Paradoxical effects of a high sucrose diet: high energy intake and reduced body weight gain.
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Animals↗
Biomedical subjects
J C Halford
Publications and source records attributed to J C Halford.
Regulation of appetite: role of leptin in signalling systems for drive and satiety.
BACKGROUND: The healthy regulation of appetite involves a balance between excitatory (drive) and inhibitory (satiety) processes. For many years research has concentrated on the identification of signalling systems that mediate satiety to the relative exclusion of drive-inducing biological events. However, the so-called long-term regulation of body weight has recently been given substance by the identification of a chemical signal believed to link the brain with adipose tissue stores. ANALYSIS: This signal, leptin, is in position to modulate the expression of a drive to eat. Studies on the relationship between leptin and perceived hunger, and on the eating behaviour of leptin-deficient individuals, are consistent with the intervention of leptin in a drive system. The contrast between the roles of leptin and serotonin in appetite regulation reflects the difference between drive-signalling and satiety signalling processes. CONCLUSION: It is proposed that leptin modulates the drive signals arising from the metabolic demand for energy but also shows some properties of a post-prandial satiety signal.
Animals↗
SB-334867, a selective orexin-1 receptor antagonist, enhances behavioural satiety and blocks the hyperphagic effect of orexin-A in rats.
Intracerebroventricular (i.c.v.) administration of the novel hypothalamic neuropeptide orexin-A stimulates food intake in rats, and delays the onset of behavioural satiety (i.e. the natural transition from feeding to resting). Furthermore, preliminary findings with the selective orexin-1 receptor antagonist, SB-334867, suggest that orexin-A regulation of food intake is mediated via the orexin-1 receptor. At present, however, little is known about either the intrinsic effects of SB-334867 on the normal structure of feeding behaviour, or its effects upon orexin-A-induced behavioural change. In the present study, we have employed a continuous monitoring technique to characterize the effects of SB-334867 (3-30 mg/kg, i.p.) on the microstructure of rat behaviour during a 1-h test with palatable wet mash. Administered alone, SB-334867 (30 mg/kg, but not lower doses) significantly reduced food intake and most active behaviours (eating, grooming, sniffing, locomotion and rearing), while increasing resting. Although suggestive of a behaviourally nonselective (i.e. sedative) action, the structure of feeding behaviour was well-preserved at this dose level, with the reduction in behavioural output clearly attributable to an earlier onset of behavioural satiety. As previously reported, orexin-A (10 microg per rat i.c.v.) stimulated food intake, increased grooming and delayed the onset of behavioural satiety. Pretreatment with SB-334867 dose-dependently blocked these effects of orexin-A, with significant antagonism evident at dose levels (3-10 mg/kg) below those required to produce intrinsic behavioural effects under present test conditions. Together, these findings strongly support the view that orexin-A is involved in the regulation of feeding patterns and that this influence is mediated through the orexin-1 receptor.
Animals↗
Pharmacology of appetite suppression: implication for the treatment of obesity.
Given the current global epidemic of obesity there is a demand for new anti-obesity drugs to overcome the problem. Many pharmacological agents reduce food intake and significantly decrease body mass when administered to animals but affect feeding behaviour in a profoundly different way indicating the variety of biological mechanisms by which such agents act (appetite verses non-appetite). More limited clinical data demonstrates that some of the same drugs produce decreases in food intake and weight loss in humans. A few of these drugs do so by modifying the functioning of the appetite system as measured by subjective changes in feelings of hunger and fullness (indices of satiety). These drugs that modify the daily flux of appetite could be considered as 'appetite suppressants' with clinical potential as anti-obesity agents. Drugs that can be considered suitable candidates for appetite suppressants are agents that enhance peripherally satiety peptide systems (such as CCK, Bombesin/GRP, Enterostatin and GLP-1), alter the CNS levels of various hypothalamic neuropeptides (NPY, Galanin, Orexin, CART and Melanocortins) or monoamine neurotransmitters (such as serotonin, nor-adrenaline and possibly dopamine). Recently, the hormone leptin has become regarded as a key hormonal signal linking adipose tissue status with a number of key central nervous system circuits (NPY, CART, CRF, Melanocortins and possibly Orexins). This tonic system may also provide drug targets for the control of appetite. Any changes induced by a potential appetite suppressant should be considered in terms of the (i) psychological experience and behavioural expression of appetite, (ii) metabolism and peripheral physiology, and (iii) functioning of CNS neural pathways. In humans, such modulation of appetite will involve changes in total caloric consumption, subjective changes in feelings of hunger and fullness, preferences for specific food items, and general macronutrient preferences. These may be expressed behaviourally as changes in meal patterns, snacking behaviour and food choice. Within the next 20 years it is certain that clinicians will have a new range of anti-obesity compounds available to choose from. Such novel compounds may act on a single component of the appetite system or target a combination of these components detailed in this review. Such compounds used in combination with life style changes and dietary intervention may be critical in dealing with the rising world epidemic of obesity.
Animals↗
Dose-response effects of orexin-A on food intake and the behavioural satiety sequence in rats.
Although intracerebroventricular (i.c.v.) administration of orexin-A has been reported to stimulate food intake and/or feeding behaviour in rats, mice and goldfish, little attention has thus far been paid to its effects on normal patterns of feeding. In the present study, a continuous monitoring technique was used to characterise the effects of this novel neuropeptide on the microstructure of rat behaviour during a 1-h test with palatable wet mash. Particular attention was devoted to the behavioural satiety sequence, in which feeding is followed by grooming and resting. Although results confirmed the hyperphagic effects of orexin-A (3.33-30.0 microg i.c. v.), gross behavioural analysis failed to reveal any reliable effects of peptide treatment on eating, drinking, sniffing, grooming, resting, locomotion or rearing. However, microstructural analysis revealed behavioural effects of orexin-A that are both dose- and time-dependent. At lower doses (3.33-10.0 microg), orexin-A primarily delayed behavioural satiety, i.e. the normal transition from eating to resting. In contrast, the 30 microg dose initially induced a sedative-like effect, significantly suppressing eating and other active behaviours for the first 15-20 min of the test period. This sedative-like effect resulted in a phase-shifting of the entire behavioural sequence with higher than control levels of eating, grooming, locomotion, rearing and sniffing observed over the second half of the test session. Present findings illustrate the advantages of microstructural behavioural analysis and suggest that the hyperphagic response to low doses of orexin-A results largely from a delay in behavioural satiety while that seen in response to high doses may occur in rebound to initial behavioural suppression. Further studies will be required to confirm the identity of the specific orexin receptors (i.e. OX(1) or OX(2)) involved in mediating the dose-dependent behavioural effects reported.
Animals↗
Developmental onset of eating-related color-naming interference: the role of restraint and eating psychopathology.
OBJECTIVE: This study investigated the developmental onset of the Stroop interference effect for food and body shape words in 12- and 14-year-old females to determine whether dietary restraint and eating psychopathology influenced Stroop performance times. METHOD: A Stroop task containing neutral, food, and body shape-related words was administered to 152 schoolgirls. Participants completed the restraint scale of the Dutch Eating Behavior Questionnaire and the Drive for Thinness (DFT) subscale of the Eating Disorders Inventory. RESULTS: Significant color-naming impairments were observed for food-related words in 12- and 14-year-olds, in 14-year-old restrained eaters, and in 12-year-old unrestrained eaters. There were no significant differences between restrained and unrestrained eaters in either age group. Participants scoring high on the DFT subscale showed significant impairments for food-related words, but did not differ significantly from those scoring low on the DFT. There were no significant impairments in color-naming body shape-related words in any subgroups. DISCUSSION: This study did not confirm a different developmental onset for the food and body shape Stroop interference effect. Consideration of dietary restraint did add clarity to previously observed food-related interference effects in both age groups. The results for high- and low-DFT participants do not support the use of the eating-related Stroop tests as an early objective indicator of eating psychopathology.
Adolescent↗
Pharmacology of appetite suppression.
Despite a rising worldwide epidemic of obesity there is currently only a very small number of anti-obesity drugs available to manage the problem. Large numbers of differing pharmacological agents reliably produce a reduction in food intake when administered acutely to animals, and when administered chronically they result in a significant decrease in body mass. Behavioural analysis of drug-induced anorexia in animals demonstrates that various compounds profoundly effect feeding behaviour in differing ways. This indicates the variety of mechanisms by which pharmacological agents can induce changes in food intake, body weight and eventually body composition. Some of the same drugs produce decreases in food intake and weight loss in humans. Some of these drugs do so by modifying the functioning of the appetite system as measured by subjective changes in feelings of hunger and fullness (indices of satiety). Such drugs can be considered as "appetite suppressants" with clinical potential as anti-obesity agents. Other drugs induce changes in food intake and body weight through various physiological mechanisms inducing feelings of nausea or even by side effect related malaise. Of the drugs considered suitable candidates for appetite suppressants are agents which act via peripherally satiety peptide systems (such as CCK, Bombesin/GRP, Enterostatin and GLP-1), or alter the CNS levels of various hypothalamic neuropeptides (NPY, Galanin, Orexin and Melanocortins) or levels of the key CNS appetite monoamine neurotransmitters such as serotonin (5-HT) and noradrenaline (NA). Recently, the hormone leptin has been regarded as a hormonal signal linking adipose tissue status with a number of key central nervous system circuits. The peptide itself stimulates leptin receptors and it links with POMC and MC-4 receptors. These receptors may also provide drug targets for the control of appetite. Any changes induced by a potential appetite suppressant should be considered in terms of the (i) psychological experience and behavioural expression of appetite, (ii) metabolism and peripheral physiology, and (iii) functioning of CNS neural pathways. In humans, modulation of appetite may involve changes in total caloric consumption, subjective changes in feelings of hunger and fullness, preferences for specific food items, and general macronutrient preferences. These may be expressed behaviourally as changes in meal patterns, snacking behaviour and food choice. Within the next 20 years it is certain that clinicians will have a new range of anti-obesity compounds available to choose from. Such novel compounds may act on a single component of the appetite system or target a combination of these components detailed in this review. Such compounds used in combination with lifestyle changes and dietary intervention may be useful in dealing with the rising world epidemic of obesity.
Animals↗
Separate systems for serotonin and leptin in appetite control.
Appetite control involves an integration of the drive signals arising form energy stores in the body with the satiety signals generated by periodic episodes of food consumption. Serotonin (5-hydroxytryptamine, 5-HT) has been implicated in the processes of within-meal satiation and postmeal satiety (5-HT1B and 5-HT2C postsynaptic receptors) which are concerned with the signals arising form the pattern of food intake. Central nervous system (CNS) 5-HT is sensitive to circulating levels of the precursor tryptophan, certain macronutrients and peripheral satiety factors such as cholecystokinin (CCK) and enterostatin. Hypothalamic 5-HT receptor systems inhibit neuropeptide Y (NPY), a potent stimulator of hunger and food intake. In contrast to the linking of 5-HT with the consequences of food ingestion, the hormone leptin (OB protein) is regarded as a signal linking adipose tissue status with a number of key CNS circuits. Leptin itself stimulates CNS leptin receptors (OB-r receptor) which link with pro-opiomelanocortin (POMC)/ MC-4 receptors. The effects of leptin may also be modulated by factors such as the corticotrophin-releasing factor (CRF), cocaine and amphetamine-regulated transcript (CART), orexins and galanin. Very little evidence exists to support any direct link between the actions of 5-HT and leptin, suggesting that they are separate systems. 5-HT is a part of an integrated network for short-acting satiety signals (episodic in nature), and leptin is a hormonal indicator of long-term (tonic) energy reserves. At a conceptual level, these may represent the distinction between 'satiety' and 'drive'. Interestingly, both 5-HT and leptin modulate the action of NPY, which may form a part of a common output pathway for the expression of appetite.
Animals↗
Behavioral satiety sequence (BSS) for the diagnosis of drug action on food intake.
The Behavioral Satiety Sequence (BSS) is the name given to the orderly transitions of eating, activity grooming and resting measured during the postingestive period. Because the BSS is considered to reflect the operations of natural physiological processes underlying satiety, the sequence can be used to discriminate between different drugs (and other manipulations) that reduce food intake via these natural physiological mechanisms or those that do so by interference. The BSS is only produced by the presence of a caloric load in the gut, and the preabsorptive satiety factors (such as CCK) the caloric load triggers. The BSS is most accurately defined by continuous observation rather than time or event sampling techniques [Partial Time Sampling (PTS) or Momentary Time Sampling (MTS)]. Continuous observation also allows the true duration and true frequency of each behavior to be analyzed. Continuous observation can be used to determine if the profiles associated with the reduction in food intake is caused by nausea, sedation, hyperactivity, or altered palatability of food. At the present time is it possible to identify a number of drugs whose suppression of food intake is associated with the disruption or preservation of the BSS. Drugs that increase synaptic 5-HT activity such d-fenfluramine, fluoxetine. and sibutramine all preserve the BSS and advance the onset of resting. The 5-HT1b/2c agonists mCPP and TFMPP and the 5-HT1b agonist CP-94,253 produce similar effects. However, the 5-HT2 agonist DOI and the 5-HT1a/1b agonist RU-24969 disrupt the BSS by inducing hyperactivity as does amphetamine. The 5-HT2 agonist MK-212 disrupts the BSS by inducing sedation. Selective dopamine agonists, at low doses, such as SKF-38393 (DA1) and LY-171555 (DA2) also preserve the BSS. However, detailed behavioral analysis of the effects of many recently discovered putative satiety factors remains to be carried out.
Animals↗
Volume of food consumed affects satiety in men.
This study tested the hypothesis that the amount (weight or volume) of food consumed affects the satiating potency of a food, independent of its energy content. Normal-weight young men (n = 20) were tested in a within-subjects design. Subjects were served a milk-based drink or no drink (control), followed 30 min later by a self-selected lunch and > 4 h later by a self-selected dinner. Milk drinks were equal in energy content (2088 kJ, or 499 kcal) and had similar proportions of fat (30.3%), carbohydrate (54.7%), and protein (15%) across three volumes: 300, 450, and 600 mL. Ratings of palatability, sensory properties, and energy content of the drinks and of hunger completed before consumption of the preloads were not significantly different among conditions. The results showed that preload volume affected energy intake at lunch (P < or = 0.009) such that energy intake was less after the 600-mL preload than after the 300-mL preload. This effect was still present when energy intake at dinner was included (P < or = 0.022). At lunch, including energy from the preload, subjects overate relative to the control condition (4323 +/- 322 kJ) after the 300- (5263 +/- 321 kJ) and 450-mL (5011 +/- 300 kJ) preloads but not after the 600-mL (4703 +/- 353 kJ) preload. Thus, the best adjustment for the energy in the preloads was with the largest, least energy-dense drink. Consistent with the effects on intake, the volume of the drinks affected ratings of hunger and fullness. These results indicate that the volume consumed is an important determinant of satiety after milk drinks under these conditions.
Adult↗
The 5-HT2 receptor agonist MK-212 reduces food intake and increases resting but prevents the behavioural satiety sequence.
The 5-HT2c receptor is implicated in the relationship between serotonin and satiety. However, anorexia induced by the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) has been shown to delay, not advance behaviours associated with the onset of satiety, fragmenting eating behaviour, 6-chloro-2-(1-piperazinyl)pryazine (MK-212) is also a selective agonist at the 5-HT2 receptor sites. MK-212 has greater affinity for 5-HT2c receptor sites than DOI. The effects of an ED50 dose of MK-212 (5.0 mg/kg i.p.) on the eating and other behaviours of the fasted rat were continuously monitored following the presentation of food. Continuous monitoring provides the most powerful and valid form of behavioural analysis. Temporal profiles of behaviour duration (dur) and frequency (frq) were generated. Food intake was reduced 54% by MK-212 (p < .001). The frequency of grooming was reduced (p < .01). Locomotion (dur p < .001, frq p < .001), rearing (dur p < .0005, frq p < .005) and sniffing (dur p < .05, frq p < .0001) were all reduced. The duration of resting increased (p < 0.01). This is consistent with enhanced satiety. However, the Behavioural Satiety Sequence was not present after the administration of MK-212 (5.0 mg/kg). The temporal structure of behaviour produced by MK-212 was quite different from that produced by pre-feeding. Initially resting dominated the behavioural profile. Eating increased over time from a suppressed state in the initial stages of the observation period. This lack of appearance of the Behavioural Satiety Sequence is more similar to a state of hyper-sedation than to DOI induced hyper-activity. The time course of this sedation would not have been picked up by a simple categorical analysis of behaviour. Hence, temporal analysis is an essential tool in understanding of drug induced anorexia.
Animals↗
The 5-HT1B receptor agonist CP-94,253 reduces food intake and preserves the behavioural satiety sequence.
The 5-HT1B receptor has been proposed as a link in the relationship between serotonin and satiety. However, the anorexia induced by RU-24969, a 5-HT1A/1B agonist, has been shown to delay behaviours associated with the onset of satiety, increase the frequency of intake and increase some nonfeeding activities. CP-94,253 is a highly selective agonist at the 5-HT1B receptor site with less affinity for other receptor sites, and has been used in this study to determine if agonism of 5-HT1B receptor sites adjust the behavioural satiety sequence in a way consistent with satiety. The effects of an ED50 of dose of CP-94,253 (5.0 mg/kg, IP) on eating behaviour of the fasted rat were monitored. Temporal profiles of behaviour duration and frequency were generated. Food intake was reduced 57% by CP-94,253 (p < 0.0005). Analysis confirmed that CP-94,253 reduced rearing (p < 0.05) and increased resting (p < 0.05) but preserved the overall pattern of the satiety sequence. Increased locomotion was not significant and caused no gross disruption of the behavioural repertoire. Such changes are also produced by prefeeding. In a second experiment, RU-24969 (1.0 mg/kg, IP) reduced food intake by only 30% (p < 0.05) However, RU-24969 markedly disrupted the satiety sequence profile, which did not resemble the profile produced by prefeeding. RU-24969 presumably induces this disruption via a mechanism other than 5-HT1B activation. The use of CP-95,253 demonstrates that selective activation of 5-HT1B receptor sites is sufficient to reduce food intake and enhance satiety as represented by the behavioural satiety sequence.
Animals↗
Metergoline antagonizes fluoxetine-induced suppression of food intake but not changes in the behavioural satiety sequence.
In this study continuous monitoring was used to yield a true behavioural record. This allows a bidimensional account of drug effects on every unit of behaviour. Behavioural dimensions of duration (dur) and frequency (frq) measures were utilized to monitor the effects of an ED50 anorectic dose of fluoxetine (10 mg/kg i.p.) on the behavioural satiety sequence and the effect of a metergoline (1 mg/kg i.p.) challenge. Fluoxetine reduced food intake by 45% (p < 0.005). The local eating rate was also reduced (p < 0.001), demonstrating a marked slowing of eating behaviour. Eating behaviour was reduced (frq p < 0.05) as was grooming (frq p < 0.05) and activity. Resting was increased (dur p < 0.05) and temporally advanced. There was no gross disruption of behaviour and the profile was adjusted in a way consistent with the expression of satiety. Fluoxetine-induced changes were very similar to those produced by prefeeding. Metergoline antagonised fluoxetine's effect on intake and eating duration (dur p < 0.05). However, metergoline did not antagonise the effect of fluoxetine on the frequency of eating (frq p < 0.005), thus increasing the amount consumed per eating episode. Grooming (frq p < 0.005) and activity also remained reduced. At this dose fluoxetine-induced suppression of eating is serotonin dependent as it is reversed by metergoline. Fluoxetine-induced suppression of eating at this dose is consistent with the normal operation of satiety. Fluoxetine-induced slowing of behavior appears to be mediated by a separate mechanism.
Animals↗
Serotonin, eating behavior, and fat intake.
There is an intimate relationship between nutritional intake (eating) and serotonin activity. Experimental manipulations (mainly neuropharmacological) of serotonin influence the pattern of eating behavior, subjective feelings of appetite motivation, and the response to nutritional challenges. Similarly, nutritional manipulations (food restriction, dieting, or altered nutrient supply) change the sensitivity of the serotonin network. Traditionally, serotonin has been linked to the macronutrient carbohydrate via the intermediary step of plasma amino acid ratios. However, it has also been demonstrated that 5-HT drugs will reduce energy intake and reverse body weight gain in rats exposed to weight increasing high fat diets. 5-HT drugs can also reduce food intake and block weight gain of rats on a high fat cafeteria diet. Some diet selection studies in rats indicate that the most prominent reduction of macronutrient intake is for fat. These data indicate that 5-HT activity can bring about a reduction in fat consumption. In turn, different types of dietary fat can alter brain 5-HT activity. In human studies the methodology of food choice experiments has often precluded the detection of an effect of 5-HT manipulation on fat intake. However, there is evidence that in obese and lean subjects some 5-HT drugs can readily reduce the intake of high fat foods. Data also suggest that 5-HT activation can lead to a selective avoidance of fat in the diet. These effects of 5-HT on the intake of dietary fat may involve a pre-absorptive mechanism and there is evidence that 5-HT is linked to cholecystokinin and enterostatin. These proposals have theoretical and practical implications and suggest possible strategies to intensify or advance fat-induced satiety signals.
Animals↗
Pharmacological aspects of obesity treatment: towards the 21st century.
Obesity: a bio-behavioural-environmental phenomenon: Obesity is on the increase all over the world in technologically advanced countries, developing countries and rural communities. What is causing this upward drift in body weight? Can drugs do anything to ameliorate the situation? It is generally agreed that obesity results from genetic vulnerability combined with a provocative environmental situation. This provides the basis for a psychobiological interaction in which behaviour plays a key role. This is the case since it is behaviour which translates biological propensities into action on the environment, and it is behaviour which mediates (in part) the effect of the environment upon biology. Two particularly important behavioural aspects of the genes-environment interaction are low levels of physical activity (high sedentariness) and dietary habits which favour overconsumption (high intake of energy, particularly as fat). One continuing theme of research is the development of drugs to allow people to gain control over appetite by modifying eating patterns (dietary habits) through a number of possible mechanisms. The use of drugs to make people more willing or more able to engage in physical activity is not widely discussed although the use of drugs to increase total energy expenditure (via a variety of mechanisms) is actively researched. More than a decade ago Sullivan defined the framework for the development of anti-obesity drugs by specifying that drugs could act on energy intake, energy output or on those mechanisms involved in the assimilation and storage of lipids in the body.(ABSTRACT TRUNCATED AT 250 WORDS)
Body Weight↗
Regulation of nutrient supply: the brain and appetite control.
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Appetite Regulation↗