Reduced Meal Size Research Articles

Evidence that Intestinal Glucagon-Like Peptide-1 Plays a Physiological Role in Satiety

A physiological role in satiety is proposed for glucagon-like peptide-1 (GLP-1), secreted by the distal intestine in response to ingested nutrients. Here we report that in rats, ip injection of the GLP-1 receptor (GLP-1-R) antagonist exendin 9-39 (Ex9) elicited hyperphagia, but only at times of day when intake is otherwise low. Furthermore, ip administration of Ex9 attenuated satiety induced by either a voluntarily consumed sucrose meal (by 100%) or an intragastric glucose load (by 40%). To determine whether these effects involve blockade of GLP-1-R in brain or at a peripheral site, we injected Ex9 either centrally (into the third ventricle) or peripherally (ip) prior to GLP-1 injected either centrally or peripherally. Anorexia induced by peripheral GLP-1 was fully blocked by peripheral, but not central, pretreatment with Ex9, whereas the opposite was true for anorexic effect of central GLP-1. Thus, ip Ex9 appears to attenuate satiety via peripheral GLP-1-R blockade. Finally, anorexia induced by ip injection of exendin-4 (a GLP-1-R agonist) was due to both reduced meal size and increased duration between meals. We conclude that GLP-1 released from the intestine in response to ingested nutrients is a physiologically active satiety signal.

Intrameal Hepatic Portal and Intraperitoneal Infusions of Glucagon-Like Peptide-1 Reduce Spontaneous Meal Size in the Rat via Different Mechanisms

Peripheral administration of glucagon-like peptide (GLP)-1 reduces food intake in animals and humans, but the sites and mechanism of this effect and its physiological significance are not yet clear. To investigate these issues, we prepared rats with chronic catheters and infused GLP-1 (0.2 ml/min; 2.5 or 5.0 min) during the first spontaneous dark-phase meals. Infusions were remotely triggered 2-3 min after meal onset. Hepatic portal vein (HPV) infusion of 1.0 or 3.0 (but not 0.33) nmol/kg GLP-1 reduced the size of the ongoing meal compared with vehicle without affecting the subsequent intermeal interval, the size of subsequent meals, or cumulative food intake. In double-cannulated rats, HPV and vena cava infusions of 1.0 nmol/kg GLP-1 reduced meal size similarly. HPV GLP-1 infusions of 1.0 nmol/kg GLP-1 also reduced meal size similarly in rats with subdiaphragmatic vagal deafferentations and in sham-operated rats. Finally, HPV and ip infusions of 10 nmol/kg GLP-1 reduced meal size similarly in sham-operated rats, but only HPV GLP-1 reduced meal size in subdiaphragmatic vagal deafferentation rats. These data indicate that peripherally infused GLP-1 acutely and specifically reduces the size of ongoing meals in rats and that the satiating effect of ip, but not iv, GLP-1 requires vagal afferent signaling. The findings suggest that iv GLP-1 infusions do not inhibit eating via hepatic portal or hepatic GLP-1 receptors but may act directly on the brain.

Feeding Behavior in Rats Subjected to Gastrectomy or Gastric Bypass Surgery

Background/Aim: Gastric bypass (GB) is usually designed to restrict food intake and to induce malabsorption. Gastric hormones have been thought to play a role in the regulation of food intake and body weight. The aim of the present study was to analyze feeding behavior after total gastrectomy (Gx) or GB in rats. Methods: Animals were subjected to Gx, GB, or sham operations. Eating and drinking behaviors after surgeries were assessed by a comprehensive laboratory animal monitoring system. Gastric hormones were measured by radioimmunoassay and energy density in feces by adiabatic bomb calorimeter. Results: Compared with sham operation, both Gx and GB reduced the body weight as measured during 3–8 weeks postoperatively, which was associated with increased energy expenditure per 100 g body weight. Daily accumulated food intake and meal size (during nighttime) were reduced following Gx, but not GB. The water intake (during daytime) was increased after Gx and GB. The energy density in feces was unchanged. Serum concentrations of ghrelin, obestatin, leptin, gastrin, and pancreastatin were greatly reduced after Gx. Conclusions: Control of food intake and meal size was independent of the food reservoir function of the stomach. Surgical depletion of gastric hormones is associated with reduced meal size, but increased water intake.

Adaptation of lipid-induced satiation is not dependent on caloric density in rats

Food intake is modulated by ingestive (gastrointestinal) and post-ingestive signals; ingested fat is potent to produce short-term satiety (satiation) but this can be modified by long-term ingestion of a high fat diet. Aim Determine whether altered lipid-induced satiation is dependent on the fat content of the diet, rather than increased caloric density or changes in adiposity. Methods Initial experiments determined the differences in the microstructure of meal patterns in rats fed a high fat diet (HF: 38% fat kcal) and in rats pair-fed an isocaloric, isonitrogenous low fat diet (LF: 10% fat kcal) and changes in meal patterns measured after long-term maintenance on the HF diet. Results Rats fed the HF diet had a significant 50% increase in meal frequency compared to rats fed the LF diet; in addition, there was a significant reduction in meal size (32%) and inter meal interval (38%) consistent with induction of satiation. After 8 weeks on the HF diet, these parameters tend to approach those of rats maintained on the LF diet. There was a significant 56% decrease in the activation of neurons in the NTS in response to intragastric gavage of lipid in rats maintained for 8 weeks on the HF compared to LF diet. Conclusion Dietary fat alters meal patterns consistent with induction of a short-term satiety signal. This signal is attenuated with long-term exposure to dietary lipid, in the absence of ingestion of additional calories or changes in body weight. This adaptation of short-term satiety might contribute to diet-induced obesity.

Unraveling the obesity of OLETF rats

Cholecystokinin (CCK) is a brain gut peptide that plays an important role in satiety. CCK inhibits food intake by reducing meal size. CCK's satiety actions are mediating through its interaction with CCK1 receptors. Otsuka Long Evans Tokushima Fatty (OLETF) rats are a CCK1 receptor knockout model that allows the study of multiple CCK functions. OLETF rats are hyperphagic with the hyperphagia expressed as a significant increase in the size of meals. OLETF rat obesity is secondary to the hyperphagia and has been proposed to derive from two regulatory deficits. One is secondary to the loss of a feedback satiety signal. The other results from increased dorsomedial hypothalamic NPY expression. Recent studies have examined developmental aspects of altered feeding, body weight and orexigenic signaling in OLETF rats. OLETF rats demonstrate increases in meal size in independent ingestion tests as early as two days of age. OLETF pups are also more efficient in suckling situations. Consistent with such developmental differences, examinations of patterns of hypothalamic gene expression in OLETF pups indicate significant increases in DMH NPY expression as early as postnatal day 15. Access to a running wheel and the resulting exercise have age dependent effects on OLETF food intake and obesity. With running wheel access shortly after weaning, food intake decreases to the levels of LETO controls. When running wheel access is discontinued, food intake temporarily increases resulting in an intermediate phenotype and the absence of diabetes. Together these data demonstrate roles for peripheral CCK and CCK in feeding and body weight control and support the use of the OLETF rat as a model for examining obesity development and for investigating how interventions at critical developmental time points can alter genetic influences on food intake and body weight.

Correction: Bang-Bang Control of Feeding: Role of Hypothalamic and Satiety Signals

In PLoS Computational Biology, volume 3, issue 5, in the Introduction section: 10.1371/journal.pcbi.0030097 The word glucagon was misspelled glucagons. This is the correct sentence: In addition, amylin [18] and glucagon [19], which are secreted from the pancreatic islets during meals, also reduce meal size. The following sentence was missing a reference (34): Conversely, bilateral PVN lesions cause a hyperphagic obesity syndrome, whereas bilateral lesioning of the LHA causes anorexia and weight loss [31,33,34]. The following sentence had an incorrect reference (52 is correct instead of 50): The bang-bang CINT model also accounts quantitatively for the complexities of meal-intermeal correlations [52] (see also [9,54]).

BVT.3531 reduces body weight and activates K ATP channels in isolated arcuate neurons in rats

A number of hormones, including leptin, have been shown to inhibit food intake in humans and animals. Analogues of 3-guanidinopropionic acid have also been found to reduce total food intake, but their mechanisms of action have not been well studied. The present study investigated the effects of intracerebroventricular infusion of the analogue BVT.3531 on food intake, meal pattern, and body weight in rats during 7 days. Single channel recordings from arcuate neurons and insulinoma cells were used to determine the effects of BVT.3531 on K ATP activity. Data analysis showed that BVT.3531 significantly decreased body weight and food intake, primarily by reducing meal size. BVT.3531 activated K ATP channels in cell-attached recordings from insulin-secreting cells and rat arcuate neurons but had no effect on K ATP channel activity in inside-out membrane patches from either cell type. BVT.3531 did not alter the firing rate or K + channel activity of arcuate neurons devoid of K ATP. The study suggests that small molecules capable of mimicking the effects of leptin on food intake and body weight may utilize output mechanisms similar to those of leptin to elicit changes in arcuate neuron excitability.

FG 7142 Specifically Reduces Meal Size and the Rate and Regularity of Sustained Feeding in Female Rats: Evidence that Benzodiazepine Inverse Agonists Reduce Food Palatability

Benzodiazepine receptor inverse agonists reduce food intake in males, but their actions in females, in whom stress-related eating disorders are more common, as well as their behavioral mode of action remain unclear. The consummatory effects of benzodiazepine receptor ligands have alternately been hypothesized to reflect changes in the hedonic evaluation of food or secondary effects of anxiety-related or cognitive properties. To test the anorectic mode of action of benzodiazepine inverse agonists, the effects of FG 7142 on feeding microstructure were studied in nondeprived female Wistar rats (n=32). Microstructure analysis used a novel meal definition that recognizes prandial drinking. On pharmacologically synchronized diestrus I, rats were pretreated (-30 min dark onset) with the benzodiazepine partial inverse agonist FG 7142 (i.p. 0, 3.75, 7.5, 15 mg/kg) in a between-subjects design. FG 7142 delayed the onset of (16-541%), decreased the amount eaten (36-52%) and drunk (63-87%), and reduced the time spent drinking (59-87%) within the first nocturnal meal. Dose-dependent incremental anorexia continued 6 h into the dark cycle, whereas FG 7142 did not suppress the quantity, duration or rate of drinking past the first meal. Treated rats ate smaller meals (17-42%) of normal duration. This reflected that FG 7142 slowed feeding within meals (9-38%) by decreasing the regularity and maintenance of feeding from pellet-to-pellet. FG 7142 did not influence postprandial satiety; meal frequency and inter-meal intervals were unaffected. FG 7142 anorexia was blocked by the benzodiazepine receptor antagonist flumazenil in a 2:1 molar ratio (n=17 rats). The very early, nonspecific (+10 min), but not subsequent (2.5, 4.5 h) feeding-specific phase, of FG 7142 anorexia was mirrored by anxiogenic-like behavior in FG 7142-treated (7.5 mg/kg) female rats (n=48) in the elevated plus-maze. Thus, benzodiazepine receptor inverse agonists preferentially lessen the maintenance of feeding in female rats, effects opposite to those of palatable food.

Nicotine administration effects on feeding and cocaine–amphetamine-regulated transcript (CART) expression in the hypothalamus

In previous studies food intake and meal size significantly decreased in rats two days after injecting 4 mg/kg/day nicotine tartrate. Food intake returned to normal after nine days of continued nicotine treatment, when reduced meal size is countered by an increase in meal number. Nicotine also reduced body weight after nicotine injection and body weight remained low after nine days. To begin characterizing the mechanism that modulates these changes in feeding behavior and/or body weight during nicotine exposure the transcript levels for agouti related protein (AGRP), cocaine–amphetamine-regulated transcript (CART), corticotropin releasing hormone receptor one (CRH-R1), melanocortin receptors three and four (MC3R/4R), neuropeptide Y (NPY), NPY Y1 and Y5 receptors and/or pro-opiomelanocortin (POMC) were analyzed in the arcuate (ARC), dorsomedial (DMN) and paraventricular (PVN)/periventricular (PE) hypothalamic nuclei on the second and ninth day of saline or nicotine treatment. Results show that the transcript levels of the anorexigenic molecule CART increased in the PVN and/or PE two days after nicotine treatment but after nine days CART levels equalize. In contrast, nine days of nicotine treatment reduced CART levels in the DMN as compared to saline controls. To investigate CART's role in regulating feeding, infusion of CART (55-102) into the third ventricle reduced food intake and meal size. These results are consistent with nicotine modulating feeding behavior and body weight, in part, by affecting CART transcript levels in the DMN, PVN and/or PE.

Effects of oral preload, CCK or bombesin administration on short term food intake of melanocortin 4-receptor knockout (MC4RKO) mice

We investigated whether either heterozygous (HET) or homozygous (knockout, KO) disruption of the melanocortin type 4 receptor (MC4R) gene alters post ingestive responsiveness of mice. Specifically, we tested the hypothesis that hyperphagia in MC4RKO mice might be due to a deficit in processes that sustain intermeal intervals (satiety) and/or processes that terminate ongoing episodes of eating (satiation). To test satiety, mice drank an oral preload and then we monitored intake of a subsequent liquid diet test meal. To test satiation, we examined the effect of exogenous administration of cholecystokinin (CCK) and bombesin (BN) on the size of a liquid diet meal. Experiment 1 was comprised of two studies. In the first, we determined that the intake of all three genotypes following fasts of either 6, 12, or 24 h were comparable, and so chose 12 h deprivation for the subsequent studies. In the second, 12 h fasted mice were allowed to consume a fixed preload, approximately 50% of their expected mean intake and, following delays of either 30 or 60 min, were allowed to consume to satiation. Compared with no preload, the preload significantly reduced meal size comparably in all three genotypes. The reduction in intake was greater when the test meal was presented 30 compared with 60 min after the preload, again with no genotype differences in this decay of satiety. In experiment 2, we administered either CCK or BN and examined suppression of meal size after a 12 h fast. Mice were tested repeatedly with CCK-8 (2, 6, or 18 μg/kg ip) or BN (2, 4 or 8 μg/kg ip) with vehicle injection days intervening. The 30 min intakes of HET and KO mice were suppressed more than those of WT following either CCK or BN. These experiments suggest that diminished responsiveness to nutrients or gut satiety hormones is not responsible for hyperphagia in MC4RKO mice.

Modulation of vagal afferent excitation and reduction of food intake by leptin and cholecystokinin

The gut-peptide, cholecystokinin (CCK), reduces food intake by acting at CCK-1 receptors on vagal afferent neurons, whereas the feeding effects of the adipokine hormone, leptin, are associated primarily with its action on receptors (ObRb) in the hypothalamus. Recently, however, ObRb mRNA has been reported in vagal afferent neurons, some of which also express CCK-1 receptor, suggesting that leptin, alone or in cooperation with CCK, might activate vagal afferent neurons, and influence food intake via a vagal route. To evaluate these possibilities we have been examining the cellular and behavioral effects of leptin and CCK on vagal afferent neurons. In cultured vagal afferent neurons leptin and CCK evoked short latency, transient depolarizations, often leading to action potentials, and increases in cytosolic calcium. There was a much higher prevalence of CCK and leptin sensitivity amongst cultured vagal afferent neurons that innervate stomach or duodenum than there was in the overall vagal afferent population. Furthermore, almost all leptin-responsive gastric and duodenal vagal afferents also were sensitive to CCK. Leptin, infused into the upper GI tract arterial supply, reduced meal size, and enhanced satiation evoked by CCK. These results indicate that vagal afferent neurons are activated by leptin, and that this activation is likely to participate in meal termination, perhaps by enhancing vagal sensitivity to CCK. Our findings are consistent with the view that leptin and CCK exert their influence on food intake by accessing multiple neural systems (viscerosensory, motivational, affective and motor) at multiple points along the neuroaxis.

Dietary Synergies in Appetite Control: Distal Gastrointestinal Tract

AbstractWOODS, STEPHEN C. Dietary synergies in appetite control: distal gastrointestinal tract.

Pancreatic signals controlling food intake; insulin, glucagon and amylin.

The control of food intake and body weight by the brain relies upon the detection and integration of signals reflecting energy stores and fluxes, and their interaction with many different inputs related to food palatability and gastrointestinal handling as well as social, emotional, circadian, habitual and other situational factors. This review focuses upon the role of hormones secreted by the endocrine pancreas: hormones, which individually and collectively influence food intake, with an emphasis upon insulin, glucagon and amylin. Insulin and amylin are co-secreted by B-cells and provide a signal that reflects both circulating energy in the form of glucose and stored energy in the form of visceral adipose tissue. Insulin acts directly at the liver to suppress the synthesis and secretion of glucose, and some plasma insulin is transported into the brain and especially the mediobasal hypothalamus where it elicits a net catabolic response, particularly reduced food intake and loss of body weight. Amylin reduces meal size by stimulating neurons in the hindbrain, and there is evidence that amylin additionally functions as an adiposity signal controlling body weight as well as meal size. Glucagon is secreted from A-cells and increases glucose secretion from the liver. Glucagon acts in the liver to reduce meal size, the signal being relayed to the brain via the vagus nerves. To summarize, hormones of the endocrine pancreas are collectively at the crossroads of many aspects of energy homeostasis. Glucagon and amylin act in the short term to reduce meal size, and insulin sensitizes the brain to short-term meal-generated satiety signals; and insulin and perhaps amylin as well act over longer intervals to modulate the amount of fat maintained and defended by the brain. Hormones of the endocrine pancreas interact with receptors at many points along the gut-brain axis, from the liver to the sensory vagus nerve to the hindbrain to the hypothalamus; and their signals are conveyed both neurally and humorally. Finally, their actions include gastrointestinal and metabolic as well as behavioural effects.

Serotonin-3 receptors in gastric mechanisms of cholecystokinin-induced satiety

our understanding of the controls of food intake has increased substantially during the last 30 years. Important in this has been the recognition of the meal as a controlled, physiologically relevant unit of energy intake. During a meal, ingested nutrients accumulate in the stomach and gradually

Diminished Satiation After Long‐Term Exposure to an Isocaloric, High Fat Diet in Rats

Food intake is modulated by both gastrointestinal tract and central nervous system; there is evidence that maintenance on a high fat diet leads to hyperphagia, via a peripheral, CCK-dependent mechanism, involving the GI tract. The aim of this paper was to determine whether the response to a high fat diet was dependent on calorie intake or macronutrient content. We compared the feeding behavior effects of an ad libitum isocaloric, isonitrogenous high-fat diet (38%fat kcal) and a pair-fed low-fat diet (10%fat kcal). During the first 28 days, rats fed HF increased meal frequency by 54%, but reduced meal size (36%), intermeal interval (36%) and eating rate (35%). The HF group did not gain as much weight as the LF group did (HF: 0.7 ± 2.4 g vs LF: 31.5 ± 5.1 g), but there was no difference in the adipose index (HF: 2.29 ± 0.71 % vs LF: 2.61 ± 1.00 %). However, by 8 weeks, the differences in meal-patterns between HF and LF fed rats decreased. Gavage of lipid (30 mg) increased fos in NTS of the LF group; this was significantly reduced by 60% in the HF group. These results confirm that fat, rather than calories, modify feeding behavior and confirm prior reports that long-term exposure to fat induces a reduction in the sensitivity of the detection of lipids. This decreased response to fat may contribute to diet-induced obesity.

The anorectic effect of the selective dopamine D 1-receptor agonist A-77636 determined by meal pattern analysis in free-feeding rats

Free-feeding rats meet much of their daily energy requirements by consuming food in meals during the nocturnal phase of the night/day cycle. Meal pattern analysis methodology has been developed to record the patterns of meal taken over a 24-h period, and to provide detailed information on a number of meal-related parameters. Previous work indicates that selective dopamine D 1-receptor agonists reduce food intake in short-term feeding tests under the control of homeostatic or hedonic factors. In the present study, our aim was to investigate the effects of the dopamine D 1-receptor agonist, A-77636 (0.1–1.0 mg/kg, s.c.), administered just prior to the start of the night period, on the free-feeding and drinking patterns of rats maintained on a standard ad libitum diet. The results indicate that A-77636 exerted a suppressant effect on food intake, due principally to a reduction in meal size and duration. We conclude that there is a dopamine D 1-receptor involvement in the normal controls of meal size, and that selective D 1-receptor agonists may act to limit meal size.

Highlights from the Literature

Highlights from the Literature

Changes in the satiating effect of cholecystokinin over repeated trials

The study investigated the reasons for discrepant published results concerning a diminution of the satiating action of cholecystokinin (CCK) when it is administered over several trials. Throughout the experiment, rats were maintained on a schedule in which they were fasted for 5.5 h (except 5 ml of milk), and then given access to a 10% sucrose solution for 30 min. Following a baseline period, rats received 6 μg/kg CCK-8 every day (consecutive group) or every third day (intermittent group), or saline (saline group), 15 min prior to the sucrose. In the consecutive group, CCK-8 significantly reduced meal size on day 1 (85.1 ± 7.4% of baseline) compared to the saline group (106.9 ± 7.5% of baseline), p < 0.05. This reduction was eliminated by day 5 (consecutive group = 94.9 ± 4.7% of baseline, saline group = 98.0 ± 5.2% of baseline). In contrast, the intermittent group never became insensitive to the effect of CCK-8, reducing their intake comparably after the tenth (intermittent group = 138.7 ± 8.2% of baseline, saline group = 176.0 ± 9.1% of baseline, p < 0.01), and first CCK-8 injection (intermittent group = 77.0 ± 6.1% of baseline, saline group = 106.9 ± 7.5% of baseline, p < 0.01). Although it has been hypothesized that this phenomenon is due to behavioral tolerance, the results of this experiment suggest an alternate hypothesis; i.e., that the diminution of the effect of CCK-8 over consecutive administrations is due to the extinction of a previously learned response to endogenous CCK.

A new way of looking at eating

the analysis of meals, especially of spontaneous meals, has long had a problematic place in the behavioral neuroscience of eating. Only a small minority of eating researchers now, or ever, have concerned themselves with meal patterns. On first glance this seems paradoxical. After all, eating occurs

Pancreatic Amylin as a Centrally Acting Satiating Hormone

This review summarizes the present knowledge concerning the anorectic action of the pancreatic hormone amylin. It focuses mainly on the role of amylin as a short term satiating peptide. Since there is some evidence however that basal amylin levels might play a role in the long term control of food intake and/or body weight, this aspect will be discussed briefly towards the end of this review. Concerning amylin as a satiating hormone, it is well established that amylin is released during meals, and that exogenous amylin leads to a dose-related reduction in meal size. Amylin has a rapid onset and brief duration of action. The area postrema (AP) plays a predominant role in peripheral amylin's satiating effect, involving a direct activation of AP neurons by blood-borne amylin. The nucleus of the solitary tract (NTS) relays this effect to higher brain structures, the lateral parabrachial nucleus, and possibly the central nucleus of the amygdala and the bed nucleus of the stria terminalis. Amylin's anorectic effect may in part be due to reduced expression of orexigenic neuropeptides in the lateral hypothalamic area. The anorectic action of amylin is one important factor in amylin's overall role to control the influx of nutrients into the circulation. By reducing food intake, gastric acid secretion, limiting the rate of gastric emptying and diminishing pancreatic glucagon and digestive enzyme secretion, amylin regulates nutrient appearance and postprandial glucose concentration. Amylin seems to be a necessary and complementary factor to insulin, which regulates the rate of nutrient disappearance. In this sense, amylin and insulin are adjunct players in the control of nutrient fluxes, and amylin's role to control feeding is a pivotal factor in this regard.