Ppharmp503

C Basic & Clinical Pharmacology & Toxicology 2005, 97, 61–73.
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How Palatable Food Disrupts Appetite Regulation
Charlotte Erlanson-Albertsson
Section of Endocrinology and Metabolism, Department of Experimental Medicine, University of Lund, Lund, Sweden (Received September 15, 2004; Accepted March 7, 2005) Abstract: Appetite regulation is part of a feedback system that controls the energy balance, involving a complex interplayof hunger and satiety signals, produced in the hypothalamus as well as in peripheral organs. Hunger signals may begenerated in peripheral organs (e.g. ghrelin) but most of them are expressed in the hypothalamus (neuropeptide Y, orexins,agouti-related peptide, melanin concentrating hormone, endogenous opiates and dopamine) and are expressed duringsituations of energy deficiency. Some satiety signals, such as cholecystokinin, glucagon-like peptide 1, peptide YY andenterostatin are released from the digestive tract in response to food intake. Others, such as leptin and insulin, aremobilized in response to perturbations in the nutritional state. Still others are generated in neurones of the hypothalamus(a-melanocyte-stimulating hormone and serotonin). Satiety signals act by inhibiting the expression of hunger signals and/or by blunting their effect. Palatable food, i.e. food rich in fat and sugar, up-regulates the expression of hunger signalsand satiety signals, at the same time blunting the response to satiety signals and activating the reward system. Hence,palatable food offsets normal appetite regulation, which may explain the increasing problem of obesity worldwide.
Today obesity is the greatest threat to public health in the pears to be a highly regulated process, considering the irregu- developed world. It is a silent killer in many disorders, such larity in the number and composition of meals from one day as heart disease, hypertension and diabetes that are the to the next, and the energy balance and stability in body consequences of obesity (Taubes 1998). Genetic factors are weight over longer periods of time. On the other hand obesity certainly important for the development of obesity. This is in the world is increasing, suggesting that there is a funda- true for a large number of mutations, for instance those mental weakness in the regulation of appetite and in the con- occurring in the melanocortin receptor gene (Yeo et al. trol of energy homeostasis. The aim of this article is to review 2003). Hence, it has been found that mutations in the mela- the mechanisms underlying appetite regulation and the in- nocortin receptor gene result in a distinct obesity syndrome fluence of highly palatable food on this process. This review that is inherited in a co-dominant manner (Farooqi et al. draws from previous overviews on the control of hedonic eat- 2003). Various other mutations are associated with obesity ing (Saper et al. 2002; Cummings & Schwartz 2003; Zig- as illustrated by leptin gene deficiency (Montague et al. man & Elmquist 2003; Gale et al. 2004).
1997) or leptin receptor gene deficiency (Clement et al.
1998). Although such mutations verify the importance of General aspects of hunger and satiety
genetic factors, they do not explain obesity world-wide(Froguel et al. 2000).
The regulation of food intake is based on an intricate feed- The most important cause of obesity is probably over-eat- back system, which is influenced not only by the availability ing (coupled with inactivity). Over-eating is stimulated by the of nutrients but also by various environmental and psycho- ready availability of food rich in fat and sugar. Appetite regu- logical factors. It is a complex system, as has been described lation and the understanding of the rewarding effect of food, in a number of recent reviews (Schwartz et al. 2000; Blund- in particular energy-rich food (fat and sugar), has become of ell & Gillett 2001). Basically however, food intake is con- great scientific interest. Much knowledge has been provided trolled by hunger and satiety signals. The signals are gener- by techniques of molecular biology, which have identified a ated in peripheral organs, such as the digestive tract and large number of genes and gene products responsible for sen- adipose tissue, and in the brain itself. Certain neurones in sations of hunger and satiety. On one hand food intake ap- the hypothalamus are the targets of these signals. The fairlyrecent identification of hunger- and satiety peptides as well Author for correspondence: Charlotte Erlanson-Albertsson, Divi- as their receptors has renewed the interest in appetite regu- sion of Diabetes, Metabolism and Endocrinology, Department of lation with special focus on the identification of tools that Experimental Medicine, University of Lund, Biomedical Center(BMC), F13, SE-221 84 Lund, Sweden (fax π46 46 2224022, e-mail might be useful in the pharmacological treatment of eating Charlotte.Erlanson-Albertsson/med.lu.se).
disorders, from anorexia to over-eating and obesity.
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(Tschop et al. 2000; Dornonville de la Cour et al. 2001; Hunger signals and the drive to eat
Wren et al. 2001 & 2002). It is produced in the stomach by The identification of appetite regulating signals started with endocrine cells (A-like cells) in the oxyntic glands and se- the realization that satiety peptides signals are of paramount creted into the blood stream (Dornonville de la Cour et al. importance in appetite control (to terminate food intake). It 2001). The pre-prandial rise in ghrelin is not proportional has since become clear that the sensation of hunger, the drive to the ingested caloric load during the previous meal to seek food, is the central event in appetite regulation, satiety (Callahan et al. 2004). Ghrelin receptors occur in the arcu- signals inhibiting the effect of hunger signals. Quite a few ate nucleus, where they activate neuropeptide Y neurones hunger peptides have been identified, among these neuropep- (Tschop et al. 2002). It has also been shown that ghrelin tide Y, ghrelin, the orexins and agouti-related peptide, and releases neuropeptide Y from hypothalamic explants in vi- tro, suggesting that it may be a mediator of the ghrelin ef- Neuropeptide Y is a 36 amino acid peptide with sequence fect (Wren et al. 2002). A role of endogenous ghrelin in homologies with pancreatic polypeptide and peptide YY. It appetite regulation is suggested by an increased ghrelin ex- is abundantly expressed in both the central and peripheral pression in the stomach following fasting and a decrease nervous system (Allen et al. 1983), a great density of neuro- in circulating ghrelin after intake of a regular chow meal peptide Y neurones being observed in the arcuate nucleus, (Dornonville de la Cour et al. 2001; Kim et al. 2003). The projecting to the paraventricular nucleus. Injection of suppression of plasma levels of ghrelin following a meal neuropeptide Y into the paraventricular hypothalamus may be an effect of nutrients in blood. The most striking stimulates food intake in the rat, carbohydrates in particu- effect of long-term ghrelin treatment is the increased body lar (Stanley & Leibowitz 1985). Upon intracerebroventricul- weight and accumulation of fat (Tschop et al. 2000). That ar injection neuropeptide Y suppresses energy expenditure ghrelin may be involved in the defense against human obes- from brown adipose tissue (Billington et al. 1994). A ity is suggested by the observation of decreased blood levels physiological role of neuropeptide Y is suggested by the fact of ghrelin in obese subjects, as demonstrated in obese Pima that it is released from the hypothalamus in situations of Indians who were found to have 33% lower fasting plasma fasting and in situations of increased energy demands, such ghrelin than lean subjects (Tschop et al. 2001). Ghrelin has as exercise and lactation. Long-term infusion of neuropep- been shown to increase food intake in humans (Wren et al. tide Y into the lateral ventricle of mice produces hyper- 2001), demonstrated after a 270 min. infusion of ghrelin, phagia, insulin resistance, and obesity (Raposinho et al. during which a standard free-choice buffet was served.
2001). Raised neuropeptide Y mRNA levels in specific hy- Ghrelin expression in the mouse stomach is decreased in pothalamic nuclei, including the arcuate nucleus and the response to a high-fat diet (Moesgaard et al. 2004), an effect paraventricular nucleus are found in animals with hyper- that may serve to restrain the hyperphagia induced by high- phagia and obesity (Gao et al. 2002). Upon fasting the fat diets. The effect of sucrose on ghrelin expression is not neuropeptide Y knockout mouse has a lower food intake than wild-type mice, nut normal body weight (Bannon et The orexins are two homologous peptides A and B, iden- al. 2000), supporting a role for neuropeptide Y in mediating tified as ligands for two orphan receptors, belonging to the energy intake and energy homeostasis. Both leptin and in- G-protein coupled receptor family (Sakurai et al. 1998).
sulin inhibit the expression of neuropeptide Y and its recep- The two peptides derive from the same 130 amino acid pre- tor (Schwartz et al. 1991; Erickson et al. 1996), which can cursor, prepro-orexin, that is cleaved into orexin A and B.
be interpreted to mean that hunger elicited by neuropeptide They are produced in neurones of the lateral and posterior Y is controlled by leptin and insulin.
hypothalamus, which project widely in the brain. Intracere- High-fat diets have been found to either reduce the ex- broventricular injection of orexin A or B promptly stimu- pression of neuropeptide Y in neurones of the arcuate nu- lates food intake (Sakurai et al. 1998). There is a close inter- cleus (Giraudo et al. 1994; Lin et al. 2000) or to stimulate action between neuropeptide Y, orexin and leptin, the ex- neuropeptide Y expression (Huang et al. 2004). The reason pression of orexins being increased by neuropeptide Y and for the conflicting data is not clear, but the type of fat in- suppressed by leptin (Niimi et al. 2001). Orexin neurones gested is probably important, saturated fat producing an are activated by fasting (Diano et al. 2003).
upregulation of neuropeptide Y expression in contrast to Orexin gene expression is stimulated by high plasma tri- polyunsaturated fat (Huang et al. 2004). A sucrose-contain- glyceride levels, obtained either through high-fat consump- ing diet has been found to stimulate the expression of hypo- tion or through Intralipid infusion (Wortley et al. 2003).
thalamic neuropeptide Y, and to cause hyperglycaemia, The effect of sucrose on orexin expression is not known.
hyperinsulinaemia and an increased body weight (Kaga et Agouti-related peptide is a neuropeptide, synthesized and al. 2001). Since neuropeptide Y stimulates food intake an secreted by neuropeptide Y neurones in the arcuate nucleus upregulation of hypothalamic neuropeptide Y by saturated (Korner et al. 2001). Agouti-related peptide stimulates appe- fat or by sucrose may be one reason for the hyperphagia tite and causes obesity as first described in the yellow agouti mouse having an overexpression of agouti protein (Klebig et Ghrelin is a meal initiator, circulating levels being elev- al. 1995). Agouti-related peptide interacts with the mela- ated during fasting and suppressed following a meal nocortin receptor, acting as a competitive antagonist to a- MiniReview
PALATABLE FOOD DISRUPTS APPETITE REGULATION melanocyte-stimulating hormone (a-MSH), which is an in- food intake in experimental animals, some of them, like hibitor of food intake. Administration of agouti-related pep- cholecystokinin, glucagon-like peptide 1 and peptide YY, tide to hypothalamic explants stimulated the release of have been shown to reduce food intake also in man (Gutz- neuropeptide Y, suggesting that orexigenic behaviour can be enforced via a positive feedback loop (Dhillo et al. 2002).
Cholecystokinin was the first peptide hormone to be as- Mice on a high-fat diet have higher agouti-related peptide sociated with meal-evoked satiety (Smith & Gibbs 1975).
mRNA expression in the bed nucleus of the stria terminalis Cholecystokinin is released in response to nutrients in the and in the ventral part of the lateral septal nucleus than duodenum and acts by stimulating vagal afferents, which mice on a low-fat diet suggesting that agouti-related peptide carry cholecystokinin-1 receptors (Moran et al. 1997). Cho- may be involved in fat-evoked hyperphagia (Huang et al. lecystokinin is thought to act as a neurotransmittor or 2003). The effect of sucrose on agouti-related peptide ex- neuromodulator in various parts of the brain, for instance in the nucleus tractus solitarius and in the medial basal Melanin-concentrating hormone is a proteolytic cleavage hypothalamus. Following intracerebroventricular injection product of the melanin-concentrating hormone preprohor- of cholecystokinin food intake is reduced, whereas injection mone of 165 residues, giving rise also to two other peptides, of a cholecystokinin-1-receptor antagonist stimulates food neuropeptide E-I and neuropeptide G-E (Shi 2004). Mela- intake (Corp et al. 1997). One important effect of cholecys- nin-concentrating hormone-expressing neurones in the tokinin is to suppress the neuropeptide Y expression in the brain have a restricted localization to the lateral hypothala- dorsomedial hypothalamus (Bi et al. 2001). Rats lacking the mus area and zona incerta (Zamir et al. 1986; Bittencourt cholecystokinin-1 receptor, the Otsuka Long-Evans Toku- et al. 1992) with projections to the nucleus of the solitary shima Fatty (OLETFA) rats have a five-fold elevation of tract. Cumulative evidence suggests that melanin-concen- neuropeptide Y expression in this region, which could ex- trating hormone plays an important role in maintaining en- plain their hyperphagia and obesity. Thus, cholecystokinin ergy homeostasis by regulating food intake and energy ex- seems to be important within the brain to regulate hunger penditure (Shi 2004). Intracerebroventricular injection of melanin-concentrating hormone stimulates food intake in There is no data on the expression of cholecystokinin in rats (Rossi et al. 1997; Shearman et al. 2003) and long- the upper small intestine after high-fat or sucrose diets. The term infusion of melanin-concentrating hormone induces satiety response to circulating cholecystokinin is blunted in hyperphagia and body weight gain (Ito et al. 2003). The rats maintained on a high-fat diet compared to rats main- expression of melanin-concentrating hormone is up-regu- tained on a low-fat diet (Covasa et al. 2000). Also, inhi- lated by food deprivation (Qu et al. 1996; Herve & bition of gastric emptying by cholecystokinin is markedly Fellmann 1997). It is also upregulated in the leptin-deficient attenuated in rats maintained on a high fat diet. The attenu- ob/ob mouse, suggesting that leptin controls the expression ation of cholecystokinin-induced inhibition of food intake of melanin-concentrating hormone (Segal-Lieberman et al. and gastric emptying is thought to reflect a reduced vagal 2003). In addition to being present in the hypothalamus, cholecystokinin responsiveness, measured as a decreased melanin-concentrating hormone is also present in periph- Fos expression in nuclei of the solitary tract and area post- eral tissues and in blood (Sun et al. 2004). There is a posi- rema, where the vagal sensory fibers terminate (Covasa et tive correlation between serum melanin-concentrating hor- al. 2000). There is also a blunted satiety response to chole- mone levels and body mass index and fat mass (Gavrila cystokinin during hyperglycemia (Lam et al. 1998).
et al. 2005), in line with the view that circulating melanin- Glucagon-like peptide 1 is a gut hormone derived from concentrating hormone acts as a hunger signal.
the processing of proglucagon in intestinal L cells. In ad-dition to stimulating insulin release, glucagon-like peptide 1also reduces food intake after intracerebroventricular ad- Satiety signals and the termination of feeding
ministration (Turton et al. 1996). The glucagon-like peptide- The sensation of satiety (meal termination) reflects the sup- receptor knock-out mouse did not display obesity or in- pression of hunger signals and/or the mobilization of satiety creased food intake, possibly because other satiety systems signals in response to a meal. Many of these latter signals were activated (Gallwitz & Schmidt 1997). Glucagon-like derive from the pancreas and gastrointestinal tract, trans- peptide 1 is of particular interest because it inhibits food mitting information from the periphery (via the vagus or intake also in man (Naslund et al. 1999). The mechanism via the circulation) to the brain. Other circulating satiety behind the glucagon-like peptide 1-induced inhibition of signals (nutrient metabolites) are generated in the liver, en- food intake is probably a combined effect of gastric dila- tering the brain from the blood (e.g.glucose and ketone tation and an increase in the level of circulating serotonin, associated with satiety (Owji et al. 2002). In dogs fed a high-fat diet the fasting plasma glucagon-like peptide 1 concen- Meal-initiated satiety signals from the digestive tract: chole- tration was 2.5 times higher than in controls (van Citters cystokinin, glucagon-like peptide 1 and peptide YY. et al. 2002). Additionally, expression of the glucagon-like Gastrointestinal satiety peptides are released from the intes- peptide 1 receptor in the whole pancreas was increased 2.3 tine in response to food. While all of these peptides reduce times in the fat-fed animals. This suggests that glucagon- MiniReview
like peptide 1 may provide a defence against hyperphagia Leptin has emerged as a major suppressor of appetite and induced by high-fat food. The effect of sucrose on gluca- is therefore viewed as an anti-obesity hormone (Fried- gon-like peptide 1 expression is not known.
man & Halaas 1998; Leibel 2002; Loos & Bouchard 2003).
Peptide YY is released from the intestinal L cells to re- This view is based on the finding that total deficiency of duce food intake in rodents as well as in man (Batterham leptin or its receptor leads to hyperphagia and obesity in et al. 2002). It acts to inhibit the electrical activity of neuro- mice and man (Campfield et al. 1995; Montague et al. peptide Y neurones in the arcuate nucleus (Batterham et al. 1997). Leptin is a 16-kDa protein produced in adipose 2002). It has been suggested that peptide YY serves as a tissue and secreted into the blood. Leptin has its own recep- circulating factor mediating satiety following ingestion of a tor with signalling properties similar to the interleukin-6 meal (Batterham et al. 2002). Peptide YY is active as a sat- receptor, localized to the arcuate nucleus (Tartaglia et al. iety signal with both high-fat and low-fat diets (Challis et al. 1995). Leptin is thought to pass the blood-brain barrier to 2004) and hence may provide a defence against fat-induced reach its receptor, reducing food intake and increasing ther- hyperphagia. Whether peptide YY acts as a satiety signal mogenesis (Friedman & Halaas 1998). The main role of lep- with sucrose-enriched food is unknown. Endogenous post- tin is to control the expression and activity of various other prandial levels of peptide YY were significantly lower in appetite controlling peptides. One target for leptin is the obese subjects compared to a lean group. Peptide YY in- arcuate nucleus, which harbours neuropeptide Y neurones fusion also caused a significant decrease in the cumulative that carry receptors for both leptin and insulin (Erickson 24 hr caloric intake in both obese and lean subjects, sug- et al. 1996). Fasting or weight loss lead to low blood leptin gesting that obese subjects were sensitive to the peptide YY levels, which in turn cause the hypothalamic neuropeptide action (Batterham et al. 2003).
Y expression to rise, thereby stimulating food intake (Blun- Adiposity related satiety signals: insulin, leptin and pro- opiomelanocortin (POMC)-derived peptides. Inter-meal and High-fat diet causes increased leptin expression and an long-term signalling constitutes a complementary regula- increased body weight (20%) compared with standard diet tory system that probably acts synergistically to short-term as illustrated in rodents (Moraes et al. 2003). This suggests that leptin is involved in the feedback control of fat intake.
The ability of insulin to reduce food intake at first ap- High-fat diets result in an inability to respond to leptin peared a paradox, insulin being a hormone that promotes (Moraes et al. 2003). This phenomenon will be discussed storage of energy in liver and adipose tissue. The paradox below under the name of leptin resistance. Leptin has also was resolved, when it was found that insulin induced satiety been found to inhibit the response to sweet taste (Kawai et by acting on receptors in the brain, whereas the anabolic al. 2000), suggesting that the intake of sweet food might be actions of insulin occurred peripherally (Woods et al. 2000).
regulated by leptin. A high-sucrose meal was found to in- There is evidence that insulin passes the blood-brain barrier crease adipose tissue leptin mRNA levels by at least 5 times intact and in a regulated receptor-mediated fashion (Woods within 3 hr, suggesting a feedback control of leptin to regu- et al. 2003). When blood insulin is raised following a meal, late sucrose intake (Polson & Thompson 2003). The en- the passage of insulin into the brain is thought to reflect hanced preference for sweet substances found in the db/db this increase (Baskin et al. 1999). After fasting the penetra- mice lacking the leptin receptor could hence be explained tion of insulin into the brain is greatly reduced with the by a defect leptin suppression of the reward induced by the consequence that a larger meal can be eaten before insulin sweet taste (Shigemura et al. 2004). In a comparison be- evokes satiety (Strubbe et al. 1988).
tween dietary sucrose and coconut fat (rich in saturated High-fat diets induce insulin resistance, which from the fatty acids) in ob/ob mice, lacking leptin, it was found that point of view of appetite regulation means suppressed satiety the body weight gain was greater in sucrose-fed ob/ob mice (Kim et al. 2004). That insulin indeed inhibits the intake of than in fat-fed mice (Flatt et al. 1990). Further experiments high-fat food is clear from the use of non-peptide insulin mi- are needed to establish a role of leptin in promoting satiety metics, which when given intracerebroventricular were shown to reduce over-eating and prevent obesity in rats main- Pro-opiomelanocorticotropin is a prohormone produced tained on high-fat diet (Air et al. 2002). Intracerebroventricu- by specific neurones in the arcuate nucleus that seem to op- lar injection of insulin has been shown to reduce sucrose in- erate under leptin control. Approximately 40% of the pro- take in rats, that have been stimulated to eat sucrose by treat- opiomelanocorticotropin neurones carry leptin receptors ment with the opiate k receptor agonist U50, 488 (Sipols et (Cheung et al. 1997). The pro-opiomelanocorticotropin al. 2002). However, sucrose-rich diets are known to cause the neurones generate a-melanocyte-stimulating hormone, which classical signs of insulin resistance, with increased food in- is released from terminals in the paraventricular nucleus take, adiposity, hyperinsulinaemia and hypertriglyceridaem- and lateral hypothalamus (Tritos & Maratos-Flier 1999).
ia (Davidoff et al. 2004), indicating that the defence against a-melanocyte-stimulating hormone suppresses food intake, over-eating afforded by insulin is overridden at some point.
acting through the melanocortin-4 receptor in neurones of Also the passage of insulin through the blood brain barrier is the arcuate nucleus. The leptin-induced activation of the decreased after a high-fat meal compared to a low-fat meal, melanocortin receptor seems to be critical for the regulation hence leading to a reduced satiety (Gerozissis et al. 1997).
of food intake, since interruption at any point in this chain MiniReview
PALATABLE FOOD DISRUPTS APPETITE REGULATION of events causes overeating (Yeo et al. 1998). Leptin stimu- Palatable food and appetite regulation
lates the pro-opiomelanocorticotropin neurons, while inhib-iting the neuropeptide Y neurones (Williams et al. 1999).
As stated above, palatable food, i.e. food rich in fat and Hence, the arcuate nucleus of the hypothalamus controls sugar, will increase food intake, i.e. the activity and expres- food intake, acting through neuropeptide Y neurones to sion of signals controlling appetite will be balanced in fa- stimulate and through pro-opiomelanocorticotropin neur- vour of prolonged eating (table 2). Palatable food activates ones (a-melanocyte-stimulating hormone) to inhibit food the reward system, thereby affecting ingestive behaviour.
intake. Patients with a defect of the pro-opiomelanocortico- Typical of ‘‘reward eating’’ is that the driving force is grati- tropin gene product due to mutations were found to display fication rather than energy deficit (Pelchat 2002). From an red hair, early-onset obesity, and congenital hypocortisolism evolutionary point of view it makes sense that food rich in (Krude et al. 2003; Farooqi & O’Rahilly 2004). Also, in- fat and sugar is attractive, because such food can be rapidly herited abnormalities in the synthesis and processing of converted into energy (Nesse & Berridge 1997). Long-term pro-opiomelanocorticotropin and defects in the action of overconsumption of palatable food has been compared to pro-opiomelanocorticotropin-derived peptides could help drug addiction (Berridge 1996; Gosnell 2000). The behav- to explain obesity (Coll et al. 2004).
iour induced by stimulating the reward system is to ‘‘come With a high-fat diet pro-opiomelanocorticotropin-de- back for more’’ (Kelley et al. 2002). Accordingly, free access rived peptides appear to be important to enable the individ- to palatable food may lead to over-eating, characterized by ual to resist overeating. This conclusion is based on studies prolongation of the meal because the normally induced sen- of pro-opiomelanocorticotropin-deficient mice, which re- sation of satiety is overridden. Another parallel between spond to a high-fat diet with hyperphagia and obesity palatable food and addictive drugs is the phenomenon of (Challis et al. 2004). The importance of pro-opiomelanocor- adaptation (Koob & Le Moal 1997). Addictive drugs are ticotropin-derived peptides in appetite regulation is sup- known to start a series of adaptations leading to a shift in ported by studies of mice on a high-fat diet for 13 weeks; homeostatic set points. Overconsumption of palatable food they became obese concomitantly with a reduction of pro- gradually shifts the set point for energy balance and body opiomelanocorticotropin mRNA expression in the arcuate nucleus (Huang et al. 2004). Pro-opiomelanocorticotropin There are two main explanations for compulsive over- mRNA in these animals was upregulated by a diet rich in eating of palatable food. One is the activation of the reward n-3 polyunsaturated fat, emphasising the fact that the type system, represented by endogenous opioids, dopamine and of dietary fat matters in the regulation of hypothalamic serotonin. The other is the phenomenon of ‘‘resistance‘‘, i.e.
neuropeptide expression (Huang et al. 2004).
an impaired ability to respond to food intake with a signal- During the processing of the pro-opiomelanocorticotrop- in molecule, endorphins are also produced, which stimulaterather than inhibit appetite. Mice lacking b-endorphin butnot the other pro-opiomelanocorticotropin-derived pep- tides were orexigenic, suggesting that endorphins are im- Effects of diets rich in fat or sucrose on the expression of hunger portant in normal appetite regulation and that the different pro-opiomelanocorticotropin-derived peptides interact in a complex manner in the regulation of energy homeostasis Peptides involved in appetite control.
Hunger peptides are released in the circulation or upregulated (hypothalamus) in response to food deprivation. Satiety peptides are released into the circulation or upregulated (hypothalamus) in NPY – neuropeptide Y, AgRP – agouti-related peptide, MCH – melanin-concentrating hormones, MSH – melanocyte-stimulatinghormone, CCK – cholecystokinin, GLP – glucagon-like peptide 1, ↑ upregulated, ↓downregulated, – not investigated, * saturated fat.
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eners, while dynorphin and U 50 488, two k-agonists, did Activation of the reward system by palatable food
not (Zhang & Kelley 1997 & 2002). Water intake was not The reward system. In recent years the mechanisms underly- affected, indicating that opioids are not involved in the con- ing reward and motivation have been outlined (Kelley trol of water intake. In man, the opiate receptor antagonist 2004). Nucleus accumbens is a brain region that appears to naloxone was found to reduce the preference for palatable play a crucial role in behaviour related to natural re- food, without affecting subjective ratings of hunger and sat- inforcers, such as ingestion of food and mating. The nucleus iety (Drewnowski et al. 1992). It is to be noted that opiate accumbens is also a site for the rewarding and reinforcing antagonists decrease the attractiveness of food without af- properties of addictive drugs. The nucleus accumbens re- fecting its taste, i.e. the subjects are still able to sense the ceives information from the brain stem in response to taste sweet taste, but it does not elicit the expected reward (Yeo- and gastrointestinal sensations from the food ingested mans & Gray 1996; Kelley et al. 2002). Opioids stimulate through a direct connection with the nucleus of the solitary food intake because the sensation of hunger is more intense.
tract. There is also a connection between the nucleus ac- This conclusion was drawn from experiments in which rats cumbens and the lateral hypothalamus, being important for had to press a bar to receive food (Glass et al. 1999). Upon energy homeostasis. Although there are many neurotrans- intravenous infusion of opioid agonists the number of bar mitter systems within this region, studies on the rewarding presses (i.e. the urgency) increased before the rats gave up effects of food has focused on three signal systems, involv- (Glass et al. 1999). In contrast naloxone reduced the ur- ing endogenous opioids, dopamine and serotonin.
gency of the food-seeking behaviour. Together these obser- The opioid system. Since the discovery of the endogenous vations suggest that endogenous opioids are important to opioid peptides and their receptors nearly 30 years ago there has been a need to understand the role of these com- Upon ingestion of palatable food the hypothalamic ex- pounds in the brain (Pert & Snyder 1973; Lord et al. 1977).
pression of opioid peptides and opioid receptors is in- Initially, interest was focused on pain and pain relief but creased, supporting the involvement of the opioid system in lately has included also reward, addiction and ingestive be- palatable food consumption. High-fat and sucrose diets haviour. In mammals the endogenous opioid peptides are were shown to increase the expression of prodynorphin/dy- derived from the proteins pro-opiomelanocortin (POMC), norphin in the arcuate nucleus and paraventricular nucleus proenkephalin, prodynorphin and pronociceptin/orphanin (Kim et al. 1996; Welch et al. 1996). At the same time intra- FQ. These precursors produce the opioid peptides b-endor- cerebroventricular injection of opioids stimulated the intake phins, enkephalins, dynorphins and nociceptin. b-Endorphin of sucrose or sweeteners (Zhang & Kelley 2002) and fat binds with equal affinity to m- and d-receptors, whereas dy- (Ookuma et al. 1997). While opioids induce an increased norphins bind to the k-receptor. The opiate receptors are appetite for palatable food, the intake of palatable food is found in various neuronal networks in the brain, for in- decreased by opiate receptor antagonists. Enterostatin is a stance in hypothalamic regions involved in the control of peptide produced by proteolytic cleavage of pancreatic pro- food intake and in the nucleus accumbens (reward centre).
colipase in the gut and has been found to inhibit fat intake One important property of opiates is to reinforce the behav- in an experimental rat model, provided the animals have iour best described as ‘‘coming back for more’’ (Van Ree et been adapted to fat feeding during 14 days (Erlanson-Al- al. 2000). Systemic injection of morphine causes rats to bertsson & York 1997). The mechanism of action for overeat, an effect that can be prevented by various opiate enterostatin occurs through an inhibition of the k and m antagonists. When analyzing the type of food chosen under opioid systems to reduce fat intake. The target protein for the influence of opiates, it was found that morphine stimu- enterostatin was however found to be the F1-ATPase b-sub- lates the ingestion of food rich in sugar and fat (Yeomans unit, enterostatin acting to inhibit ATP-production (Berger et al. 1997). That it is the palatability of the food rather et al. 2002 & 2004; Park et al. 2004). This suggests that than its energy content that activates the opioid system is an ATP-dependent intracellular mechanism is important for clear from experiments comparing diets rich in sugar with regulation of fat intake, opening new fields of investigation diets rich in artificial sweeteners. Such studies show that the sweet taste is important for opioid activation and not the Dopamine. Another neurotransmittor that seems to be energy content (Apfelbaum & Mandenoff 1981). It has also involved in the reward response to food is dopamine. Several been shown that the involvement of the opioid system dur- different dopaminergic pathways are thought to modulate ing intake of sweets is manifested as analgesia (Le Magnen eating behaviour (Wang et al. 2001; Del Parigi et al. 2003).
et al. 1980). Palatable food activates the opioid reward sys- Five subtypes of dopamine receptors mediate the effects of tem in the nucleus accumbens (Zhang et al. 2003). The nu- dopamine, subtype 2 being associated with food intake and cleus accumbens receives input from the medial prefrontal reward (Blum et al. 2000). The dopaminergic circuitry is a cortex, hippocampus and amygdala as well as from the target for several appetite-regulating peptides, like galanin brain stem, while output signals that promote eating target (Rada et al. 1998), leptin (Szczypka et al. 2000) and chole- the hypothalamus (Helm et al. 2003). In the rat microinjec- cystokinin (Vaccarino 1994). Thus, microinjection of gala- tion of various m-opiate agonists including morphine, en- nin into the nucleus accumbens stimulates dopamine and hanced sucrose intake as well as intake of artificial sweet- suppresses acetylcholine release, i.e. signals for initiation of MiniReview
PALATABLE FOOD DISRUPTS APPETITE REGULATION feeding (Rada et al. 1998). Leptin was found to lower dop- signals are down-regulated (Huang et al. 2003), thus lowering amine release in the nucleus accumbens during feeding, sug- the satiety response to a fat meal. Such changes in peptide ex- gesting that leptin suppresses the feeding-induced reward (Krugel et al. 2003). Dopamine is also involved in other Other hunger signals like ghrelin are down-regulated in aspects of eating behaviour, such as arousal and food seek- response to intake of fat (Moesgaard et al. 2004). A high- fat diet, on the other hand, upregulates several satiety sig- Serotonin. A third neurotransmittor that may contribute nals like leptin (Moraes et al. 2003), insulin, glucagon-like to appetite regulation is serotonin. Several observations sug- peptide 1 (van Citters et al. 2002) and enterostatin (Erlan- gest that serotonin may be involved in the control of food in- son-Albertsson & York 1997). Since a palatable food regime take as a satiety signal (Lawton et al. 1995). Brain serotonin leads to over-eating in spite of the change in appetite signals levels are affected by many factors, including circulating to restrict food intake, there must be either a blunted re- levels of tryptophan and certain macronutrients (Halford & sponse to satiety signals or food intake is stimulated by Blundell 2000). In the hypothalamus, serotonin inhibits other factors acting within the reward system. High serum neuropeptide Y expression, thus depressing hunger (Half- concentrations of leptin were noted in obese individuals ord & Blundell 2000). Whether serotonin specifically regu- (Maffei et al. 1995). There was also an inability of leptin to lates carbohydrate intake (Wurtman & Wurtman 1995) and/ inhibit food intake in such individuals, a phenomenon or fat intake (Blundell & Lawton 1995) is debated. Dietary called ‘‘leptin resistance’’ (Frederich et al. 1995; Leibel carbohydrates have been shown to raise brain serotonin turn- 2002). It was found that a high-fat diet caused a sustained over as observed in depressed patients overeating carbo- increase in circulating leptin in mice, and that the leptin hydrates to increase well-being (Wurtman & Wurtman 1995).
levels reflected the amount of fat in the body (Frederich et On the other hand treatment with the anorexic agent fenflu- al. 1995). However, despite increased leptin levels, animals ramine (Bray 2001), which is claimed to act by releasing sero- on a high-fat diet became obese, suggesting that the high- tonin as well as inhibiting serotonin reuptake, has been fat diet changed the ‘set point’ for body weight/body fat, at shown to specifically reduce fat intake (Lawton et al. 1995).
least in part by restraining the action of leptin (Frederich Opioid antagonism and serotonergic stimulation, using et al. 1995). Another explanation for the development of naloxone and fluoxetin (a selective serotonin reuptake inhibi- leptin resistance is an impaired ability of leptin to pass the tor), has been shown to reduce intake of fat and sucrose in blood-brain barrier (Banks et al. 1999; Banks & Farrell animals (Hagan et al. 1997). That serotonin is important to 2003). The depressed passage of leptin in obese individuals relieve stress was demonstrated in experiments where diets is supposed to be a consequence of a high-fat diet. A third rich in fat and carbohydrates were given to animals subjected possible explanation for leptin resistance is inhibition of to stress (Buwalda et al. 2001). A high-fat diet was found to post-receptor signalling. Such an inhibitor of leptin signal- reduce some of the behavioural responses to stressors more ling has been identified, the SOCS-3, (suppressor-of-cyto- effectively than a carbohydrate-based diet. It was also found kine-signalling) (Bjorbaek et al. 1998), being upregulated by that desensitization of central nervous 5-HT1a receptors oc- high-fat diet and proposed to be a leptin resistance signal curred in animals receiving a carbohydrate-based diet but was absent in fat- fed animals (Buwalda et al. 2001). This ex- The passage of insulin into the brain seems to be a key periment supports a role for serotonin in relieving stress, but event in insulin-induced satiety. There are specific regions in also explains the urge for eating fat to relieve stress.
the brain, e.g. the hypothalamus and the hindbrain, whereinsulin penetration occurs (Banks & Kastin 1998). That pal-atable diet may reduce insulin penetration through the Resistance mechanisms in appetite regulation
blood brain barrier was demonstrated in animals fed a with palatable food
high-fat diet for several weeks (Burguera et al. 2000). This In addition to activation of the reward system another ex- could contribute to the development of obesity in individ- planation for compulsive consumption of palatable food is uals on a high-fat diet (Banks 2003). One might speculate a blunted response to satiety signals. This may occur in dif- that a high-fat diet causes a peripheral insulin resistance, ferent ways: 1) an increased expression of hunger signals or which shuffles glucose to the brain. Gradually the blood- their receptors 2) a reduced expression of satiety signals and brain barrier becomes resistant to the penetration of insulin their receptors and 3) a default receptor targeting and/or and the satiating effect of insulin is lost as a result.
post-receptor signalling in response to palatable food, in A blunted satiety response to cholecystokinin seems to develop in response to intake of food rich in fat (Covasa et An altered expression upon long-term exposure to palat- al. 2000) and sucrose (Lam et al. 1998). The mechanism able food has been described for several of the appetite regu- behind the blunted response is not known.
lating peptides listed in table 1. Some of the hunger peptideslike neuropeptide Y (Huang et al. 2004), the orexins (Wortley Does palatable food cause addiction?
et al. 2003) and agouti-related peptide (Huang et al. 2003) areupregulated following a period of fat feeding, in line with an Palatable food mobilizes opioids and dopamine in the re- increased hunger for fat food. At the same time some satiety ward system. Opiates and dopamine, when injected into the MiniReview
Fig. 1a. Hunger and satiety signalling during intake of a standardmeal. Hunger signals, such as ghrelin in the stomach and NPY, Fig. 1b. Hunger and satiety signalling after a period on a diet of orexin, AgRP in the hypothalamus, are depressed after intake of palatable food. Hunger signals are either depressed, like ghrelin in standard food, while satiety signals like CCK, GLP-1, PYY, insulin the stomach and NPY in the hypothalamus, in response to a meal and leptin are raised. Food intake is terminated as a result. For consisting of palatable food or raised, as for orexin and AgRP in the hypothalamus. Satiety signals like insulin and leptin are in-creased. Palatable food induces resistance to several satiety signals,documented for CCK, insulin and leptin, resulting in overeating.
Food intake is driven by an increased activity in the reward system(dopamine, serotonin and opiates), triggered by the attractivenessof the taste. For abbreviations, see table 1.
nucleus accumbens, will stimulate food intake, in particular ence is facilitated by factors that enhance the attractiveness sucrose and fat, thus creating a vicious circle. Such a re- of palatable food. The attractiveness of food depends not inforcement mechanism is in line with the view that palat- only on its taste and content of carbohydrate and fat, but able food may cause dependence (Gosnell & Krahn 1992; also on the nutritional state of the individual, i.e. whether Nestler & Aghajanian 1997). The development of depend- fasted or well fed (Cabanac & Lafrance 1990; Berridge1991). Long-term food restriction has been shown to aug-ment the rewarding effect not only of food but also of vari-ous drugs of abuse (Cabeza de Vaca & Carr 1998; Carr2002) and intermittent feeding has been shown to increasethe rewarding effect of food (Colantuoni et al. 2002). Notsurprisingly therefore, binge eating can be provoked by foodrestriction (Hagan et al. 2003). A similar sensitizing effecton the reward system by intake restriction is observed foralcohol (Soderpalm & Hansen 1999). Thus food restrictionsensitizes the reward system, which triggers the craving notonly for food (palatable food in particular), but also foraddictive drugs, including alcohol.
With an intermittent feeding protocol, using concen- trated sugar solutions, sugar dependence has actually been Fig. 2. Schematic picture of the pathways for appetite signalling shown to develop in rodents (Colantuoni et al. 2002). Clas- in the brain during intake of standard food and palatable food, sically, dependence occurs in two steps. In the first step the respectively. With standard food, signals are transmitted from the consumption of the specific item is increased; in the second gastrointestinal tract to the brain stem, where the energy content step withdrawal symptoms become manifest in the absence and taste of the food is registered. In the absence of strongly attract-ive taste, hypothalamus performs the integrated energy sensing of the consumed item. The withdrawal symptoms include through the interaction of various appetite signals and their recep- anxiety, autonomic nervous system abnormalities, and tors in the hypothalamic nuclei, the arcuate nucleus being one im- changes in body temperature, tremor and shakes. In an ex- portant site for regulation of energy balance. Termination of food periment to study the addictive potential of sugar, rats were intake occurs. With palatable food the attractive taste of the food offered a 25% glucose solution together with food pellets 12 is registered, leading to an activation of the reward centre, releasingvarious reward signals, the nucleus accumbens being one important hr each day (Colantuoni et al. 2002). After one week the site. The reward centre has close connections to the hypothalamus, sugar intake had increased three times. Withdrawal of sugar thereby influencing the hypothalamic energy homeostasis mechan- precipitated symptoms such as teeth chatter, forepaw isms. The end result is prolongation of food intake (LH; lateral tremor and head shakes. Indirect evidence that the opioid hypothalamus, PVN; paraventricular nucleus, DMH; dorsomedialhypothalamus, VMH; ventromedial hypothalamus). For further ab- system had been activated during the escalated sugar intake was provided by the precipitation of withdrawal symptoms MiniReview
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