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Obesity: Special Feature |
Endocrine Unit, Imperial College Faculty of Medicine, Hammersmith Hospital, London W12 ONN, United Kingdom
Address all correspondence and requests for reprints to: Professor S. R. Bloom, Endocrine Unit, Imperial College Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London W12 ONN, United Kingdom. E-mail: s.bloom{at}imperial.ac.uk.
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Abstract |
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 Top Abstract IntroductionHungerSatietyPeptide YY (PYY) and...GLP-1 and oxyntomodulin (OXM)CCKIntegration of signalsConclusionReferences |
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Introduction |
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TopAbstractIntroductionHungerSatietyPeptide YY (PYY) and...GLP-1 and oxyntomodulin (OXM)CCKIntegration of signalsConclusionReferences |
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Over the last 10 yr, because of the discovery of leptin, many advances have been made in our understanding of the peripheral signals regulating appetite and energy homeostasis. Several peptides synthesized and secreted by the gastrointestinal tract are known to regulate food intake. Whereas social and learned behaviors significantly impact on meal patterns, peripheral factors play important roles in determining energy balance by controlling hunger and satiety.
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Hunger |
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TopAbstractIntroductionHungerSatietyPeptide YY (PYY) and...GLP-1 and oxyntomodulin (OXM)CCKIntegration of signalsConclusionReferences |
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The oxyntic cells of the stomach are the main site of ghrelin production. About two thirds of circulating ghrelin is thought to be produced by the stomach. However, ghrelin-producing cells have also been found in the duodenum, ileum, caecum, and colon. Both circulating and nutritional factors from within the gut lumen may trigger these cells to release ghrelin. It is, however, thought to be calorie intake, which is the primary regulator of plasma ghrelin levels (2). Circulating ghrelin concentrations have been shown to rise during a period of fasting, peak (to double the baseline concentration) just before eating, and fall rapidly after a meal, suggesting a role as a meal initiator (3). However, recent work has failed show a relationship between plasma ghrelin concentrations and meal initiation (4). Furthermore, plasma ghrelin peaks can be conditioned by altering feeding schedule, suggesting a possible role in physiological preparation for a meal, rather than initiation of feeding (5). Plasma ghrelin concentrations also show a diurnal variation, in phase with leptin, with highest levels in the morning and lowest at night (3).
GHS-Rs are widely expressed. In the central nervous system (CNS), they are found in the pituitary and hypothalamus, whereas peripheral receptor expression has been described in the myocardium, stomach, small intestine, pancreas, colon, adipose tissue, liver, kidney, placenta, and T cells. In addition, there is some evidence of additional receptor subtype(s) that bind the nonoctanoylated form of ghrelin.
Ghrelin has been demonstrated to be a short-term regulator of food intake in both animals and man. Both central and peripheral ghrelin administrations increase calorie intake in animals (6). Furthermore, infusing antighrelin antibodies into the rat brain inhibits fasting-induced feeding, supporting ghrelin’s role as an endogenous regulator of food intake (7). Ghrelin is also effective in man, producing a 28% increase in food intake, when given iv to normal weight volunteers (8).
Ghrelin may also be a regulator of long-term energy balance. Plasma ghrelin levels are strongly correlated with body weight. There is a reversible suppression of ghrelin associated with obesity, such that ghrelin levels normalize after diet-induced weight loss (9). The fall in plasma ghrelin concentration after bariatric surgery for obesity is thought to be partly responsible for the suppression of appetite and weight loss seen after these operations (9). Seven-day administration of ghrelin to rodents stimulates weight gain and adiposity secondary to increased food intake (2, 6). This fat deposition is promoted by a change in metabolism from fatty acid oxidation to glycolysis (2). However, ghrelin null animals do not have significantly altered body weight or food intake when compared with wild-type littermates (10).
In addition to its actions on food intake, ghrelin induces a dose-dependent stimulation of GH release from the pituitary via its actions on the GHS-R in the hypothalamus (1, 2). However, it is important to note that the effects of ghrelin on food intake are independent of its effects on GH. Whereas ghrelin is known to increase adiposity, GH reduces adiposity. The effect of chronic ghrelin administration on food intake and body weight is still effective in dwarf GH-deficient rats (2).
Ghrelin may be the first of a number of orexigenic factors that have physiological activity in man. However, as yet, no other circulating hormone derived from the gastrointestinal tract has been shown to stimulate food intake.
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Satiety |
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TopAbstractIntroductionHungerSatietyPeptide YY (PYY) and...GLP-1 and oxyntomodulin (OXM)CCKIntegration of signalsConclusionReferences |
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Peptide YY (PYY) and pancreatic polypeptide (PP) |
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TopAbstractIntroductionHungerSatietyPeptide YY (PYY) and...GLP-1 and oxyntomodulin (OXM)CCKIntegration of signalsConclusionReferences |
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-helix and polyproline helix connected by a ß-turn, results in a characteristic U-shaped peptide known as a PP-fold. In addition to a shared tertiary structure, there is significant homology between peptide sequences within the family. They all have 36 amino acids and contain several tyrosine residues. Furthermore, their biological activity is dependent on C-terminal amidation. However, there are important structural differences between PYY and PP. The N terminal of PYY is very different from PP, allowing PYY (but not PP) to cross the blood-brain barrier (BBB). In addition, unlike PP, PYY is present in two forms, PYY (1–36) and PYY (3–36). PYY (3–36), the major circulating form (11), is a truncated 34-amino acid form created by cleavage of the N terminus Tyr-Pro residues by dipeptidyl peptidase IV (DPPIV) (12). DPPIV is found in two forms; as a transmembrane protein widely expressed on endothelial, epithelial, and lymphoid tissue and as a circulating form in plasma. It is responsible for dipeptide cleavage from many peptides including hormones, neuropeptides, and chemokines (see Ref.13 for review). However, the actions of DPPIV in regulating the relative postprandial concentrations of PYY (1–36) and PYY (3–36) are unknown.
PYY is secreted from the entire gastrointestinal tract but particularly from the distal portion. PYY immunoreactive cells are almost absent in the stomach, sparse in the duodenum and jejunum, common in the ileum and colon, and at very high levels in the rectum. Food intake results in release of PYY from these cells. The PYY level rises to a plateau at 1–2 h post ingestion, with these peak levels influenced by both the number of calories and the composition of the food consumed. Higher plasma concentrations are seen after isocaloric meals of fat, compared with intake of protein or carbohydrate. Other stimuli, such as gastric acid, cholecystokinin, and luminal bile salts (but not gastric distension), also stimulate PYY release. The onset of this release occurs even before nutrients have reached the distal parts of the gastrointestinal tract in which PYY is produced. This infers peptide release may occur via a neural reflex, possibly through the vagus nerve. Other factors also alter circulating PYY. Plasma PYY concentrations are increased by IGF-1, bombesin, and calcitonin-gene-related peptide, and they are reduced by glucagon-like peptide 1 (GLP-1).
PP is produced largely in the endocrine pancreas, particularly the duodenal segment, but it is also found in the exocrine pancreas, colon, and rectum. The majority of PP-immunoreactive cells are found at the periphery of the pancreatic islets. Like PYY, the main stimulus to the release of PP is food intake, with the circulating levels proportional to the caloric load. Postprandial PP release is biphasic: in response to the first meal of the day, there is a relatively small first-phase release of PP, but the contribution of this first phase increases with subsequent meals. However, the overall release with an isocaloric meal remains unchanged (14). Other stimuli can also influence PP release, e.g. gastric distension, vagal tone, or adrenergic stimulation (e.g. due to exercise or hypoglycemia). Pancreatic and gastrointestinal hormones can also regulate circulating PP levels. Ghrelin, motilin, and secretin rapidly stimulate PP release, whereas somatostatin and its analogs significantly reduce plasma PP concentrations. These acute fluctuations in plasma PP levels take place on a background diurnal rhythm, with circulating PP at its nadir at 0200 h and at its peak at 2100 h (14).
The PP-fold family, PPY, PP, and NPY bind to the seven-transmembrane domain, G protein-coupled receptors, Y1-Y5 (15). These receptors are classified according to their affinity for PYY, PP, and NPY. Whereas PYY binds with high affinity to all Y receptors, PYY (3–36) shows high affinity for Y2 and some affinity for Y1 and Y5 receptors. PP binds with greatest affinity to Y4 receptors (with greater affinity than PYY) and Y5 receptors (15) (Fig. 1
).
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The truncated form, PYY (3–36) has been reported to have potent effects on appetite. In man, PYY (3–36), given iv at physiological levels, to normal-weight human volunteers, reduces calorific intake by over 30% (16). Furthermore, the duration of food intake and their subjective feelings of hunger decrease, without an alteration in gastric emptying. This effect persists 2 h after the infusion is terminated, despite the concentration of circulating PYY (3–36) returning to basal levels. Plasma PYY is suppressed in patients with morbid obesity. However, the anorectic effect is preserved in obese subjects, with calorific intake reduced to the same extent as lean subjects (17). This suggests that administration of PYY (3–36) could perhaps be an effective therapy for obesity. Indeed, chronic peripheral administration to rodents results in a depressed food intake throughout the study, and body weight is reduced in comparison with controls (16).
The central actions of PYY, in contrast to peripheral PYY, are orexigenic. PYY injections into the third, lateral, or fourth cerebral ventricles (18), paraventricular nucleus, or hippocampus potently stimulate food intake in rodents (19). The truncated form, PYY (3–36), also simulates food intake when administered intracerebroventricularly. This effect is reduced in both Y1–/– mice and Y5–/– mice (20). Therefore, although PYY (3–36) does not have a high affinity for these receptors, they may mediate its central feeding effect.
The role of PP in appetite regulation has been investigated for over 30 yr. It was initially noted that ob/ob mice lacked pancreatic PP cells, and peripheral administration of PP could reduce their food intake and body weight (21). Conversely, transgenic mice that overexpress PP have a lean phenotype with reduced food intake (22). Physiological doses of PP administered peripherally to normal mice have been shown to produce a rapid reduction in food intake, associated with reduced gastric emptying, reduced gastric expression of ghrelin, and increased vagal tone. The effect on food intake persists for 24 h (23). Because it also increased oxygen consumption and stimulated sympathetic activity, it was postulated that PP also increased energy expenditure.
Normal-weight human volunteers reduce food intake during an infusion of PP and have a reduced food intake over the following 24 h (24). However, unlike rodents, PP does not appear to alter gastric emptying in humans. A blunted basal and meal-stimulated PP response has been observed in human subjects with Prader-Willi syndrome, characterized by obesity and hyperphagia. It is possible that PP contributes to the hyperphagia in this human model of obesity (25). Furthermore, the suppression of appetite by PP has also been demonstrated in subjects with Prader-Willi syndrome (26).
Apart from its acute effects on appetite and food intake, PP may also modulate long-term energy balance. Repeated administration of PP to ob/ob mice does decrease body weight gain and ameliorates insulin resistance and dyslipidemia (23). However, rodents with diet-induced obesity are less sensitive to the anorectic actions of PP. Long-term energy stores may influence the circulating PP levels as well as short-term food intake. Plasma PP is increased in individuals with anorexia nervosa, and there have been reports of suppressed plasma PP in obese subjects. However, the effects of obesity on circulating concentrations of PP are conflicting; others have found no difference between lean and obese subjects or between obese subjects before and after weight loss. The acute effects of PP on appetite and its long-term actions on body weight in human obesity are unknown. Further investigation in obese subjects may indicate whether PP has the potential to be a novel treatment for obesity.
PP, like PYY, has opposing effects on appetite, depending on the route of administration. Injection of human PP into the third ventricle stimulated daytime food intake in satiated rats (27). Similarly, central injection of PP has the opposite effect to peripheral administration on gastric motility, stimulating rather than inhibiting gastric emptying. These contrasting effects of central and peripheral administration of PP probably reflect differing sites of receptor activation. As discussed earlier, PP is unable to cross the BBB so acts on the CNS via areas that have a deficient BBB, such as the area postrema (AP). The passage of PP into the AP has been demonstrated by autoradiographic studies and neuronal activation by expression of the immediate early gene, c-fos, in the AP (28). The anorectic effect seen after peripheral administration of PP may occur via the Y4, which is highly expressed in this region. The receptor mediating the orexigenic effect of PP after central injection is unclear. The stimulation of food intake is blunted in Y5 –/– transgenic mice but not by Y5 receptor antisense oligonucleotides.
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GLP-1 and oxyntomodulin (OXM) |
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TopAbstractIntroductionHungerSatietyPeptide YY (PYY) and...GLP-1 and oxyntomodulin (OXM)CCKIntegration of signalsConclusionReferences |
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Central administration of GLP-1, both intracerebroventricularly and into the paraventricular nucleus, has been shown to reduce calorie intake in animal models (32). Chronic administration of GLP-1 to the CNS results in a reduction in weight gain (33). Peripheral GLP-1 injection also inhibits food intake in rodents. Similarly, OXM inhibits calorie intake in rodents when given either centrally or peripherally and results in decreased weight gain when administered peripherally.
In humans, iv administration of GLP-1 decreases food intake and results in feelings of satiety. A recent metaanalysis of the effect of GLP-1 infusion demonstrated an average reduction in calorie intake of 11.7%. This reduction in calorie intake is dose dependent and occurs in both obese and lean individuals (34). Evidence suggests GLP-1 secretion is reduced in obese subjects, and weight loss normalizes the levels (35). Reduced GLP-1 secretion could therefore contribute to the pathogenesis of obesity, and replacement may restore satiety. Obese subjects receiving sc GLP-1 for 5 d just before each meal reduced their calorie intake by 15% and lost 0.5 kg in weight (36).
OXM is also an effective anorectic peptide in human subjects. An infusion of OXM to normal-weight human subjects reduced immediate calorie intake by 19.3% and was effective at reducing food intake up to 12 h post infusion (37). Part of its anorectic effect may be via suppression of plasma ghrelin levels. Peripheral administration of OXM, at postprandial concentrations, reduces circulating ghrelin by around 15–20% in rodents and 44% in human subjects (37). It is possible that postprandial OXM release may contribute to the normal physiological inhibition of plasma ghrelin after meals. However, the longer-term actions of OXM on body weight, the circulating concentrations of OXM in obese subjects, and its actions on food intake in the obese remain unknown.
In addition to their effects on food intake, OXM and GLP-1 also augment postprandial insulin secretion, inhibit gastric acid secretion, and reduce gastric motility. GLP-1 has been found to up-regulate insulin gene expression and potentiate all steps of insulin biosynthesis. An iv infusion of GLP-1 is capable of normalizing blood glucose levels in patients with long-standing type 2 diabetes who cannot be controlled by sulfonylurea therapy (38). Furthermore, a 6-wk sc infusion of GLP-1 to type 2 diabetics normalized glycosylated fructosamine and reduced hemoglobin A1c by 1.3%. This infusion of GLP-1 was also found to reduce body weight by 2 kg (39). GLP-1’s function as an incretin hormone and its effect on body weight make it particularly useful in patients with type 2 diabetes, in whom obesity is often a significant problem. However, GLP-1 has been reported to cause hypoglycemia in nondiabetic subjects (40), which may limit its use as a treatment for simple obesity.
Both GLP-1 and OXM are thought to exert their effects via the GLP-1 receptor (GLP-1R). Specific antagonists of the GLP-1R, such as exendin (9–39), antagonize the effect of both GLP-1 and OXM (41). However, the affinity of OXM for GLP-1R is approximately 2 orders of magnitude less than that of GLP-1, yet they appear to be similarly efficacious at reducing food intake. It is possible there may be a separate OXM receptor not yet cloned. The GLP-1R is present in the nucleus of the solitary tract (NTS) in the brain stem and the hypothalamic arcuate nucleus. In addition to the CNS, GLP-1 Rs are also widespread in the periphery: in the pancreas, lung, brain, kidney, gastrointestinal tract, and heart.
The rapid breakdown of OXM and GLP-1 could limit their therapeutic usefulness. DPPIV cleaves the two N-terminal amino acid residues of GLP-1. The GLP-1 fragment is no longer bioactive and furthermore acts as an antagonist of the GLP-1R. Recent trials have shown that inhibition of DPPIV, to prolong the biological activity of GLP-1, may be an effective treatment for type 2 diabetes (42). Analogs of GLP-1, which are resistant to breakdown, and some albumen-based forms, with longer half-lives, are also in development. These compounds may prove useful as novel therapies for both type 2 diabetes and obesity.
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CCK |
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TopAbstractIntroductionHungerSatietyPeptide YY (PYY) and...GLP-1 and oxyntomodulin (OXM)CCKIntegration of signalsConclusionReferences |
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There are two distinct forms of receptors for CCK. Both receptors consist of seven-transmembrane spanning protein domains and are members of the G protein-coupled receptor family. In the rat, CCKA receptors are found in the pancreas, on vagal afferent and enteric neurons. CCKA receptors are also found throughout the brain, including the nucleus of the solitary tract, AP, and dorsomedial hypothalamus. CCKB receptors are distributed throughout the brain, are present in the afferent vagus nerve, and are found within the stomach.
As early as the 1980s, administration of CCK, to humans and animals, was known to inhibit food intake by reducing meal size and duration (44). This effect is enhanced by gastric distension. Although at high dose, nausea and taste aversion have been detected, at low dose, feeding is inhibited without these effects (45). It appears to be the CCKA receptor that mediates its effect on appetite (46). CCKA receptors bind with high affinity only to the sulfated form of CCK, and it is only this form that produces a suppression of food intake (44). It is thought that the reduction in food intake may be mediated by a paracrine or neurocrine effect because high concentrations of CCK, which occur only local to the site release, are required for activation (47). For instance, locally released CCK may increase vagal tone, without a significant increase in plasma CCK level.
As you would expect, CCKA receptor antagonists increase calorie intake and reduce satiety, suggesting endogenous CCK plays a role in appetite regulation (48). CCK alone may be a very short-term modulator of appetite. It has a half-life of only 1–2 min, and it is not effective at reducing meal size if the peptide is administered more than 15 min before a meal (44). However, Matson et al. (49) demonstrated greater body weight loss with a combination of peripheral CCK and central leptin administration than with central leptin administration alone. Thus, the short-term meal terminator CCK may interact with leptin, a long-term signal of adiposity.
The use of CCK as a potential novel obesity therapy is in some doubt. In animals, repeated preprandial administration of CCK does reduce food intake but is seen to increase meal frequency, with no resulting effect on body weight (50). Continuous administration of CCK is ineffective after the first 24 h (51). However, there is further evidence for a more long-term effect on energy balance. Chronic administration of either CCK antibodies or CCKA antagonists does result in weight gain in rodent models but with no significant increase in food intake (52, 53). In addition, the CCKA receptor knock-out rat (but not the knockout mouse) is hyperphagic and obese (54).
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Integration of signals |
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TopAbstractIntroductionHungerSatietyPeptide YY (PYY) and...GLP-1 and oxyntomodulin (OXM)CCKIntegration of signalsConclusionReferences |
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It is vital that hunger and satiety signals from both gut and adipose tissue are integrated to provide efficient energy homeostasis (Fig. 3). Signals from these peripheral organs converge on the CNS, most importantly on the hypothalamus. Here the arcuate nucleus is thought to play a pivotal role in integration of signals regulating appetite. There are postulated to be two populations of neurones controlling appetite within the arcuate nucleus. One neuronal circuit, consisting of neurones that coexpress proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript, inhibits food intake. The other circuit coexpresses NPY and agouti-related peptide (AgRP) and stimulates food intake (55).
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Gut hormones may also work indirectly to influence the activity of afferent neuronal pathways and brain stem circuits, which in turn project to the arcuate nucleus. CCK, for instance, acts on the vagus nerve (56), which projects to the brain stem NTS and in turn relays information to the hypothalamus. Similarly, the GLP-1R-expressing neurones of the NTS project forward to hypothalamic regions involved in appetite control such as the arcuate, dorsomedial, and paraventricular nucleus. Ghrelin’s orexigenic effects may be mediated both via direct actions on the arcuate NPY/AgRP neurones that express GHS-R (7) and indirectly via the vagus. However, it seems the postprandial reduction in levels and the response to fasting may be mediated via different anatomical pathways. Vagotomy can prevent the elevation of ghrelin levels secondary to food deprivation but does not affect the basal circulating level or the suppression secondary to nutrient load (57). Thus, the pathways that regulate different aspects of feeding may be dissociated.
Complex reciprocal circuits between the hypothalamus and brain stem enable signals from many circulating peptides to be integrated by arcuate neuronal populations that in turn regulate appetite and energy expenditure.
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Conclusion |
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TopAbstractIntroductionHungerSatietyPeptide YY (PYY) and...GLP-1 and oxyntomodulin (OXM)CCKIntegration of signalsConclusionReferences |
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Footnotes |
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Abbreviations: AgRP, Agouti-related peptide; AP, area postrema; BBB, blood-brain barrier; CCK, cholecystokinin; CNS, central nervous system; DPPIV, dipeptidyl peptidase IV; GHS-R, GH secretagogue receptor; GLP-1, glucagon-like peptide 1; GLP-1R, GLP-1 receptor; NPY, neuropeptide Y; NTS, nucleus of the solitary tract; OXM, oxyntomodulin; POMC, proopiomelanocortin; PP, pancreatic polypeptide; PYY, peptide YY.
Received February 4, 2004.
Accepted March 23, 2004.
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TopAbstractIntroductionHungerSatietyPeptide YY (PYY) and...GLP-1 and oxyntomodulin (OXM)CCKIntegration of signalsConclusionReferences |
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