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Endocrinology Vol. 145, No. 6 2660-2665
Copyright © 2004 by The Endocrine Society

MINIREVIEW

Minireview: Gut Peptides Regulating Satiety

Maralyn R. Druce, Caroline J. Small and Stephen R. Bloom

Department of Metabolic Medicine, Division of Investigative Science, Imperial College London, Hammersmith Campus, London W12 ONN, United Kingdom

Address all correspondence and requests for reprints to: Stephen R. Bloom, Department of Metabolic Medicine, Division of Investigative Science, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 ONN, United Kingdom. E-mail: s.bloom{at}imperial.ac.uk.

Abstract

The gastrointestinal tract and the pancreas release hormones regulating satiety and body weight. Ghrelin stimulates appetite, and glucagon-like peptide-1, oxyntomodulin, peptide YY, cholecystokinin, and pancreatic polypeptide inhibit appetite. These gut hormones act to markedly alter food intake in humans and rodents. Obesity is the current major cause of premature death in the United Kingdom, killing almost 1000 people per week. Worldwide, its prevalence is accelerating. There is currently no effective answer to the pandemic of obesity, but replacement of the low levels of peptide YY observed in the obese may represent an effective antiobesity therapy.

OBESITY AND ITS associated complications present significant public health problems. The prevalence has increased by over 75% worldwide since 1980 (1) while in the United Kingdom, treatment of the complications associated with obesity costs the National Health Service over 0.5 billion pounds per year (2). Many advances have been made recently in the understanding of the homeostatic system that regulates body weight.

Despite the increase in population obesity, in an individual person energy balance is tightly regulated. For most people, the amount and composition of food eaten varies considerably from meal to meal and from day to day. Yet over time, energy intake is matched to expenditure, and body weight is tightly conserved. Thus, food intake, both meal frequency and meal size, must also be highly regulated.

One part of this system involves signals of body energy reserves. These include insulin and leptin, which are released into the blood in proportion to the amount of body fat and inhibit food intake. Another component of the system is the control of feeding by the gastrointestinal tract. Hunger signals trigger eating, and satiety signals inhibit appetite for a period thereafter. Together, these control frequency of eating and meal size, and hence total energy intake. The gut hormones ghrelin, peptide YY (PYY), pancreatic polypeptide (PP), oxyntomodulin (Oxm), cholecystokinin, and glucagon-like peptide-1 (GLP-1) may all play a role. The sites of production of these hormones are summarized in Fig. 1Go.



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  		FIG. 1. Schematic summary of the central pathways involved in appetite regulation.

 
Central Pathways Involved in Appetite Regulation

Long-term and short-term hormonal signals from the periphery act on the central nervous system to influence feeding behavior. The main regions involved are the hypothalamus, in particular the arcuate nucleus, and the dorsal vagal complex in the brain stem (3, 4). The interactions between these areas are summarized in Fig. 2Go.



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  		FIG. 2. Hormones produced by the gut. Those shown in bold are known to alter food intake and body weight.

 
The arcuate nucleus integrates signals from the periphery (it is accessible to circulating factors because the blood-brain barrier is incomplete here) and from the brain stem (5, 6). The arcuate nucleus contains two distinct subsets of neurons controlling food intake. One acts as a stimulus to feeding; these neurons contain neuropeptide Y (NPY) and agouti-related peptide. The products of these neurons stimulate food intake when injected into the central nervous system. The second subset of neurons acts as an inhibitor; these contain {alpha}-MSH and cocaine- and amphetamine-regulated transcript (CART). Direct administration of either {alpha}-MSH or CART into the central nervous system inhibits food intake. Typically, when one of these subsets is activated, the other is inhibited. The neurons are responsive to circulating hunger and satiety signals such as ghrelin, cholecystokinin, and PYY. They are also modulated by signals of long-term body energy stores such as leptin and insulin (4).

From the arcuate, neurons project to the paraventricular nucleus, the dorsomedial nucleus, and along the neuraxis from the olfactory nucleus to the nucleus tractus solitarius. The paraventricular nucleus coordinates outputs for feeding, energy metabolism, and the sympathetic nervous system and endocrine axes. It also receives inputs from the melanin-concentrating hormone projections from the lateral hypothalamus (which is a stimulator of feeding), the brain stem, and the amygdala that have an impact on food intake (7, 8).

How Your Gut Tells You It’s Time to Eat

Ghrelin
Many cues for meal initiation are learned by association. Endocrine signals are also involved. Ghrelin is a hormone synthesized in the stomach (9), and both the expression and circulating levels are up-regulated by fasting (10, 11). Ghrelin is the endogenous ligand for the GH secretagogue receptor (12, 13), which is expressed in hypothalamic and brain stem nuclei including the arcuate nucleus (14). The structure of ghrelin is highly conserved across species, suggesting an important physiological role.

In rodents, ghrelin is a potent stimulus to feeding, with a maximum effect observed within 1 h of peripheral administration (11, 15). The resultant plasma levels are comparable to those observed after a 24-h fast (11). Ghrelin levels are influenced by gut nutrients rather than gastric distension, with fasting ghrelin levels being suppressed by an oral glucose load but not altered by the same volume of water (16). Chronic ghrelin administration induces adiposity (11, 16) without attenuation of the effects on food intake (11, 15). Ghrelin also has local gut effects in addition to its effects on appetite, stimulating gastric emptying and decreasing gastric acid secretion in rodents (17). It has also been reported to reverse the temporary paralysis of the gut (ileus) observed after abdominal surgery (18).

Human data also support a role for ghrelin in appetite regulation (19). As in rodents, ghrelin is principally secreted by the stomach, with levels in gastrectomy patients around 35% of those of age-matched controls (20). Plasma levels are high in the fasted state and fall after eating (21). Exogenous infusion of ghrelin increases food intake at a buffet meal by 28% in human subjects, compared with a saline control day (19). Despite the increased food intake, there is no difference in satiety after the meal, and total food intake on the ghrelin day is more than on the control day (19).

A role for ghrelin in the etiology of human obesity has been proposed. Ghrelin has an inverse relationship with body mass index and is significantly lower in obese subjects compared with lean (22). Ghrelin is the "hormone of hunger," and this picture would fit with the notion of homeostatic control of body weight; high circulating ghrelin in thin individuals would favor increased food intake and positive energy balance. Weight loss in obese people results in an elevation in ghrelin level (23), which may contribute to the difficulty seen in maintaining body weight after weight loss. Food fails to suppress ghrelin levels in obese humans (24), which again could impair postprandial satiety and contribute to overeating. Indeed, individuals with Prader Willi syndrome have grossly elevated ghrelin levels, and this could be a cause of the hyperphagia (25). Mutations in the ghrelin gene have been identified in man, but a role for these in weight determination remains controversial (26, 27, 28).

How Your Gut Tells You You’ve Eaten Enough

PYY
PYY is a peptide belonging to the NPY family. It is produced by the gut and is released into the circulation after meals (29, 30). The main form of PYY both stored and in circulation is PYY 3-36 (31), and this is an N-terminally truncated form of the full-length peptide.

Peripheral administration of PYY was first reported in 1993 to decrease appetite (32). In addition, when PYY 3-36 is administered peripherally to mouse, rat, or human, there is marked inhibition of food intake (30, 33). The pattern of c-fos expression in the brain after peripheral administration of PYY 3-36 shows a marked induction of c-fos in the arcuate nucleus. Injection of PYY 3-36 directly into the arcuate nucleus inhibits food intake, and chronic administration of PYY 3-36 leads to a decrease in food intake and body weight. Addition of PYY 3-36 to ex vivo hypothalamic explants inhibits release of NPY and stimulates release of {alpha}-MSH. Peripheral administration of PYY 3-36 in rats causes a decrease in expression of arcuate NPY mRNA. PYY 3-36 has a high affinity for the Y2 receptor (Y2R), a member of the NPY family of G protein-coupled receptors. Inhibition of appetite is also seen with a Y2R-specific agonist and is absent in the Y2R knockout mouse (30, 33). It appears that circulating PYY 3-36 inhibits appetite by acting directly on the arcuate nucleus via the Y2R, a presynaptic inhibitory auto receptor (30, 33).

In humans, food intake in a free-choice meal is reduced by 30% after an iv infusion of PYY 3-36, which results in plasma levels similar to those achieved physiologically after a meal (30, 33). Obese subjects have lower basal fasting PYY 3-36 levels and a smaller rise in postprandial levels (34). Obesity does not appear to be associated with resistance to PYY (as it is with leptin), and exogenous infusion of PYY 3-36 results in a reduction in food intake by 30% in an obese group and 31% in a lean group (34).

After a meal, PYY is released shortly after food intake; this is likely to be under neural control because it occurs before ingested nutrients reach the distal small intestine and colon, where the greatest concentrations of PYY 3-36 are found (29, 35). Further release is seen when the nutrients arrive at this region of gut and is particularly stimulated by carbohydrates and lipids. PYY is likely to affect appetite via a direct central effect and also via its effects on gut motility; it acts as an "ileal brake" and so leads to a sensation of fullness and satiety (30, 33).

PP
PP is a 36-amino acid peptide from the NPY family. It is produced in the pancreatic islets (36). The amount of PP release is dependent on the digestive state: release is low when fasted and increased throughout all phases of digestion (37, 38, 39).

Evidence from rodents for a role for PP in appetite control includes the finding that chronic ip administration of PP to genetically obese mice reduces food intake and weight gain (40). Mice that overexpress PP have reduced food intake and body mass (41). PP reduces food intake in both obese and lean mice, with the obese mice being less sensitive to its effects (42), but this finding is not always replicated (43). Whether these findings mirror a physiological role is unclear.

In humans, obese individuals with Prader-Willi syndrome have low basal and meal-stimulated levels of PP, and exogenous administration of iv PP reduces food intake (44). PP administration to normal-weight individuals reduces food intake by a mean of 21.8% at a free-choice buffet meal, and this reduction in intake was maintained until the morning after the infusion (37).

Oxm
Oxm is produced by processing of preproglucagon in the gut and brain and is released after eating (45, 46, 47, 48). Central administration of Oxm inhibits food intake in the rat with greater potency than does GLP-1 (49). Oxm appears to act via a GLP-1-like receptor because its anorectic actions are blocked by coadministration of the GLP-1 receptor antagonist, exendin 9-39 (49).

Recently, it was shown that Oxm is also a potent inhibitor of food intake when administered ip to rats (49A ). Intraperitoneal administration of Oxm results in c-fos expression in the arcuate nucleus, a region partially outside the blood-brain barrier, but there is little activation of neurons in the nucleus of the solitary tract in the brain stem. These experiments demonstrate that Oxm has a very different pattern of neuronal activation from that of GLP-1. When the antagonist exendin 9-39 is injected into the arcuate nucleus, circulating Oxm no longer inhibits food intake, suggesting an arcuate site of action. By contrast, the effect of circulating GLP-1, acting via the brain stem, is unaffected.

In humans, iv infusion of Oxm reduces food intake at a free-choice buffet meal by 19.3%, with the total calorie intake remaining lower at 12 h after infusion (50). Further work is needed to establish a role physiologically for reduction in appetite after a meal and for homeostatic regulation of body weight.

GLP-1
Like Oxm, GLP-1 is produced by processing of the proglucagon gene in the gut and the brain, and GLP-1 (7-36) amide is the active truncated form of this peptide (45, 46, 47, 48). Feeding releases GLP-1 from the gut and into the circulation. GLP-1 acts on the pancreas to cause insulin release (51, 52, 53) but also has effects on appetite (Ref. 54 ; for extensive review, see Ref. 55).

In rodents, peripheral administration inhibits food intake, and the expression of the early gene c-fos is increased in the brain stem (56). This contrasts with the probable arcuate site of action of Oxm. Central administration also inhibits food intake, and the specific GLP-1 receptor antagonist exendin 9-39 leads to increased food intake (54).

The role for GLP-1 in physiological control of human appetite is not clear. Peripheral administration does inhibit food intake in normal individuals (57), in diabetics (58, 59), and in nondiabetic obese men (60). However, when infusions achieve levels comparable to those seen in the physiological state after meals, the effect on appetite and food intake is small (61, 62).

Some reports have suggested that GLP-1 secretion is reduced in obese subjects, and weight loss normalizes the levels (61). However, other findings do not support these observations (63, 64, 65, 66). The anorectic effects of GLP-1 are, however, preserved in obesity. Prandial sc GLP-1 given for 5 d to obese, but otherwise healthy, human subjects results in a reduction of calorie intake of 15% and weight loss of 0.5 kg (67). A reduced secretion of GLP-1 could therefore contribute to the pathogenesis of obesity, and agonists of the GLP-1 receptor are potential targets for treatment. The therapeutic potential of GLP-1 is limited by its rapid breakdown. GLP-1 is deactivated by dipeptidyl peptidase IV, which cleaves off the two N-terminal amino acid residues. Recent trials have shown that inhibition of dipeptidyl peptidase IV may be an effective treatment for type II diabetes mellitus (68) but does not affect weight. Various resistant analogs in development such as exendin 4 (69) (exenatide, Amylin Pharmaceuticals, Inc., San Diego, CA) and albumin-based forms such as Liraglutide (70, 71) (Novo Nordisk, Bagsvaerd, Denmark) may improve glycemic control and reduce body weight.

Signals of Long-Term Energy Stores

The adipocyte hormone leptin was first discovered in 1994 (72). It circulates at concentrations proportional to body fat mass and inhibits food intake (73). It acts on the arcuate nucleus to stimulate the anorexigenic neurons and inhibit the orexigenic population (74) and modulates the effects of the shorter-term circulating signals. It plays an important part in the homeostatic control of body-fat mass and in particular in the response to fasting (75). In addition, some leptin has now been shown to be secreted by the gastrointestinal tract and, contentiously, may also function as a gut hormone (76, 77). Insulin also circulates at levels proportional to fat mass and is also likely to function as another adiposity signal (78). The levels of the long-term signals of body adiposity, e.g. leptin and the postprandial levels of gut hormones, e.g. ghrelin and PYY, influence the activity of the NPY/agouti-related peptide and proopiomelanocortin/CART neurons in the arcuate nucleus. The activity of these two neuronal populations increases or decreases the drive to eat and integrates both the long-term and short-term circulating signals of nutritional status.

Clinical Applications

Evidence suggests that the gut acts as a nutriment sensor, resulting in the release of several hormones. These signal hunger or satiety, and these messages integrate with signals of long-term energy stores to control feeding behavior. Thus, energy intake and hence body weight are tightly regulated.

The homeostatic control of body weight makes obesity an intractable problem for the individual. Several approaches are currently used to treat obesity, but all have associated problems, and many, in particular pharmacological agents such as orlistat and sibutramine, have limited effectiveness (79, 80). In contrast, gastric and intestinal bypass surgery can result in lasting weight loss (81). After such surgery, malabsorption, if it occurs, is temporary, yet the appetite effects may last many years, and this may be due to the alterations in hormonal milieu with changes in several of the signals known to affect appetite. For example, ghrelin is reduced, and the usual peaks before meals are no longer seen (21, 82), whereas PYY is increased (83).

Alteration of the levels of hormones controlling appetite by means other than surgery may thus prove equally successful at reducing food intake and body weight. Evidence from humans at present mostly has used single iv infusions. This method would clearly be impractical for long-term therapy, but results after chronic administration by other means such as sc injections, pumps, and other routes are awaited.

Footnotes

Abbreviations: CART, Cocaine- and amphetamine-regulated transcript; GLP-1, glucagon-like peptide-1; NPY, neuropeptide Y; Oxm, oxyntomodulin; PP, pancreatic polypeptide; PYY, peptide YY; Y2R, Y2 receptor.

Received January 26, 2004.

Accepted for publication March 8, 2004.

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