Satiation, satiety and their effects on eating behaviournbu_

Transcription

1 BRIEFING PAPER Satiation, satiety and their effects on eating behaviournbu_ B. Benelam British Nutrition Foundation, London, UK Summary 1. Introduction 2. Physiological mechanisms of satiation and satiety 2.1 Physiological mechanisms of satiation Gastric mechanisms of satiation Intestinal mechanisms of satiation 2.2 Physiological mechanisms of satiety Gut hormones episodic signals of satiety Tonic satiety signals 2.3 The integration of satiety signals in the brain Anorexigenic pathways in the hypothalamus Orexigenic pathways in the hypothalamus Other areas of the brain involved in satiation and satiety Reward pathways 3. Measuring satiation and satiety 3.1 Measuring satiation 3.2 Measuring satiety Free living vs. laboratory studies Preload studies Self-reported measures of satiety Measuring food intake Quantifying satiety 3.3 Confounders in satiety research Physiological confounders Behavioural confounders 4. The effects of foods and drinks on satiety 4.1 Protein and satiety 4.2 Carbohydrates and satiety 4.3 Fibre and satiety 4.4 Intense sweeteners and satiety 4.5 Fat and satiety 4.6 Liquids and satiety Correspondence: Bridget Benelam, Nutrition Scientist, British Nutrition Foundation, High Holborn House, High Holborn, London WC1V 6RQ, UK

2 Satiation, satiety and their effects on eating behaviour Alcohol and satiety 4.8 Energy density and satiety 5. The effect of external factors on satiation and satiety 5.1 Palatability 5.2 Variety 5.3 Portion size 5.4 Sleep 5.5 Physical activity 5.6 Television viewing and other distractions 5.7 Social situations 6. Satiation, satiety and weight control 6.1 Obesity genes and satiety 6.2 Physiological differences in satiation and satiety responses in obese people 6.3 Behavioural differences in the response to satiation and satiety in obesity 7. Conclusions Summary In the context of the rising prevalence of obesity around the world, it is vital to understand how energy balance and bodyweight are controlled. The ability to balance energy intake and expenditure is critical to survival, and sophisticated physiological mechanisms have developed in order to do this, including the control of appetite. Satiation and satiety are part of the body s appetite control system and are involved in limiting energy intake. Satiation is the process that causes one to stop eating; satiety is the feeling of fullness that persists after eating, suppressing further consumption, and both are important in determining total energy intake. Satiation and satiety are controlled by a cascade of factors that begin when a food or drink is consumed and continues as it enters the gastrointestinal tract and is digested and absorbed. Signals about the ingestion of energy feed into specific areas of the brain that are involved in the regulation of energy intake, in response to the sensory and cognitive perceptions of the food or drink consumed, and distension of the stomach. These signals are integrated by the brain, and satiation is stimulated. When nutrients reach the intestine and are absorbed, a number of hormonal signals that are again integrated in the brain to induce satiety are released. In addition to these episodic signals, satiety is also affected by fluctuations in hormones, such as leptin and insulin, which indicate the level of fat storage in the body. Satiation and satiety can be measured directly via food intake or indirectly via ratings of subjective sensations of appetite. The most common study design when measuring satiation or satiety over a short period is using a test preload in which the variables of interest are carefully controlled. This is followed by subjects rating aspects of their appetite sensations, such as fullness or hunger, at intervals and then, after a predetermined time interval, a test meal at which energy intake is measured. Longer-term studies may provide foods or drinks of known composition to be consumed ad libitum and use measures of energy intake and/or appetite ratings as indicators of satiety. The measurement of satiation and satiety is complicated by the fact that many factors besides these internal signals may influence appetite and energy intake, for example, physical factors such as bodyweight, age or gender, or

3 128 B. Benelam behavioural factors such as diet or the influence of other people present. For this reason, the majority of studies on satiation and satiety take place in a laboratory, where confounders can be controlled as much as possible, and are, therefore, of short duration. It is possible for any food or drink to affect appetite, and so it is important to determine whether, for a given amount of energy, particular variables have the potential to enhance or reduce satiation or satiety. A great deal of research has been conducted to investigate the effect of different foods, drinks, food components and nutrients on satiety. Overall, the characteristic of a food or drink that appears to have the most impact on satiety is its energy density. That is the amount of energy it contains per unit weight (kj/g, kcal/g). When energy density is controlled, the macronutrient composition of foods does not appear to have a major impact on satiety. In practice, high-fat foods tend to have a higher energy density than high-protein or high-carbohydrate foods, and foods with the highest water content tend to have the lowest energy density. Some studies have shown that energy from protein is more satiating than energy from carbohydrate or fat. In addition, certain types of fibre have been shown to enhance satiation and satiety. It has been suggested that energy from liquids is less satiating then energy from solids. However, evidence for this is inconsistent, and it may be the mode of consumption (i.e. whether the liquid is perceived to be a food or drink) that influences its effect on satiety. Alcohol appears to stimulate energy intake in the short-term, and consuming energy from alcohol does not appear to lead to a subsequent compensatory reduction in energy intake. The consumption of food and drink to provide energy is a voluntary behaviour, and, despite the existence of sophisticated physiological mechanisms to match intake to requirements, humans often eat when sated and sometimes refrain from eating when hungry. Thus, there are numerous influences on eating behaviour beyond satiation and satiety. These include: the portion size, appeal, palatability and variety of foods and drinks available; the physiological impact on the body of physical activity and sleep; and other external influences such as television viewing and the effect of social situations. Because satiation and satiety are key to controlling energy intake, inter-individual differences in the strength of these signals and responsiveness to their effects could affect risk of obesity. Such differences have been observed at a genetic, physiological and behavioural level and may be important to consider in strategies to prevent or treat obesity. Overall, it is clear that, although the processes of satiation and satiety have the potential to control energy intake, many individuals override the signals generated. Hence, in such people, satiation and satiety alone are not sufficient to prevent weight gain in the current obesogenic environment. Knowledge about foods, ingredients and dietary patterns that can enhance satiation and satiety is potentially useful for controlling bodyweight. However, this must be coupled with an understanding of the myriad of other factors that influence eating behaviour, in order to help people to control their energy intake. Keywords: appetite, behaviour, obesity, satiation, satiety

4 Satiation, satiety and their effects on eating behaviour Introduction Maintenance of energy balance and a healthy bodyweight has been critical to human survival, and sophisticated physiological mechanisms exist in the body to maintain homeostasis (the maintenance of a constant internal environment in the body) (Woods & D Alessio 2008). The control of energy intake is vital to energy balance, and satiation and satiety are part of a complex system of appetite control, which regulates how much we consume. Definitions of satiation and satiety are shown in Box 1. Box 1 Definitions Satiation Satiety The process that leads to the termination of eating, which may be accompanied by a feeling of satisfaction The feeling of fullness that persists after eating, potentially suppressing further energy intake until hunger returns Over the course of a day, people typically have a number of eating occasions including meals, drinks and snacks. Satiation is important in controlling the amount of energy consumed at each of these eating occasions, while satiety affects the period of time between eating occasions and potentially the amount consumed at the next. Total daily energy intake is a function of both the number of eating occasions that day and their size. Hence, both satiation and satiety affect energy intake. In the context of the rising prevalence of obesity, it is important to consider the impact of satiation and satiety on energy balance, and whether they can be enhanced in order to facilitate the reduction of energy intake, aiding weight control. However, although this briefing paper will focus on the relationship of satiation and satiety to obesity, it is worth remembering that there are many instances where low energy intake is of concern, for example, in the elderly or those with eating disorders. In these cases, it may be desirable to reduce the effects of satiation and satiety in order to allow greater energy intake. The factors affecting satiation and satiety from the start of eating to late satiety have been characterised by Blundell et al. (1987) in the satiety cascade, showing sensory, cognitive, post-ingestive and post-absorptive stages shown in Figure 1. As this figure demonstrates, satiation and satiety are initially affected by sensory and cognitive factors including expectations about what is to be consumed, the Satiety Cascade Sensory FOOD Cognitive Early Post-ingestive (Blundell et al, 1987) Post-absorptive Late Figure 1 The satiety cascade showing the influences on satiation and satiety over time (Source: Blundell et al reproduced with permission). taste, texture and smell of the food or drink and any associations with previous experience that arise. Once the food or drink reaches the stomach, post-ingestive factors start to take effect. Initially, the distension of the stomach sends signals to the brain, initiating satiation. As digestion continues in the intestines, hormones that promote satiation and satiety are released from the gut. In the post-absorptive stage of the satiety cascade, nutrients themselves are detected by specialist receptors in various sites of the body, including the brain, providing information about nutrient status that also affects satiety (Blundell et al. 1987). In the longer term, satiety may also be affected by signals such as leptin, which convey information about the level of fat storage in the body (Wynne et al. 2005a). Thus, the body has a complex network of signals involved in the development of satiation and satiety. However, for free-living humans, choices about what and how much to eat are affected not only by internal appetite signals such as satiation and satiety but also by many other factors including the palatability of the food in question, the portion size provided, the time of day and the presence of other people (Bellisle 2003). The amount of energy we consume is completely accounted for by voluntary behaviour, namely the acts of eating and drinking, influenced by physiological, psychological and cultural factors. This is in contrast to energy expenditure, between 20% and 40% of which is under behavioural control via voluntary physical activity (Blundell 2006). Thus, the study of appetite, including satiation and satiety, must take account of both physiological and behavioural evidence in order to gain a full picture of how satiation and satiety affect eating behaviour. This briefing paper aims to give an overview of how satiation and satiety develop in the body, the factors that affect this and how satiation and satiety interact

5 130 B. Benelam with external influences to impact on eating behaviour, particularly with regard to excessive energy intake and obesity. The physiological mechanisms of satiation and satiety will first be outlined, followed by a description of the different techniques used to measure satiation and satiety. There is a potential for any food or drink to induce satiety. Thus, it is important to gain evidence as to whether, for a given energy content, particular foods, drinks or their components are more satiating than others. The evidence for the effect of a number of foods, food components and nutrients on satiety is reviewed. Humans may eat when sated and refrain from eating when hungry, so it is clear that internal appetite controls are not the only influence on energy intake. Some of the potential external influences on energy intake are then discussed. Appetite control is one of the potential factors that could affect the risk of obesity (Foresight 2007). In light of the current prevalence of obesity, it may be important to consider whether differences in satiation and satiety or sensitivity to these signals can increase the risk of obesity. There is evidence that this may be the case, and this is outlined in the final section. This Briefing Paper does not examine functional foods and ingredients and satiety in detail, as these have recently been reviewed elsewhere (Thomas & Chapman 2008). Changes in satiation and satiety in those with eating disorders or other clinical conditions (other than obesity) are also not included. In addition, the area of health claims, satiation and satiety, with reference to the European Commission regulation that came into force in 2007 (EC/1924/2006), is not included in this paper because this is currently the subject of the Institute of Life Sciences International, Europe Appetite Regulation Task Force, which will provide a thorough investigation of the methodologies, relevant food components and appropriate physiological biomarkers to provide scientific substantiation to a satiety claim. This paper does not constitute a systematic review but aims to give a picture of the research in the area of satiation, satiety and eating behaviour. 2. Physiological mechanisms of satiation and satiety Early animal experiments characterised areas of the brain involved in satiation and satiety by observing the effects of damage in particular locations in the brain, on food intake behaviour. In this way, a number of areas within the hypothalamus were identified as important in the control of hunger and energy balance (Morgane & Jacobs 1969). More recently, the way the body communicates influx, circulation and storage of nutrients and the integration of these signals in the brain to affect satiation and satiety have become more fully understood. An outline of the pathways involved in communication of satiation and satiety between the body and the brain is described in Figure 2. This section describes the mechanisms by which satiation and satiety signals affect specific areas of the brain to maintain energy homeostasis. It also highlights the possibility that hedonic systems within the brain (i.e. those affected by the pleasurable aspects of food) may interact with homeostatic systems and may override satiation and satiety signals. 2.1 Physiological mechanisms of satiation Satiation is the feeling of satisfaction that signals eating to stop. The time course of satiation means that factors affecting it must occur early in the satiety cascade, when the food is selected, smelled and eaten and in the first stages of digestion. Satiation appears to be a very basic animal function that even rats with only a hindbrain exhibit (Ritter 2004) Gastric mechanisms of satiation When food or drink reaches the stomach, nerves communicate an increase in gastric volume to the brain (Ritter 2004). It appears that gastric distension promotes satiation, independently of nutrient content (Phillips & Powley 2000). In addition, there is evidence that when food is removed from the stomach after ingestion, satiation does not occur. In experiments where cannulas are fitted that allow food to drain from the stomach, animals eat continuously, but quickly reach satiation when the cannula is closed allowing food to fill the stomach normally (Davis & Smith 1990). There is the possibility that gastric distension could be used as a biomarker of satiation. There are a number of possible indirect methods for measuring gastric distension, for example, measuring changes in water pressure in the stomach, which are outlined in a review of biomarkers in satiation and satiety by De Graaf et al. (2004). Although further work is needed to develop direct markers of gastric distension, this is a possible marker for future research on satiation Intestinal mechanisms of satiation From the stomach, food and drink are released into the small intestine where digestion continues and nutrients are absorbed. It appears that information about the absorption of nutrients can be communicated to the

6 Satiation, satiety and their effects on eating behaviour 131 Effects on energy intake Brain Insulin Leptin Pancreas Adipose tissue Figure 2 A schematic representation of physiological satiation and satiety signalling. When food is consumed, the gastric distension is communicated to the brain via the vagus nerve, which connects the gastrointestinal tract to the brain, initiating satiation. Gut hormones from the stomach and intestine are released when food is consumed and act on areas of the brain involved in appetite. Leptin from adipose tissue and insulin from the pancreas are related to the amount of fat stored in the body and act on the brain to modulate satiation and satiety in the longer term. All signals are integrated in the brain to affect energy intake and expenditure (Adapted from Wynne et al. 2005a). Gut hormones Stomach Intestines Vagus nerve Gut hormones brain and contributes to satiation. Experimental infusions of fat, carbohydrates and proteins directly into the intestine promote satiation. In the case of protein, carbohydrate and fat, digestion to their respective building blocks of amino acids, sugars and fatty acids is necessary in order for satiation to take place (Ritter 2004). The gut hormone cholecystokinin (CCK) appears to be involved in satiation. The satiating effects of CCK were first demonstrated in 1973, when Gibbs et al. showed that administering CCK reduces subsequent meal size in a dose dependant manner in rats (Gibbs et al. 1973). This has since been confirmed in humans (Kissileff et al. 1981; Muurahainen et al. 1988), although the distension of the stomach by food or drink is necessary for this effect to take place (Lieverse et al. 1995). CCK is mainly synthesised by the endocrine L cells in the duodenum and jejunum (the beginning and middle of the small intestine) and is rapidly released into the circulation in response to the presence of nutrients in the gut, particularly after fat- or protein-rich meals (Wren & Bloom 2007). CCK s effects on satiety appear to be mediated via receptors in the vagus nerve (the nerve that connects the gut to the brain) and are blocked when this nerve is removed in rats (Smith et al. 1981). The mechanisms by which signals from CCK are integrated within the brain are discussed in section 2.3. CCK is a potential biomarker for satiation (De Graaf et al. 2004). However, it must be noted that changes in the levels of this gut hormone are only one part of the process leading to satiation and cannot be seen as a direct marker of satiation. In addition to effects on satiation, CCK also delays gastric emptying and stimulates pancreatic enzyme secretion and gall bladder contraction (Liddle et al. 1985; Moran & Schwartz 1994), thus playing a role in co-ordinating digestion. CCK is also found in the brain, where it acts as a neurotransmitter involved in reward behaviour, memory and anxiety, as well as satiety (Crawley & Corwin 1994). CCK may act synergistically

7 132 B. Benelam Table 1 Gut hormones and their actions Name Site of production Effect on appetite Mechanism Additional effects Ghrelin Stomach Hunger Via ghrelin receptors in the brain Long-term effect on energy balance Cholecystokinin (CCK) Duodenum and jejunum Satiation Via vagus nerve Delays gastric emptying Stimulates pancreatic enzyme secretion Stimulates gall bladder contraction Acts as a neurotransmitter Glucagon-like peptide-1 (GLP-1) Intestine and brain Satiety Via GLP-1R in brain Incretin (stimulates insulin production) Slows gastric emptying Oxyntomodulin (OXM) Intestine and brain Satiety Via GLP-1R in brain Slows gastric emptying Via reductions in ghrelin Peptide YY (3-36) (PYY 3-36) Ileum, colon and rectum Satiety Via Y2 receptors in brain Slows gastric emptying and intestinal transport Reduces gastric secretions Pancreatic polypeptide (PP) Pancreas Satiety Via Y5 receptors in brain Via vagus nerve with the hormone leptin, which signals the level of fat storage in the body. This is discussed in section In summary, there are a number of variables that influence satiation and thus the amount of food eaten at one sitting. When nutrients reach the small intestine, satiety signalling, which affects the time interval before hunger and the desire to eat returns, is initiated. Although the distinction between satiation and satiety is an important one, they are part of a continuum in the ingestive process, and there may be some overlap between the later stages of satiation signalling and that of early satiety. The next section outlines the mechanisms affecting satiety. 2.2 Physiological mechanisms of satiety Broadly, satiety is influenced both by short term or episodic signals in response to the consumption of food and by longer term or tonic signals indicating the levels of energy stores in the body. These act in various ways on the hypothalamus in the brain, which in turn produces signals that affect energy intake and expenditure. This section explores the satiety signals from the body and their effects in the brain Gut hormones episodic signals of satiety A number of hormones are secreted from the gut to indicate that food has been consumed. These act directly or indirectly on specific areas of the brain to promote satiety. A summary of gut hormones and their actions is shown in Table 1. Ghrelin is the only known gut hormone that causes hunger and, as its suppression is relevant to the onset of satiety, it has also been included for discussion. These hormonal signals are termed as episodic signals of satiety as they occur alongside episodes of eating. These are considered separately from tonic signals, which signal the level of energy storage in the body, but it is important to note that there may be interactions between tonic and episodic satiety signalling. The way in which all these signals are integrated by the brain are discussed in section 2.3. Ghrelin is a peptide hormone mainly produced in the stomach and, when administered experimentally to animals and humans, stimulates appetite and increases food intake (Tschöp et al. 2000; Wren et al. 2001). When released, ghrelin acts on receptors in specific areas in the brain. The integration in the brain of signals from gut hormones is described in detail in section 2.3. Ghrelin levels rise before meals, suggesting that it may play a role in meal initiation in humans (Cummings et al. 2001), although studies have not found that ghrelin levels predict the interval between meals (Callahan et al. 2004). The mechanisms causing release of ghrelin from endocrine cells in the stomach are not yet known. However, the suppression of ghrelin after meals is proportional to the energy intake at the meal (Callahan et al. 2004). In addition, on a per-kilojoule basis, fat appears to be less effective than carbohydrate or protein at suppressing ghrelin (Monteleone et al. 2003; Overduin et al. 2005). Ghrelin may also play a role in long-term energy balance. In humans, ghrelin levels are inversely correlated with levels of body fatness; that is, they are low in obese subjects (Tschöp et al. 2001), higher in lean

8 Satiation, satiety and their effects on eating behaviour 133 subjects (Shiyya et al. 2002) and abnormally high in subjects whose energy intake is chronically restricted, such as those suffering from anorexia nervosa (Tolle et al. 2003). Glucagon-like peptide-1 (GLP-1) and oxyntomodulin (OXM) are both products of the preproglucagon gene, which is expressed in the brain, pancreas and intestine. In the pancreas, the preproglucagon gene product is processed to produce the hormone glucagon, whereas, in the intestine and brain, GLP-1 and OXM are produced (Murphy & Bloom 2004). Both GLP-1 and OXM are released into the circulation in response to nutrients in the gut (Le Quellec et al. 1992; Herrmann et al. 1995) and appear to have an effect on satiety. Experimental administration of GLP-1 to humans reduces food intake, decreases ratings of hunger and increases ratings of fullness in normalweight, diabetic and obese subjects (Flint et al. 1998, 2000a; Näslund et al. 1998, 1999a; Gutzwiller et al. 1999a, 1999b; Toft-Nielsen et al. 1999). There is some evidence that GLP-1 is reduced in obese subjects (Holst et al. 1983; Ranganath et al. 1996; Näslund et al. 1999a) and that levels are restored by weight loss (Verdich et al. 2001). Receptors for GLP-1 (GLP-1R) can be found in areas of the brain involved in appetite, and it is thought that GLP-1 mediates its effects on satiety by acting directly upon these areas (Yamamoto et al. 2003). GLP-1 also slows gastric emptying and modulates gastric acid secretion, contributing to the ileal brake mechanism of the upper gastrointestinal tract, a combination of effects that controls the transit of food from the stomach into the intestines, allowing effective digestion (Näslund et al. 1999b). In addition to its effects on satiety and digestion, GLP-1 is a potent incretin, in that it potentiates the production of insulin (MacDonald et al. 2002). Thus, GLP-1 appears to have multiple roles in promoting satiety, in the ileal brake and in encouraging the release of insulin. GLP-1 is a potential biomarker for satiety (De Graaf et al. 2004). GLP-1 can be measured from blood samples and is seen to rise for two hours after a meal, compared with the fasting level (Orskov & Holst 1987). More work is needed to establish whether or not GLP-1 is a reliable marker of appetite. A recent study on protein and satiety found that, despite an increase in ratings of satiety after a high-protein vs. low-protein preload, GLP-1 levels were unchanged between the two conditions. Other peptide hormones, peptide YY (PYY) and ghrelin (also discussed in section 2.2.1), were also found to be unaffected (Smeets et al. 2008). OXM has also been found to reduce food intake in humans (Cohen et al. 2003) and enhance weight loss (Wynne et al. 2005b) and appears to increase energy expenditure (Wynne et al. 2006). OXM can bind to the GLP-1R found in areas of the brain involved in appetite control (Dakin et al. 2001) and reduces plasma ghrelin concentrations in rats (Dakin et al. 2004) and in human subjects. A study using physiological doses, administered intravenously, found that fasting levels of ghrelin were suppressed by 40% compared with those in controls when OXM was administered (Cohen et al. 2003), and this might be a factor in its satiating properties. Similar to GLP-1, OXM also slows gastric emptying (Schjoldager et al. 1989). Overall, GLP-1 and OXM have similar actions on satiety and gastric emptying, although OXM, as well as the GLP-1R, may work via effects on ghrelin. OXM does not have the incretin effects of GLP-1 but may have more potent effects on weight loss (Wren & Bloom 2007). The PP fold peptides include peptide YY (PYY), pancreatic polypeptide (PP) and neuropeptide Y (NPY). PYY and PP are produced in the gut and are discussed below. NPY is produced in the brain and is described in section 2.3 on the integration of satiety signals in the brain. PYY is produced in the L cells of the ileum, colon and rectum (Adrian et al. 1985a; Ekblad & Sundler 2002) and is released into the circulation in proportion to the amount of energy consumed, reaching a plateau after 1 2 hours and remaining elevated for approximately six hours (Adrian et al. 1985a). This release begins before the nutrients reach the distal portion of the gut where PYY is produced, so it appears that PYY secretion may initially be stimulated indirectly, possibly via the vagal nerve (Fu-Cheng et al. 1997). Fasting suppresses the secretion of PYY (Adrian et al. 1985a). The main form of stored and circulating PYY is known as PYY(3-36) (a truncated version of the full peptide) (Grandt et al. 1994). The administration of PYY has been found to reduce food intake both in rodents (Batterham et al. 2002; Adams et al. 2004; Chelikani et al. 2005) and in humans (Batterham et al. 2003a; Degen et al. 2005). Batterham et al. investigated the effects of PYY(3-36) on both lean and obese subjects and found that, in both cases, energy intake at a buffet lunch two hours after administration was reduced by approximately 30% and that there was also a significant decrease in energy intake during the 24 hours after treatment. In addition, fasting PYY levels were lower in obese than in lean subjects, and body mass index (BMI) correlated

9 134 B. Benelam negatively with PYY levels. Post-prandial PYY release was also lower in the obese subjects, despite the fact that they consumed more energy (Batterham et al. 2003a). This raises the possibility that a deficiency in circulating PYY could be involved in the development of obesity, although it is currently unclear whether low levels of PYY are a cause or an effect of obesity. PYY also inhibits gastric emptying, increases transit time through the intestine (Savage et al. 1987) and reduces gastric secretions (Adrian et al. 1985b), indicating it may play a role in the ilieal brake mechanism. PYY, like other PP fold peptides, binds to Y 1-Y 5 receptors (Larhammar 1996). PYY(3-36) binds most strongly to the Y2 receptor and it is thought that its effects on satiety are mediated by binding to this receptor in the brain. PP is mainly produced by the pancreas but also in small amounts in the colon and rectum (Adrian et al. 1976). Like PYY, it is released into the circulation after eating, in proportion to the amount of energy consumed (Track et al. 1980). Experiments have also shown that PP administration reduces food intake in humans. When administered two hours before a buffet meal, PP reduced energy intake by 22% at this meal and throughout the evening and the following morning, leading to a 25% decrease in energy intake over the 24-hour period (Batterham et al. 2003b). PP, like PPY, signals to the brain via the Y family of receptors and is thought to act on Y5 receptors. It may also signal to the brain via the vagus nerve (Wynne et al. 2005a). Interestingly, both basal and post-prandial levels of PP are suppressed in those with Prader Willi Syndrome (PWS), a genetic condition associated with hyperphagia (overeating) and obesity (Zipf et al. 1981). Administration of PP reduces food intake in some PWS subjects (Berntson et al. 1993), indicating that an altered PP response may be a component of this syndrome Tonic satiety signals Tonic satiety signals communicate the levels of fat storage in the body to the brain, so that energy intake and expenditure can be balanced to maintain a relatively constant bodyweight. These signals act over the longer term than episodic satiety signals that are activated at each eating occasion. Leptin is a peptide hormone, mainly produced by the adipose tissue. It is a product of the ob gene, which was first identified and cloned in a severely hyperphagic (over-eating) and obese strain of mutant mouse (Zhang et al. 1994). Circulating leptin levels are proportional to fat mass and BMI, and are reduced by weight loss. However, there is inter-individual variation in the amount of leptin produced at a given percentage of body fat (Maffei et al. 1995). Leptin appears to influence bodyweight via its effect on energy intake and expenditure. Chronic administration of leptin to rodents causes increased energy expenditure, reduced food intake and loss of bodyweight and fat mass (Halaas et al. 1995). Reduction in leptin levels as a result of weight loss is associated with increased hunger in humans (Keim et al. 1998). Leptin may have a synergistic interaction with CCK, a gut hormone involved in satiation (see section 2.1.2), in that small doses of CCK (which are not effective alone) decrease food intake when leptin is administered at the same time (Barrachina et al. 1997). A mutation of the ob gene, resulting in a lack of circulating leptin, causes severe obesity in humans (Montague et al. 1997), which can be reversed by administering exogenous leptin both in children (Farooqi et al. 1999) and adults (Licinio et al. 2004). In addition, in those with a heterozygous leptin deficiency (i.e. one rather than two functional copies of the ob gene), there is a greater prevalence of obesity and a higher percentage body fat than in subjects with a fully functional ob gene (Farooqi et al. 2001). The leptin receptor is expressed in areas of the brain involved in appetite control, and leptin is thought to mediate its effects by acting directly on these receptors (Flier 2004). The effect of leptin in the brain will be discussed in section 2.3. Leptin is transported across the blood brain barrier via a saturable process (Banks et al. 1996). This appears to be affected by energy balance in that starvation reduces leptin transport across the blood brain barrier, and refeeding increases it (Kastin & Pan 2000). Although, as mentioned above, a very small proportion of obesity cases involve impaired leptin secretion, most obese people have relatively high levels of circulating leptin (Maffei et al. 1995), and the administration of exogenous leptin has only a modest effect on bodyweight (Heymsfield et al. 1999; Fogteloo et al. 2003). This indicates that leptin resistance, rather than deficiency, may be associated with obesity. The mechanisms by which this could occur are not yet clear, but impaired transport across the blood brain barrier may be involved (Kastin & Pan 2000). Blood brain barrier transport of leptin in mice is reduced by diet-induced obesity (Banks et al. 1999). There is also some evidence in animal models to suggest that neurones in the brain that respond to leptin may become resistant to its effects after chronic exposure to high levels of leptin (Sahu 2002).

10 Satiation, satiety and their effects on eating behaviour 135 Leptin has been suggested as a biomarker for satiety (De Graaf et al. 2004). However, because high leptin levels do not appear to reliably increase satiety, it cannot be assumed that changes in leptin will cause a corresponding change in appetite. Thus, leptin might be useful as a biomarker of satiety in the longer term but may not be useful in subjects with chronically high leptin levels. Thus, while a lack of leptin causes severe obesity, high circulating levels do not have a similarly dramatic effect in reducing body fat, which has been described as leptin resistance. It is also important to consider that leptin s ineffectiveness in preventing obesity at high levels may be a result of internal satiety signals being ignored in the face of easily available, energy-dense and palatable foods. Insulin is a metabolic hormone produced by the pancreas. Unlike leptin, which does not rise directly in response to food intake, insulin secretion increases rapidly after meals (Polonsky et al. 1988) and acts to control blood glucose levels. However, over the longer term, levels of plasma insulin are directly related to changes in adiposity, so that levels increase with obesity (Bagade et al. 1967). In animal models, experimental administration of insulin results in a decrease in food intake and loss of bodyweight (Woods et al. 1979; Ikeda et al. 1986), and inhibition of insulin s actions leads to increased energy intake and weight gain (McGowan et al. 1992). This suggests that insulin contributes to satiety. Obesity and lack of physical activity are associated with insulin resistance, which may be accompanied by dislipidaemia (high plasma triglycerides, and low high density lipoprotein (HDL) ( good cholesterol ), central fat deposition and high blood pressure (Coppack et al. 2005). It is also possible that obese subjects are less sensitive to the satiating effects of insulin. In a study investigating passive over-consumption of high-fat foods in lean and obese males, hyperinsulinaemia in the obese subjects was associated with a lack of appetite control compared with lean subjects (Speechly & Buffenstein 2000). The results of a study that measured responses to insulin in the specific parts of the brain involved in satiety, suggested that insulin resistance may attenuate the effect of insulin on these areas (Anthony et al. 2006). Insulin crosses the blood brain barrier and is thought to act on insulin receptors that are found in the brain (Corp et al. 1986). The signalling pathways activated by insulin are discussed in section 2.3. Interestingly, it has been suggested that there is cross talk between leptin and insulin. Although leptin levels are associated with fat mass, there appear to be other factors involved, and insulin may play a role in stimulating leptin production. In turn, the leptin receptor is expressed in the pancreatic b cells that produce insulin, raising the possibility that leptin affects insulin production (for a review see Kieffer & Habener 2000). 2.3 The integration of satiety signals in the brain Both tonic and episodic signals of appetite control act directly through receptors in the brain or indirectly via the nervous system on areas of the brain involved in appetite control. Neurones within these areas express neuropeptides that have downstream effects on energy homeostasis. This section describes how these signals are integrated to affect energy intake and expenditure. Early animal experiments involving stimulation or damage to different brain regions established the hypothalamus as a centre for appetite control (Morgane & Jacobs 1969), and this picture has since been developed by establishing pathways originating within the arcurate nucleus area of the hypothalamus, which controls feeding and satiety. These pathways can broadly be divided into anorexigenic (inhibit feeding) and orexigenic (stimulate feeding) pathways. Each pathway can be both stimulated and inhibited by signals from the gut, pancreas and adipose tissue. The overall effect is to increase feeding and decrease energy expenditure or vice versa, depending on the availability of nutrients and the levels of energy storage in the body. The pathways involved and how they integrate the tonic and episodic signals that have been described in previous sections are summarised in Figure 3. Other areas of the brain are also involved in satiation and satiety, and these are briefly outlined in section In addition, reward pathways, conveying the pleasurable qualities of food, may also influence satiety and are discussed in section Anorexigenic pathways in the hypothalamus Neurones that express the neuropeptides proopiomelanocortin (POMC) and cocaine-andamphetamine-related transcript (CART) have an anorexigenic effect and are stimulated by leptin. POMC is a precursor for the neuropeptide a-melanocytestimulating hormone (amsh), which acts on melanocortin 3 (MC3) and melanocortin 4 (MC4) receptors (Ellacott & Cone 2004). Administration of amsh to rats inhibits feeding (Rossi et al. 1998) and increases energy expenditure (Pierroz et al. 2002); humans and animals that have a mutant POMC or MC4 gene are hyperphagic and obese (Yang & Harmon 2003). CART is co-expressed with POMC in the hypothalamus. Administration of CART to rats inhibits feeding both

11 136 B. Benelam Arcurate nucleus Increased food intake and decreased energy expenditure Stomach Grehlin NPY/AgRP NPY Y1 &Y5 receptors Intestine PPY(3-36) GLP-1 OXM PP AgRP Pancreas Adipose tissue Insulin PP Leptin POMC/CART αmsh CART MC3 & MC4 receptors Decreased food intake and increased energy expenditure Figure 3 Circulating hormones influencing energy homeostasis via the arcuate nucleus (adapted from Murphy & Bloom 2004). Continuous lines indicate stimulatory effects, and dashed lines indicate inhibitory effects. AgRP, agouti-related peptide; CART, cocaine-and amphetamine-related transcript; GLP-1, glucagon-like-peptide 1; amsh, alpha-melanocyte-stimulating hormone; NPY, neuropeptide Y, OXM, oxyntomodulin; POMC, pro-opiomelanocortin; PP, pancreatic polypeptide; PYY, peptide YY. under normal conditions and during starvation. Conversely, inhibiting the actions of CART increases feeding (Kristensen et al. 1998) Orexigenic pathways in the hypothalamus Neurones that express NPY and agouti-related peptide (AgRP) are orexigenic and are stimulated by ghrelin and inhibited by PYY 3-36, GLP-1, OXM, PP, insulin and leptin. Administration of NPY in animal models causes hyperphagia and obesity (Stanley et al. 1986) and reduces energy expenditure (Billington et al. 1991). NPY is thought to increase food intake and decrease energy expenditure by acting on Y1 and Y5 receptors in the hypothalamus (Gehlert 1999). NPY may also have an inhibitory effect on neurones, producing POMC (Roseberry et al. 2004), therefore having a dual effect of stimulating feeding while inhibiting pathways that reduce feeding. AgRP is an antagonist of the MC3 and MC4 receptors, inhibiting the reductive effects of amsh on appetite, so injection of AgRP causes an increase in food intake in rats (Rossi et al. 1998) Other areas of the brain involved in satiation and satiety Neurones that express POMC/CART and NPY/AgRP connect with other areas in the hypothalamus and convey their signals downstream, producing the effects on energy homeostasis described in section 2.3. A detailed description of the neurotransmitters and pathways involved is beyond the scope of this paper, but see Wynne et al. (2005a) for a review. The brainstem is also an important area of the brain for energy homeostasis. It receives signals from the gut via the vagus nerve (Sawchenko 1983) regarding gastric volume and information about the presence of nutrients in the gut via signals from CCK (Schwartz et al. 1993; Mathias et al. 1998). The brainstem is thought to affect energy homeostasis both through downstream signals in response to input from the vagus nerve, peripheral circulating signals and via reciprocal connections with the hypothalamus (Wynne et al. 2005a) Reward pathways Reward pathways, which are involved in signalling the hedonic qualities of food and drink, may also influence satiety, at least in the short-term. Several signalling systems are involved in the hedonic response to food. Opioids appear to affect food intake. In mice, a lack of opioids removed the reinforcing quality of foods (the amount of work subjects are prepared to put in to obtain food), in the fed but not the fasted condition (Hayward et al. 2002). Similarly, opioid antagonists have been found to decrease palatability but not to

12 Satiation, satiety and their effects on eating behaviour 137 Key points Satiation is induced via a number of mechanisms, including gastric distension and the gut hormone CCK. Satiety is controlled by both episodic (following an eating episode) and tonic (longer-term) signals. Episodic satiety signals are made by gut hormones. Release of ghrelin, which is associated with hunger, is suppressed after energy intake. A number of gut hormones are released from the gastrointestinal tract when energy is consumed, inducing satiety. Tonic satiety signals provide information about the amount of fat stored in the body. Leptin is secreted in proportion to the amount of body fat, although there are inter-individual differences in leptin levels at comparable body compositions. Although low leptin levels strongly stimulate energy intake, obese people have chronically high levels of leptin, suggesting that leptin resistance is developed. Baseline levels of insulin also vary according to adiposity, and insulin can impact on satiety. Specific areas in the brain, particularly the hypothalamus, are involved in integrating signals of satiation and satiety. In these areas, populations of orexigenic and anorexigenic neurones translate signals of satiation and satiety via downstream pathways to modulate energy intake. In addition to the pathways controlling energy intake, reward pathways involved in the pleasurable perception of food may interact with homeostatic controls and could also affect eating behaviour. affect hunger or satiety in humans (Yeomans et al. 1990). However, in one study, subjects prone to binge eating consumed fewer snacks when given opioid antagonists, despite ratings of hunger and satiety being unaffected by the treatment (Drewnowski et al. 1992). The dopaminergic system is also involved in feedingreward behaviour. Mice that cannot produce dopamine die because they do not feed, and dopamine replacement restores preferences for palatable foods (Szczypka et al. 2001). Endocannabinoids appear to act on both the homeostatic and hedonic systems controlling feeding behaviour via the hypothalamus and other areas of the brain. They act on receptors throughout the body, including the brain, adipose tissue, muscle and gastrointestinal (GI) tract, increasing energy intake and fat deposition and decreasing energy expenditure. In the presence of palatable food, they affect appetite by both stimulating the desire to eat and blocking signals to terminate eating (Woods 2007). The ability to block these actions was exploited by using the cannabinoid 1 receptor (CB1) inverse agonist known as Rimonabant (Sanofi-Aventis). This prevented the effects of endocannabinoids, which reduced appetite and aided weight loss (Poirier et al. 2005). However, Rimonabant was withdrawn from the European market in 2008 because of the incidence of psychological side effects, such as depression, associated with its use. Both homeostatic and hedonic pathways in the brain are complex, and it is not clear whether they operate independently or interact. Indeed, these possibilities are not mutually exclusive and either process may occur under particular circumstances. It is self-evident that the pleasurable sensory aspects of food can override internal satiety signals, and increased sensitivity to hedonic stimuli might be a risk factor for over-consumption and obesity (Blundell & Finlayson 2004). 3. Measuring satiation and satiety Both satiation and satiety are processes that affect eating behaviour. They can be measured directly via food intake or indirectly via subjective sensations. The methods used and the issues that must be considered when using them are outlined below. 3.1 Measuring satiation The satiating qualities of foods and drinks can be measured by allowing subjects to consume them ad libitum and monitoring how much is eaten before satiation is reached, compared with a control food. Because the termination of a meal may be affected by factors other than physiological signals, measurement of satiation is usually performed in a laboratory setting, where the environment can be controlled to eliminate confounding effects. These include the variety of foods offered, the dietary restraint (tendency to consciously restrict the amount of food eaten) of subjects or the appeal and palatability of the food (Mattes et al. 2005). Confounders are discussed further in section 3.3.

13 138 B. Benelam 3.2 Measuring satiety The measurement of satiety can be achieved through methods that allow subjects to record feelings of satiety or hunger, and/or by measuring food intake directly. Studies on satiety are complicated by the psychological and environmental factors that can conjointly affect eating behaviour, and these may be controlled where possible in studies on satiety. Some of the methods for studying satiety are outlined below Free living vs. laboratory studies In attempting to measure satiety and eating behaviour, there has to be a compromise between being able to measure these precisely and making the results applicable to the real world. Because of potential confounding by behavioural and environmental factors on satiety and energy intake, studies are often conducted in a laboratory environment. This allows the greatest possible degree of control over the external conditions of the study and this means that the endpoints of interest can be measured accurately. However, when extrapolating the results of laboratory studies to free-living subjects, where conditions are not subject to the same rigorous control, it may be difficult to determine how relevant these are. In particular, short-term laboratory studies generally make efforts to reduce the effect of learning about the post-ingestive effects of consuming a particular food or drink, for example that hunger returns more quickly after a reduced energy version of a product. These effects might have a meaningful impact on eating behaviour in the longer term (Livingstone et al. 2000). In practice, free-living studies require subjects to selfreport dietary intakes, and these measurements are prone to bias. In particular, the underreporting of energy intakes (Black et al. 1993; Goldberg & Black 1998) and misreporting of macronutrient consumption (e.g. underreporting of fat consumption) (Pomerleau et al. 1999; Goris et al. 2000) can be problematic in obtaining an accurate picture of dietary intakes. In addition, the lack of control over the subjects environment may make it difficult to interpret results and draw conclusions about the effects of the dietary manipulation in question. Thus, although it is desirable to conduct studies whose results are relevant to free-living populations, in reality, it is extremely difficult to gain meaningful results in uncontrolled conditions. Therefore, the vast majority of studies on satiety have been conducted in the laboratory under controlled conditions. Many studies use a preload design, which is discussed in the following section Preload studies Studies that aim to measure the effects of a particular variable or variables on the short-term regulation of food intake and appetite often follow a preload design, generally carried out over part or all of a single day. This involves first giving subjects a preload food or drink where the variable of interest is manipulated in order to monitor subsequent effects. The test and control preloads are matched (as far as possible) for taste, appearance, texture and other sensory qualities that might affect palatability. However, they may be different in energy content, macronutrient or ingredient composition, depending on the hypothesis to be tested. The subjects should be blinded to the differences between control and test preloads if the investigators wish to measure only the physiological effects of the manipulation. If the purpose of the study is to measure both physiological and cognitive effects of the changes made, the subjects may be told how the preloads differ. The formulation of the preload is very important in the ability of the study to measure a difference between the test and control preloads. Energy content appears to be particularly important. Small differences in the energy content of test and control preloads or comparisons of preloads containing relatively small amounts of energy, but differing in their composition, may mean that no effect of the test preload is detected; whereas, if the same variables are changed in preloads with higher energy content, significant effects may be seen (Livingstone et al. 2000) Typically, visual analogue scales (VAS), a type of selfreported measure of appetite, are used to monitor hunger, fullness and motivation to eat (see section 3.2.3). VAS may be recorded both before and at intervals after the preload is given to monitor changes in reported satiety. After a pre-determined time interval after the preload, a test meal is given, and energy intake is measured. The time interval between the preload and the test meal is critical to the results of the study because different physiological mechanisms play a role in satiety during the sensory, cognitive, post-ingestive and postabsorptive phases of the satiety cascade (see Fig. 1). If sensory, cognitive or gastrointestinal factors are of interest, then the time delay must be 30 minutes or less. A longer time interval is needed to measure postabsorptive effects on satiety. However, if the interval is too long, differences between the test and control