Endocrine Unit, Imperial College Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London W12 ONN, United Kingdom
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ABSTRACT |
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GLP-1 AND OXM |
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In the pancreas, the glucagon sequence is cleaved out, whereas the part containing the GLP-1 and -2 is secreted as a single, large inactive peptide. The posttranslational processing in the gut and brain are similar. The glucagon sequence remains in a larger peptide, glicentin, thought to be inactive. The two GLPs are cleaved out and secreted separately. Glicentin is later cleaved into gincentin-related pancreatic peptide (GRPP) (inactive NH2-terminal fragment) and OXM (Fig. 1).
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OXM and GLP-1 are released from the L cells of the distal small intestine, 530 min after food ingestion and in proportion to meal calorie intake. The secretion of OXM may be in response to fat that has undergone hydrolysis to fatty acids within the gut. L cells may coexpress other anorexigenic peptides such as PYY(336) and cholecystokinin.
Increasing plasma levels of GLP-1 and OXM result in postprandial satiety. The raised plasma levels of the two gut hormones also inhibit gastric acid secretion and motility.
GLP-1 has been shown to decrease calorie intake in animal models by administration intracerebroventricularly and directly into the hypothalamic paraventricular nucleus (PVN) (8, 19). Chronic administration via this route produces weight loss in rodents (15).
In human subjects, peripheral administration of GLP-1 via an intravenous route results in satiety. An infusion of OXM to normal-weight human subjects produced a reduction in calorie intake of 19.3% (6). A recent meta-analysis of the effect of GLP-1 infusion demonstrated an average reduction in calorie intake of 11.7% (21). The reduction in calorie intake is dose dependant and does not differ between obese and lean individuals.
Both GLP-1 and OXM may exert their effects via the GLP-1 receptor (GLP-1R). Exendin 939, an antagonist at the GLP-1R, opposes the effect of GLP-1 and OXM. However, the affinity of OXM for GLP-1R is approximately two orders of magnitude weaker than that of GLP-1, even though OXM exerts a comparable effect on food intake. It is therefore possible that there may be a separate OXM receptor that has not yet been cloned.
The feeling of satiety produced by OXM and GLP-1 is likely due to their effects on the CNS as well as their effect on gastric emptying. The GLP-1 receptor is present in the NTS and arcuate region. The NTS receives afferent input from the vagal and glossopharngeal nerves and integrates both neuronal and humoral factors. This area is also able to synthesize GLP-1; thus the GLP-1-containing neurones may influence their own activity.
GLP-1 containing neurones of the NTS project to the arcuate nucleus and hypothalamic nuclei, such as the dorsal medial nucleus (DMN) and PVN, which are involved in appetite control. There are two populations of neuronal circuits within the arcuate. One circuit inhibits food intake and consists of neurones that coexpress proopiomelanocortin (POMC), and cocaine and amphetamine-regulated transcript. The other circuit, coexpressing neuropeptide Y (NPY) and agouti-related peptide, stimulates food intake (7). The GLP-1 projections may act on these neurones to inhibit appetite. There is also evidence that the arcuate is influenced by GLP-1 from the periphery via the area postrema and subfornical organ (17). Thus there are several routes by which the gut can communicate with appetite circuits.
OXM may also exert its effects on appetite via suppression of ghrelin, an orexigenic peptide produced by endocrine cells in the oxyntic glands of the stomach. OXM administration, producing plasma concentrations comparable with postprandial levels, reduces ghrelin by 44% in human subjects (6).
Evidence suggests GLP-1 secretion is reduced in obese subjects and weight loss normalizes the levels (22). The anorectic effects of GLP-1 are, however, preserved in obesity. A reduced secretion of GLP-1 could therefore contribute to the pathogenesis of obesity, and OXM and GLP-1 are potential targets for treatment.
In addition to their effects on satiety, OXM and GLP-1 also promote meal-induced insulin secretion. GLP-1 has been found to upregulate insulin gene expression and potentiate all steps of insulin biosynthesis. An intravenous infusion of GLP-1 is capable of completely normalizing blood glucose levels in patients with long-standing type 2 diabetes who cannot be controlled by sulphonylurea therapy. Furthermore, a 6-wk subcutaneous infusion of GLP-1 to type 2 diabetics normalizes glycosylated fructosamine and reduces HbA1c by 1.3%. This infusion of GLP-1 was also found to reduce body weight by 2 kg (23). This potential therapeutic application is particularly useful in type 2 diabetes where obesity is commonly a significant issue.
The therapeutic potential of these gut hormones is limited by their rapid breakdown. GLP-1 is deactivated by dipeptidyl peptidase IV (DPP-IV), which cleaves off the two NH2-terminal amino acid residues, transforming the peptide into an antagonist of the GLP-1 receptor. However, recent trials have shown that inhibition of DPP-IV may be an effective treatment for type II diabetes mellitus. Various resistant analogs in development, such as exendin 4 (exenatide, Amylin), and albumin-based forms, such as Liraglutide (NovoNordisk), may improve glycemic control and reduce body weight.
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PP AND PYY |
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However, there are important differences between PP and PYY. Despite their overall high homology, the NH2 terminus of PP has little similarity to that of PYY. As a consequence, PP interacts poorly with membrane phospholipids and, unlike PYY, does not readily cross the blood-brain barrier (BBB). In animal models, increasing plasma PP concentrations in response to food intake or by infusion does not alter cerebrospinal fluid (CSF) PP levels. In contrast, PYY crosses the BBB freely by nonsaturable mechanisms. A further difference is the presence of an additional 34-amino acid form of PYY, PYY(336), created by cleavage of the NH2-terminus Tyr-Pro residues by DPP-IV.
Five cloned receptors for the PP-fold peptide family have been described, Y1Y5 (nomenclature as recommended by International Union of Pharmacology) (13). They are all seven transmembrane domain receptors coupled to Gi resulting in inhibition of adenylate cyclase. However, Y1 also increases intracellular calcium, and Y2 regulates both calcium and potassium channels.
The receptors are classified according to their affinity for PYY, PP, and NPY fragments and analogs and have diverse distributions and functions (see Table 1 for summary).
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Whereas PYY binds with high affinity to all Y receptors, PYY(336) shows selectivity for Y2 and Y5 receptors. In contrast, PP binds with greatest affinity to Y4 receptors, where its affinity is greater than that of PYY, but also to Y5 receptors.
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DISTRIBUTION OF PP AND PYY |
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In contrast to PP, PYY is widely expressed throughout the gastrointestinal tract in endocrine cells where it is colocalized with GLP-1. PYY immunoreactive cells are almost absent in the stomach, relatively few in the duodenum and jejunum, but dramatically increased in frequency in the ileum and colon, and are at very high levels in the rectum. PYY has been described in the myenteric plexus and endocrine pancreas of many species, but not in humans. PYY immunoreactivity has also been reported in human adrenal medulla. PYY is present in the CNS, with PYY immunoreactive nerve terminals in the hypothalamus, medulla, pons, and spinal cord (9).
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REGULATION OF PP AND PYY RELEASE. |
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Both diurnal and postprandial PP release appears to be regulated by vagal tone. Propantheline blocks the diurnal changes in plasma PP seen in fasting and reduces postprandial release by 60%, whereas vagotomy abolishes postprandial PP release.
Although ingestion is the main stimulus to PP release, other factors have also been shown to alter circulating PP concentrations. Adrenergic stimulation, for example, due to hypoglycemia or exercise, increases plasma PP concentrations. Other pancreatic and gastrointestinal hormones also regulate circulating PP levels. Ghrelin, motilin, and secretin rapidly stimulate PP release, whereas somatostatin and its analogs significantly reduce plasma PP concentrations.
PYY is also released into the circulation in response to food intake, rising to a plateau after 12 h. Release is partly proportional to calorie intake but also influenced by meal composition. Higher plasma concentrations are seen following isocaloric meals of fat compared with intake of protein or carbohydrate. In addition to nutrients, PYY release is also stimulated by gastric acid, cholecystokinin, and infusion of bile acids into the ileum or colon in animal studies. Unlike PP, PYY is not released by gastric distension. An intraduodenal meal increases plasma PYY even before nutrients have reached the PYY-containing cells of the ileum. This suggests release through a neural reflex, probably via the vagus.
Other factors also alter circulating PYY. Plasma PYY concentrations are increased by insulin-like growth factor-1, bombesin, and calcitonin gene-related peptide and decreased by GLP-1.
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ACTIONS OF PP |
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The effects of PP on appetite in humans were first examined in subjects with Prader-Willi syndrome, characterized by obesity and marked hyperphagia. Food intake was reduced during intravenous infusion of PP (5). Recently, PP has also been shown to alter appetite in normal-weight individuals. As in rodents, PP infusion resulted in a rapid reduction in food intake, after just 2 h, but also a prolonged action decreasing food intake over the following 24 h (4). However, PP does not appear to alter gastric emptying in humans.
In contrast to the anorectic effects of peripheral PP, central PP administration increased food intake in animal models. Third-ventricle injection of human PP stimulated daytime food intake in satiated rats. Similarly, central injection of PP has the opposite effect to peripheral administration on gastric motility, stimulating rather than inhibiting gastric emptying.
The divergent actions of central and peripheral PP on appetite probably reflect the differential receptor activation. PP is unable to cross the BBB and therefore enters the CNS via regions that have a deficient BBB, such as the area postrema. After intravenous administration, autoradiographic studies demonstrate PP accumulation in the area postrema (AP) and expression of the early gene c-fos is seen in the AP following peripheral administration. Y4 receptors are highly expressed in this region, suggesting that the anorectic actions of PP are mediated by this receptor. The central Y receptors mediating the feeding effects of PP are unclear. Whereas PP binds with high affinity to Y4 receptors, human and bovine PP (but not rat PP) also bind to Y5 receptors. The orexigenic effects of PP are blunted in Y5-/- transgenic mice but not by Y5 receptor antisense oligonucleotides, and the role of Y4 receptors in PP's central stimulation of food intake has not been confirmed (see Ref. 11 for review).
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ACTIONS OF PYY |
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The actions of peripheral PYY(336) on satiety appear to be mediated by the Y2 receptor expressed in the hypothalamic arcuate nucleus. PYY(336) increased arcuate expression of the early gene c-fos, its peripheral actions were mimicked by intra-arcuate injection of PYY(336) and a selective Y2 agonist also reduced food intake. In addition, the effects of PYY(336) were abolished in Y2-/- mice. The arcuate Y2 receptor acts as a presynaptic inhibitor receptor. Activation of this receptor by PYY(336) reduced NPY expression and release. Arcuate NPY inhibits the activity of anorectic POMC neurons. This brake on POMC neurons is therefore reduced by PYY(336) binding to arcuate presynaptic Y2 receptors allowing increased POMC neuronal activity and hence a reduction in appetite.
PYY also has direct effects on adipocytes, reducing lipolysis in vitro. Other actions of peripherally administered PYY included decreasing glomerular filtration rate, reduction in plasma renin activity, and, in aldosterone, vasoconstriction and a fall in cardiac output.
In common with PP, PYY administration to the CNS has opposite actions to patients seen with peripheral PYY. PYY injections into the third, lateral, or fourth cerebral ventricles, into the paraventricular nucleus, or into the hippocampus potently stimulated food intake in rodents. Intracerebroventricular PYY(336) injection also stimulated food intake; PYY binds with high affinity to Y1, Y2, and Y5 receptors, and PYY(336) binds with high affinity to Y2; and with less avidity to Y1 and Y5 receptors. The effects of PYY(336) on food intake are diminished in both Y1-/- mice and in Y5-/- mice, suggesting these receptors play a role in central PYY(336)-mediated food intake (see Ref. 10 for review). Administration of PYY in the dorsal vagal complex stimulated gastric acid secretion, again the opposite effect to that seen following peripheral administration.
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PP AND PYY IN DISEASE |
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The effects of gastrointestinal disease on plasma PYY are diverse. Elevated basal plasma PYY is seen in those with celiac disease, hepatic cirrhosis, previous ileal resection, or symptomatic Crohn's disease. However, tissue concentration of PYY is reduced in Crohn's disease. The changes in plasma PYY reported in active ulcerative colitis vary, being described either as unchanged compared with controls or decreased and with reduced tissue concentrations. The number of colonic PYY-immunoreactive cells is increased in diabetic patients with gastroparesis.
The effects of gastrointestinal surgery are also variable and depend partly on the site of resection. Gastrectomy increased plasma PYY. Ileal resection raised both PYY and PP concentrations, but colonic resection has been variously reported to reduce or increase plasma PYY. PP release is blunted in subjects with chronic pancreatitis, but plasma PYY is increased in postpancreatectomy patients. Gastric bypass has no effect on basal or meal-stimulated PP but increases basal and postprandial PYY.
The most interesting changes in circulating PP and PYY are those seen at extremes of body weight. Plasma PP was increased in individuals with anorexia nervosa. The circulating levels of PYY in eating disorders are not known, but CSF PYY is raised in those with bulimia nervosa. The effects of obesity on circulating concentrations of PP are conflicting; whereas some report suppressed plasma PP, others have found no difference between lean and obese subjects or between obese subjects before and after weight loss. However, in morbidly obese children with Prader-Willi syndrome, both basal and meal-stimulated PP release are diminished. Circulating PYY is suppressed in patients with morbid obesity and rises to levels seen in nonobese subjects after gastric banding.
In conclusion, the physiological roles of GLP-1, OXM, PP, and PYY are diverse. Recent work suggests their actions are not limited to regulation of gut secretions and motility but that they also play an important role in appetite regulation. Plasma concentrations of GLP-1, PP, and PYY are reduced at extremes of body weight and could contribute to increasing adiposity. All have been shown to be effective in reducing food intake in humans, and, importantly, for both GLP-1 and PYY(336), these actions are preserved in obese individuals. Whether these peptides are also effective as long-term modulators of appetite and body weight remains to be seen. At present, their potential is limited by short half-life and the need for parenteral administration. However, compounds based on GLP-1, OXM, PYY, and PP may offer novel effective treatments for obesity.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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