Martin R. Yeomans

Opioid peptides and the control of human ingestive behaviour

A variety of evidence suggests that endogenous opioid peptides play a role in the short-term control of eating. More recently, opioid receptor antagonists like naltrexone have been approved as a treatment for alcohol dependence. Here we review the evidence for a role of opioid peptides in both normal and abnormal eating and drinking behaviours and in particular try to identify the nature of the role of opioids in these behaviours. Particular attention is paid to the idea that opioid reward processes may be involved both in the short-term control of eating and hedonic aspects of alcohol consumption, and parallels are drawn between the effects of opiate antagonists on food pleasantness and the experience of drinking alcohol. The review also explores the extent to which data from studies using opiate antagonists and agonists provide evidence for a direct role of endogenous opioids in the control of ingestive behaviour, or alternatively whether these data may be better explained through non-specific effects such as the nausea commonly reported following administration of opiate antagonists. The review concludes that the present data suggests a single opioid mechanism is unlikely to explain all aspects of ingestive behaviour, but also concludes that opioid-mediated reward mechanisms play an important control in hedonic aspects of ingestion. The review also highlights the need for further empirical work in order to elucidate further the role of opioid peptides in human ingestive behaviour.

Palatability: response to nutritional need or need-free stimulation of appetite?

The traditional view of palatability was that it reflected some underlying nutritional deficit and was part of a homeostatically driven motivational system. However, this idea does not fit with the common observation that palatability can lead to short-term overconsumption. Here, we attempt to re-evaluate the basis of palatability, first by reviewing the role of salt-need both in the expression of liking for salty tastes, and paradoxically, in dissociating need from palatability, and second by examining the role of palatability in short-term control of appetite. Despite the clarity of this system in animals, however, most salt (NaCl) intake in man occurs in a need-free state. Similar conclusions can be drawn in relation to the palatability of food in general. Importantly, the neural systems underlying the hedonic system relating to palatability and homeostatic controls of eating are separate, involving distinct brain structures and neurochemicals. If palatability was a component of homeostatic control, reducing need-state should reduce palatability. However, this is not so, and if anything palatability exerts a stronger stimulatory effect on eating when sated, and over-consumption induced by palatability may contribute to obesity. Differential responsivity to palatability may be a component of the obese phenotype, perhaps through sensitisation of the neural structures related to hedonic aspects of eating. Together, these disparate data clearly indicate that palatability is not a simple reflection of need state, but acts to promote intake through a distinct hedonic system, which has inputs from a variety of other systems, including those regulating need. This conclusion leads to the possibility of novel therapies for obesity based on modulation of hedonic rather than homeostatic controls. Potential developments are discussed.

Palatability and the Micro-structure of Feeding in Humans: the Appetizer Effect

The effects of manipulated palatability on eating were assessed in 54 human volunteers eating pasta with a tomato sauce, with palatability adjusted by the addition of three levels of oregano. Meals were divided into 2 min eating episodes separated by brief pauses during which subjects rated aspects of appetite. Both intake and eating rate were greatest in the most palatable condition (0.27% oregano), whereas the addition of 0.54% reduced intake and eating rate. Hunger ratings increased during the initial stages of the meal with 0.27% oregano, but fell throughout the meal in the other conditions, whereas fullness ratings increased similarly in all three conditions. Rated food attractiveness was greatest with 0.27% oregano, and least with 0.54% oregano, but declined similarly through the meal with all three foods. Initial ratings of palatability were similar to those for food attractiveness, but changes in palatability across meals varied between subjects. Male subjects consistently ate more and faster than females, but similar effects of manipulated palatability on intake and subjective appetite were seen in both sexes. These data are consistent with the idea that palatability increases intake through a positive-feedback reward mechanism, and offers a novel method for measuring these effects.

Alcohol, appetite and energy balance: is alcohol intake a risk factor for obesity?

The increased recognition that the worldwide increase in incidence of obesity is due to a positive energy balance has lead to a focus on lifestyle choices that may contribute to excess energy intake, including the widespread belief that alcohol intake is a significant risk factor for development of obesity. This brief review examines this issue by contrasting short-term laboratory-based studies of the effects of alcohol on appetite and energy balance and longer-term epidemiological data exploring the relationship between alcohol intake and body weight. Current research clearly shows that energy consumed as alcohol is additive to that from other dietary sources, leading to short-term passive over-consumption of energy when alcohol is consumed. Indeed, alcohol consumed before or with meals tends to increase food intake, probably through enhancing the short-term rewarding effects of food. However, while these data might suggest that alcohol is a risk factor for obesity, epidemiological data suggests that moderate alcohol intake may protect against obesity, particularly in women. In contrast, higher intakes of alcohol in the absence of alcohol dependence may increase the risk of obesity, as may binge-drinking, however these effects may be secondary to personality and habitual beverage preferences.

Independent effects of palatability and within-meal pauses on intake and appetite ratings in human volunteers

The effects of the introduction of timed pauses within meals and palatability on food intake and changes in rated appetite during a meal were assessed in three experiments in which volunteers ate a lunch of pasta with a tomato sauce. Eating was monitored using a disguised electronic balance attached to a micro-computer, which also allowed the introduction of timed pauses within meals. In the first experiment, 16 subjects were tested with both a bland and palatable food (with 0.27% oregano), with eating uninterrupted or with pauses after every 50 g consumed during which appetite ratings were completed. Both the addition of oregano and the introduction of regular within-meal pauses enhanced overall intake. Rated hunger increased in the early stages of eating the palatable food in the interrupted condition, and then declined, whereas hunger declined throughout with the bland food. Similarly, the linear function relating intake to time in the uninterrupted condition was greater with the palatable food. In the second experiment, nine subjects ate the palatable food with no pauses within meals, with 30-second pauses with appetite ratings or with 30-second pauses in a non-appetite task. Intake was greater in both pause conditions than when eating was uninterrupted. In Experiment 3, the effect of pause duration was investigated in a further 16 subjects, with either no pause or a pause of 5, 30 or 60 seconds. Subjects ate more in all pause conditions than with no pauses, while ratings of hunger and fullness suggested that subjects were less satisfied at the end of the meal with longer pauses. These data confirm previous work which suggests that palatability exerts its effect by stimulating appetite and eating rate, but also suggest that the introduction of pauses within meals enhances intake as well, contradicting the idea that pausing within meals should reduce intake by allowing more time for post-ingestive satiety to develop.

Effects of naltrexone on food intake and changes in subjective appetite during eating: evidence for opioid involvement in the appetizer effect.

The effects of 50 mg naltrexone on eating and subjective appetite were assessed in a double-blind placebo-controlled study with 20 male volunteers. Appetite was monitored using a disguised digital balance connected to a micro-computer, which constantly monitored the amount of food remaining, and which automatically interrupted feeding for 30 s after every 50 g consumed to allow appetite ratings to be made. Half the subjects ate pasta with a cheese sauce, and the remainder pasta with a tomato sauce. Subjects ate significantly less of both foods after 50 mg naltrexone than in either the placebo condition or on the initial (familiarisation) day. Naltrexone also reduced the rated pleasantness of both foods, and reduced overall eating rate. When best-fit quadratic functions were used to describe changes in rated hunger in relation to intake within the meal, naltrexone abolished the positive linear component reflecting the initial stimulation of appetite without altering either intercept or the negative quadratic function. Although mood ratings suggested that naltrexone had a mild sedative effect, mood changes alone could not explain the effects of naltrexone on appetite. Overall, these data suggest a specific role for opioids in the stimulation of appetite through palatability.

Selective effects of naltrexone on food pleasantness and intake

The effects of 50 mg naltrexone on both pleasantness and intake of 10 common food items were investigated using a double-blind placebo-controlled study with 16 male volunteers. Rated food pleasantness was reduced significantly in the naltrexone condition compared with both controls (placebo and baseline). However, pleasantness ratings were not affected uniformly across foods, with sweetened, fatty, and high-protein foods being most affected. Changes in rated unpleasantness generally mirrored those for pleasantness, but evaluations of saltiness and sweetness were unaffected by naltrexone. Although total intake was reduced in the naltrexone condition, this was not significant compared with placebo. However, fat and protein intakes were significantly less following naltrexone. The effect of naltrexone on intake was also food dependent, but in this case intake of sweet foods was spared relative to other food categories. The apparent discrepancy between liking and intake data with sweet foods could be interpreted in terms of the likely influence of normal eating styles on food selection during a buffet-style meal, and may explain some contradictions in previous studies of this kind. The implications for understanding opioid involvement in food acceptability are discussed.

Peripheral and central signals in the control of eating in normal, obese and binge-eating human subjects

The worldwide increase in the incidence of obesity is a consequence of a positive energy balance, with energy intake exceeding expenditure. The signalling systems that underlie appetite control are complex, and the present review highlights our current understanding of key components of these systems. The pattern of eating in obesity ranges from over-eating associated with binge-eating disorder to the absence of binge-eating. The present review also examines evidence of defects in signalling that differentiate these sub-types. The signalling network underlying hunger, satiety and metabolic status includes the hormonal signals leptin and insulin from energy stores, and cholecystokinin, glucagon-like peptide-1, ghrelin and peptide YY3-36 from the gastrointestinal tract, as well as neuronal influences via the vagus nerve from the digestive tract. This information is routed to specific nuclei of the hypothalamus and brain stem, such as the arcuate nucleus and the solitary tract nucleus respectively, which in turn activate distinct neuronal networks. Of the numerous neuropeptides in the brain, neuropeptide Y, agouti gene-related peptide and orexin stimulate appetite, while melanocortins and alpha-melanocortin-stimulating hormone are involved in satiety. Of the many gastrointestinal peptides, ghrelin is the only appetite-stimulating hormone, whereas cholecystokinin, glucagon-like peptide-1 and peptide YY3-36 promote satiety. Adipose tissue provides signals about energy storage levels to the brain through leptin, adiponectin and resistin. Binge-eating has been related to a dysfunction in the ghrelin signalling system. Moreover, changes in gastric capacity are observed, and as gastric capacity is increased, so satiety signals arising from gastric and post-gastric cues are reduced. Understanding the host of neuropeptides and peptide hormones through which hunger and satiety operate should lead to novel therapeutic approaches for obesity; potential therapeutic strategies are highlighted.

Does low-energy sweetener consumption affect energy intake and body weight? A systematic review, including meta- analyses, of the evidence from human and animal studies

By reducing energy density, low-energy sweeteners (LES) might be expected to reduce energy intake (EI) and body weight (BW). To assess the totality of the evidence testing the null hypothesis that LES exposure (versus sugars or unsweetened alternatives) has no effect on EI or BW, we conducted a systematic review of relevant studies in animals and humans consuming LES with ad libitum access to food energy. In 62 of 90 animal studies exposure to LES did not affect or decreased BW. Of 28 reporting increased BW, 19 compared LES with glucose exposure using a specific ‘learning’ paradigm. Twelve prospective cohort studies in humans reported inconsistent associations between LES use and body mass index (−0.002 kg m−2 per year, 95% confidence interval (CI) −0.009 to 0.005). Meta-analysis of short-term randomized controlled trials (129 comparisons) showed reduced total EI for LES versus sugar-sweetened food or beverage consumption before an ad libitum meal (−94 kcal, 95% CI −122 to −66), with no difference versus water (−2 kcal, 95% CI −30 to 26). This was consistent with EI results from sustained intervention randomized controlled trials (10 comparisons). Meta-analysis of sustained intervention randomized controlled trials (4 weeks to 40 months) showed that consumption of LES versus sugar led to relatively reduced BW (nine comparisons; −1.35 kg, 95% CI –2.28 to −0.42), and a similar relative reduction in BW versus water (three comparisons; −1.24 kg, 95% CI –2.22 to −0.26). Most animal studies did not mimic LES consumption by humans, and reverse causation may influence the results of prospective cohort studies. The preponderance of evidence from all human randomized controlled trials indicates that LES do not increase EI or BW, whether compared with caloric or non-caloric (for example, water) control conditions. Overall, the balance of evidence indicates that use of LES in place of sugar, in children and adults, leads to reduced EI and BW, and possibly also when compared with water.

Satiating effects of protein but not carbohydrate consumed in a between-meal beverage context.

Previous research has suggested that protein is the most satiating macronutrient; however some experiments have found no difference in satiating efficiency of protein and carbohydrate during short intervals after consumption. There is also evidence that the satiating effects of carbohydrate are minimal when in a beverage rather than solid context. To evaluate whether protein-based satiety was evident in a drink context, and clarify further effects of preload time on satiety, the present study compared iso-energetic dairy fruit drink preloads ( approximately 1250 kJ), differing in macronutrient composition and consumed at two time intervals in the morning. Using a counterbalanced within-subjects design, 18 unrestrained lean male volunteers consumed 300 ml of carbohydrate-enriched (CHO), protein-enriched and low-energy control (327 kJ) dairy fruit drinks, 120 min and 30 min before an ad libitum lunch. Significantly less energy was consumed at lunch after the protein (3234 kJ) compared to the control (3468 kJ, p<0.05) and CHO preloads (3588 kJ, p<0.05). However, this was not sufficient to show complete energy compensation. Preload time of consumption did not impact upon any measures. Only satiety ratings at the beginning of lunch varied significantly by preload type, reflecting differences in test meal intake. These findings are consistent with previous research that protein is more satiating than carbohydrate. The roles of sensory and hedonic characteristics are discussed.