fasted rats pretreated with saline, MK-801 (0.1mg/kg), clonidine (0.1mg/kg), chlorpromazine (2 and 4 mg/kg), valproate (200mg/kg), diazepam (1.5 and 2mg/kg) or gabapentin (50mg/kg) were treated i.p. with saline or scopolamine (2.4 mg/kg) and were allowed to eat ad lib. Clonidine, MK-801, chlorpromazine (4 mg/kg) and diazepam (2 mg/kg) reduced the incidence of scopolamine-induced convulsions in fasted rats. Gabapentin could only prolong the onset of convulsions. Neither treatment was effective against myoclonus of hindlimbs. Present results showed that fasted rats also develop antimuscarinic-induced convulsions which do not completely respond to treatments found effective in convulsions of fasted mice.     

Neuropeptide AF is associated with short-term reduced food intake in rats

Neuropeptide AF (NPAF), a member of the RFamide family, was centrally administered to rats to determine its effect on food intake. Rats responded with a linear dose-dependent reduction in cumulative food intake up to 3 h post injection, but when analyzed on a noncumulative basis, food intake was only significantly reduced at 0.5 h. To our knowledge, this is the first report of NPAF-induced reduction in food intake in a mammalian model.     

Sex differences in averaged visual evoked potentials during food intake in rats

Averaged visual evoked potentials (AVEP's) were recorded in unrestrained male and female rats during alert wakefulness (baseline condition), feeding and drinking. The rats had been deprived of food and water for 23 hr prior to testing. Peak-to-peak amplitude of the AVEP's was measured between the slow negative and the preceding positive component. Under baseline conditions females had higher amplitude AVEP's than males. It is suggested that sex differences in adrenal steroid secretion could account for this observation. During feeding and drinking, AVEP's increased significantly in amplitude in both sexes, and high-voltage, slow EEG activity was observed to appear in most animals. During feeding, these increases in AVEO amplitude were significantly larger in males than in females. These findings support recent views on sex differences in the regulation of feeding behavior.     

The effect of intracerebroventricular administration of baclofen on food intake in rats

In the present study the effects of intracerebroventricular (ICV) administration of baclofen (0.1-5.0 nmol) was investigated on food intake in non-fasted rats. Baclofen (1.0, 2.5 and 5.0 nmol) increased food consumption in a dose-related manner during the first 15-30 min after administration. The effects of baclofen (5.0 nmol) on feeding were prevented by pretreating the rats with the specific GABA-B receptor antagonist phaclofen (40 nmol, ICV). These results suggest that baclofen increases food intake in rats by an action at central GABA-B receptors.