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Ghrelin is released by proximal gastrointestinal X/A cells and increases appetite. It is stimulated by the sympathetic nervous system and inhibited by high glucose and insulin levels. The gastrointestinal L cell releases GLP-1, GLP-2, oxyntomodulin, and PYY in response to nutrient ingestion. These hormones have various roles in nutrient homeostasis such as enhancing nutrient absorption and suppressing appetite. Dysregulation of these hormones is implicated in obesity and diabetes, and manipulating their levels through surgical or pharmacological means may provide clinical benefits.
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Nrgastro.2012.185
- 1. REVIEWS Ghrelin, the proglucagon-derived peptides and peptide YY in nutrient homeostasis Charlotte X. Dong and Patricia L. Brubaker Abstract | Dysregulation of nutrient homeostasis is implicated in the current epidemics of obesity and type 2 diabetes mellitus. The maintenance of homeostasis in the setting of repeated cycles of feeding and fasting occurs through complex interactions between metabolic, hormonal and neural factors. Although pancreatic islets, the liver, muscle, adipocytes and the central nervous system are all key players in this network, the gastrointestinal tract is the first tissue exposed to ingested nutrients and thus has an important role. This Review focuses on several of the endocrine hormones released by the gastrointestinal tract prior to or during nutrient ingestion that have key roles in maintaining energy balance. These hormones include the gastric orexigenic hormone, ghrelin, and the distal L cell anorexigenic and metabolic hormones, glucagon-like peptide (GLP)‑1, GLP‑2, oxyntomodulin and peptide YY. Each of these hormones exerts a distinct set of biological actions to maintain nutrient homeostasis, the properties of which are currently, or might soon be, exploited in the clinic for the treatment of obesity and type 2 diabetes mellitus. Dong, C. X. & Brubaker, P Nat. Rev. Gastroenterol. Hepatol. 9, 705–715 (2012); published online 2 October 2012; . L. doi:10.1038/nrgastro.2012.185 Introduction A complex interplay of metabolic, hormonal and neural factors is required to maintain nutrient homeostasis under a wide variety of environmental conditions includ ing, most notably, the daily cycle of feeding and fasting. Although pancreatic islets, the liver, muscle, adipocytes and the central nervous system (CNS) are all key players in this network, the gastrointestinal tract is the first tissue affected by nutrient ingestion. As dysregulation of nutri ent homeostasis might be linked to the current epidemics of obesity and type 2 diabetes mellitus, this Review focuses on several of the hormones released by the gastrointestinal tract prior to or during nutrient ingestion that have key roles in maintaining energy balance. Many gastrointestinal hormones have now been iden tified,1 making the gut the largest endocrine organ of the body; most of these hormones are produced by entero endocrine cells scattered throughout the gastrointestinal epithelium. 2 These cells were originally classified as being either ‘open’ or ‘closed’ to the intestinal lumen on the basis of the presence or absence of microvilli on the luminal surface.3 Some enteroendocrine cells are also directly innervated and/or extend long ‘axonal-like’ pro cesses into the lamina propria, both of which probably permit direct interactions with the nervous system.4,5 These findings are consistent with the expression of multiple entero ndocrine hormone receptors by the e Competing interests C. X. Dong declares no competing interests. P Brubaker . L. declares associations with the following companies: Eli Lilly; Merck, Sharp & Dome; NPS Pharmaceuticals. See the article online for full details of the relationships. vagus nerve.6 Open-type enteroendocrine cells seem to ‘sense’ luminal nutrients through multiple mechanisms, including both classic transporters and membranebound nutrient receptors, through which intracellular signalling pathways are activated.7 Collectively, these findings indicate the existence of a highly inter-related network between luminal nutrients, gut hormones and the nervous system. Two enteroendocrine cells have been selected for this Review on the basis of the demonstrated importance of their constituent hormones to whole body energy homeo tasis, as well as on the basis of their actual or s potential use in the treatment of the prevalent syndromes of nutrient dysregulation, obesity and type 2 diabetes mellitus. These two cells are the proximal X/A-like cell, which releases ghrelin, and the distal L cell, which pro duces the proglucagon- erived peptides, glucagon-like d peptide (GLP)‑1, GLP‑2 and oxynto odulin, as well as m peptide YY (PYY). Of note, although all of these peptides are also synthesized in the brain, the focus of this Review is on the gastro ntestinal tract as the major source of i these hormones in the peripheral circulation. Finally, the focus of this Review on these specific peptides does not discount the key contributions of other gut hormones to nutrient homeostasis, including glucose-dependent insulino ropic peptide (GIP) and cholecystokinin.8,9 t Indeed, develop ental, functional and compensatory m relationships between ghrelin, GLP‑1, GLP‑2, PYY, GIP and cholecystokinin have been reported,8,10,11 indicat ing that the gastrointestinal hormones function in a highly integrated fashion to optimize nutrient digestion, absorption and assimilation. NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY © 2012 Macmillan Publishers Limited. All rights reserved Department of Physiology, Medical Sciences Building, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada (C. X. Dong, P. L. Brubaker). Correspondence to: P Brubaker . L. p.brubaker@utoronto.ca VOLUME 9 | DECEMBER 2012 | 705
- 2. REVIEWS Key points ■■ Enteroendocrine cells in the gastrointestinal tract produce various hormones that have essential roles in the maintenance of nutrient homeostasis in both the fasting and fed states ■■ Ghrelin is an orexigenic peptide released by the proximal X/A-like cells prior to nutrient ingestion; the enteroendocrine L cells release glucagon-like peptide (GLP)‑1, GLP‑2, oxyntomodulin and peptide YY (PYY) in response to nutrient ingestion ■■ GLP‑1 is a key incretin hormone, which also inhibits glucagon release, gastric emptying and appetite; agents that increase GLP‑1 action are used to treat type 2 diabetes mellitus ■■ GLP‑2 regulates nutrient absorption by the gastrointestinal tract through enhancement of intestinal growth, nutrient digestion and transport, as well as blood flow ■■ The physiologic role of oxyntomodulin remains to be established, but exogenous administration suppresses food intake; PYY3–36NH2 has an important role as an anorexigenic gut hormone ■■ Surgically induced alterations in the levels of ghrelin and/or GLP‑1, oxyntomodulin and PYY improve glycaemic control and induce weight loss; pharmacological manipulation of these gut hormones might prove beneficial The X/A-like cell Ghrelin was first discovered in 1999 as a growthhormone-releasing peptide.12 The following character istics make ghrelin unique amongst the gut hormones: first, it is located primarily in the proximal gut; second, it is produced by both closed-type and open-type entero endocrine cells; third, it is acylated; fourth, levels are increased in the fasting state; and fifth, it is orexigenic. As a consequence, the regulation of ghrelin synthesis, secretion and biological activities differs markedly from that of GLP‑1, GLP‑2, oxyntomodulin and PYY. The rat X/A-like cell (known as the P/D 1 cell in humans) was identified as the ghrelin-producing cell in 2000, having originally been named ‘X’ for its unknown hormone product and ‘A-like’ for the morphologic simi larity of its secretory granules with those of the pancre atic A cell.13,14 X/A-like cells represent ~20% of the total number of endocrine cells of the gastric corpus mucosa in rats, with profoundly reduced cell numbers along the aboral axis.15 Interestingly, the proximal X/A-like cells are almost exclusively closed-type enteroendocrine cells, whereas >60% of the distal X/A-like cells (that is, ileal, cecal and colonic) are open type.15 Although the func tional importance of these different cell types remains unclear, their morphologic characteristics suggest that these cells might be differentially regulated, such that the distal, but not the proximal, cells might be responsive to the presence of nutrients in the intestinal lumen. Synthesized by post-translational processing of proghrelin through the actions of prohormone con vertase (PC) 1/3,16 ghrelin is modified on Ser3 through covalent linkage to a medium-chain (C8–C10) fatty acid by ghrelin O‑acyltransferase (GOAT).17 This acyla tion is required for the activity of ghrelin on the growth hormone secretagogue receptor, now also known as the ghrelin receptor (GRLN‑R),12 and is a unique posttranslational modification amongst all of the known peptide hormones. Hence, GOAT levels determine the proportion of bioactive ghrelin that is released by the X/A-like cell. 706 | DECEMBER 2012 | VOLUME 9 Circulating levels of ghrelin increase before a meal in both rodents and humans, and are suppressed by nutri ent ingestion (Figure 1).18,19 Given the closed nature of the proximal X/A-like cell, it has proven difficult to elu cidate the exact mechanisms regulating ghrelin release in response to fasting and nutrient ingestion. Nonetheless, in vivo studies have implicated both sympathetic and parasympathetic neurons as stimulatory effectors of the X/A-like cell, as well as hyperglycaemia, insulin and somato tatin from gastric D cells as inhibitory regulators s of ghrelin release.20–24 Studies on primary rodent gastric X/A-like cell cultures have confirmed the stimulatory effects of epinephrine and norepinephrine on ghrelin release.25,26 Furthermore, 1 mM glucose (comparable to hypo lycaemia) enhanced ghrelin release, whereas g 5 mM ‘normoglycaemic’ glucose had no effect and 10 mM glucose inhibited ghrelin release; inhibitory effects of insulin were also observed but only in the setting of low or normal glucose levels.25,26 These findings are consistent with the demonstration that these cells express glucosesensing machinery, including transporters, hexokinases and the KATP channel, as well as a functional insulin recep tor/phosphatidylinositol 3 (PI3)-kinase/Akt signalling pathway.25,26 Hence, the available data suggest that ghrelin release before a meal is coupled to activation of the sym pathetic nervous system. Conversely, the prandial suppres sion of ghrelin secretion is probably mediated, at least in part, by increasing levels of glucose and/or insulin. Finally, given the original identification of ghrelin-producing cells as ‘A-like’ on the basis of their morphological characteris tics,13,14 it is interesting that the regulation of ghrelin secre tion by X/A-like cells bears a striking resemblance to that of pancreatic glucagon by the A cell, which is also stimu lated by the sympathetic nervous system and inhibited by high levels of both glucose and insulin.27,28 The finding of a lineage relationship between pancreatic islet ghrelin and A cells further suggests that the gastric X/A-like and islet A cells might also be related,29 although transgenic expres sion studies have not identified any such link to date.29–31 Nonetheless, these findings suggest that, under both fasting and fed conditions, ghrelin and glucagon secretion are coordinated to maintain nutrient homeostasis. The orexigenic action of ghrelin and the require ment for the GRLN‑R in nutrient homeostasis has been demonstrated in rodents and humans using a wide variety of gain-of-function and loss-of-function approaches, and is mediated not only by increased food intake, but also via decreased energy expenditure.32–36 As ghrelin crosses the blood–brain barrier, related in part to its acylation status,37 the orexigenic effects of this gut hormone are thought to be mediated through direct effects on neurons in the central feeding centre, including those expressing the orexins.32,38 However, the GRLN‑R is also expressed by the vagus nerve and, although controversial, one study has demonstrated that both truncal vagotomy and vagal afferent ablation can prevent the orexigenic actions of peripherally administered ghrelin on food intake.39 Studies have also demonstrated that ghrelin has a role in glucose homeostasis through expression of the GRLN‑R in pancreatic islets, the liver and, to a much www.nature.com/nrgastro © 2012 Macmillan Publishers Limited. All rights reserved
- 3. REVIEWS lesser extent, muscle. 40 Consistent with these find ings, ghrelin has been shown to both inhibit glucose- stimulated insulin secretion and decrease insulin sensitivity in normal mice, with improved glucose toler ance found in knockout animals.34,36 Administration of a GOAT inhibitor also enhances glucose tolerance in mice, in a ghrelin- ependent manner.35 However, the glycae d mic actions of ghrelin might also be mediated through its effects as a growth hormone secretagogue, as GOAT knockout mice subjected to severe caloric restriction experience lethal hypoglycaemia, even in the setting of profoundly reduced insulin levels, and ghrelin replace ment prevents the mortality through increased growth hormone levels.41 Together, these findings suggest the existence of a metabolic negative feedback loop that regulates circulating ghrelin levels, probably through modulation of blood glucose levels. Given the important role of ghrelin in stimulat ing appetite, it is not surprising that ghrelin levels are decreased in obese individuals, consistent with negative feedback regulation under conditions of positive energy balance. 42–44 However, concentrations of circulating ghrelin are reduced even further by insulin resistance that is associated with either obesity or type 2 diabe tes mellitus.43,45 These in vivo data are in keeping with reports that ghrelin release by primary X/A-like cells is inhibited by physiological concentrations of insulin in the setting of low glucose levels,25,26 but not with the finding that insulin resistance in these cells prevents insulin-induced suppression of ghrelin.26 Furthermore, the suppression of endogenous ghrelin levels in all of these conditions raises the question as to whether antagonism of the ghrelin system will provide additional benefit to body weight regulation in any of these condi tions. Collectively, therefore, it remains to be established whether manipulation of ghrelin signalling will be of clinical benefit in conditions characterized by obesity. No strong link has been found between body weight dysregulation and polymorphisms in the ghrelin– GRLN‑R axis.46 However, increased ghrelin levels have been reported in individuals with anorexia, which sug gests a role for ghrelin resistance in this condition.47 A number of clinical trials have now examined the effects of ghrelin administration in a variety of conditions char acterized by reduced food intake due to cachexia; to date, results from these trials have been generally positive.48 Conversely, ghrelin receptor antagonists have been pro posed for use in obesity,49 with a reduction in body weight associated with decreased food intake demonstrated in diet-induced obese mice; enhanced glycaemic control during an intraperitoneal glucose tolerance test was also noted in these animals.32 Similar findings have been reported for a GOAT inhibitor.35 However, results from clinical trials using either approach are still pending. The L cell In contrast to ghrelin, peptides synthesized by the intes tinal L cell have the following characteristics: first, they are produced predominantly in the distal small intestine (that is, the ileum) and colon; second, they are found Norepinephrine Glucose Insulin IR β1R GLUT1/4/5 PI3K cAMP Glucokinase or hexokinase AKT ?? Low concentrations of glucose High concentrations of glucose PKA Ghrelin Figure 1 | The X/A-like cell. Under fasting conditions (for example, low levels of insulin and glucose), the X/A-like cell is stimulated by the sympathetic nervous system through release of norepinephrine and activation of the β1R, which is known to be coupled to cAMP and PKA signalling. Low concentrations of glucose also directly stimulate ghrelin release, at least in vitro. Under fed conditions (for example, high levels of insulin and glucose), insulin inhibits ghrelin release through the canonical PI3K/Akt pathway, whereas glucose inhibits secretion through a pathway that might involve glucose transporters and glucokinase or hexokinase. Abbreviations: β1R, β1 adrenergic receptor; GLUT1/4/5, glucose transporter 1, 4 or 5; IR, insulin receptor; PI3K, phosphatidylinositol‑3 kinase‑1; PKA, protein kinase A. only in open-type L cells; third, their levels are increased by feeding; and fourth, they are anorexigenic. GLP‑1, GLP‑2 and oxyntomodulin are synthesized by PC1/3-mediated cleavage of proglucagon, and are cosecreted by the L cell.50–52 Although glicentin and two intervening peptides are also liberated from proglucagon in the L cell, no physiological actions have been delin eated for these hormones and we do not discuss them further in this Review. The highest density of L cells is in the distal gut, but they are also localized in the upper gastro ntestinal tract of rats and humans, although i in markedly lower numbers than in the distal gut.53,54 Interestingly, findings have indicated that ~20% percent of proximal L cells co-express GIP, and 40% express cholecystokinin.11,55 By contrast, GIP and cholecysto kinin expression by distal L cells is fairly low, but ~45% of the ileal and ~70% of the colonic L cells co-express PYY, the functions of which are described below. 11,55 Furthermore, a study has indicated that the phenotype of the colonic L cell is altered by abnormal carbohydrate flux to this tissue, such that the cell increases its capacity to respond to the presence of these luminal nutrients.56 Compared with proximal L cells, colonic L cells might NATURE REVIEWS | GASTROENTEROLOGY HEPATOLOGY © 2012 Macmillan Publishers Limited. All rights reserved VOLUME 9 | DECEMBER 2012 | 707
- 4. REVIEWS Insulin Acetylcholine Leptin IR M1R LR PI3K MEK AKT ERK1/2 STAT3 GLP1/2 Oxyntomodulin PYY Ca2+ PKCζ PKA/PKC GPRs Fatty acids Oleoylethanoloamide 2-Oleoylglycerol ∆ψ FATP4 Oleic acid SGLT1 Glucose Na+ Figure 2 | The L cell. In the fed state, secretion by the L cell is rapidly stimulated by the vagus, through release of acetylcholine and activation of M1R. After passage down the gastrointestinal tract, luminal nutrients then enhance secretion through a variety of pathways: GPRs for long and short-chain fatty acids, oleoylethanoloamide and 2‑oleoylglycerol (leading to activation of PKA or PKC); FATP4 for oleic acid (leading to PKCζ signalling); and SGLT1 for sodium and glucose (resulting in depolarization (Ψ)-induced calcium signalling). Insulin and leptin also enhance secretion by the intestinal L cell in a positive-feedback fashion, through canonical signalling pathways. Abbreviations: ERK1/2, extracellular signal-regulated kinase 1/2; FATP4, fatty acid transport protein 4; GLP‑1/2, glucagon-like peptide 1 or 2; GPRs, G protein-coupled receptors; IR, insulin receptor; LR; leptin receptor isoform b; M1R, the M1 muscarinic receptor; MEK, MAPK/ERK kinase; PI3K, phosphatidylinositol‑3 kinase‑1; PKA, protein kinase A; PKC, protein kinase C; PYY, peptide YY; SGLT1, sodium-glucose transporter 1; STAT3, signal transducer activator of transcription 3. also respond preferentially to short-chain fatty acids,57 which is consistent with the high density of gut bacteria in this organ. The physiological importance of the differ ences between the proximal and distal L cell populations, as well as their developmental aetiology, clearly requires further examination. Hormone secretion by the L cell is stimulated by nutri ent ingestion; plasma levels of these hormones exhibit an early rise followed by a prolonged plateau phase.58 Studies 708 | DECEMBER 2012 | VOLUME 9 in rodents have demonstrated that the early L cell response is mediated indirectly by proximal activation of the vagus nerve, leading to muscarinic receptor signalling in the distal L cell; some evidence exists for a similar pathway in humans (Figure 2).4,59,60 By contrast, the prolonged secretory phase is triggered by nutrients in the gut lumen that act directly on ileal and/or colonic L cells through a variety of mechanisms, including the following: sig nalling coupled through transporters (for example, for glucose: sodium–glucose transporter‑1 and, to a lesser extent, KATP channels, leading to Na+ and K+-induced depolarization, respectively; and for oleic acid: fatty acid transport protein 4 and atypical protein kinase C‑ζ);7,61–65 or G‑protein-coupled receptor signalling (for example, for short-chain fatty acids: GRP40 and GRP43; for long-chain fatty acids: GPR40 and GPR120; for oleoylethanol mide a and 2‑oleoylglycerol: GPR119; and for glucose: sweet taste receptors). The bile acid receptor, TGR5, is also expressed by the distal L cell.56,57,66–70 Thus, luminal nutrient compo sition has a key role in the stimulation of L cell secretion, with diets enriched in oleic acid, for example, increasing hormone release to a greater extent than diets high in saturated fatty acids.71,72 Although L cell secretion is also known to be modulated by a number of hormones and neuropeptides (for example, cholecysto inin, gastrink releasing peptide, GIP, insulin, leptin and somatostatin),73 the physiological role of many of these factors and how their actions are coupled to nutrient ingestion remain to be fully elucidated. Finally, just as the X/A-like cell shares many regulatory features with the pancreatic A cell, so too is hormone secretion by the L cell similar to that of islet β cells, particularly with respect to the pathways regulating glucose and fatty acid responses.74 Not only is hormone secretion by the gut and pancreatic islets thereby coor dinated in the fed state, but many of these pathways are currently under investigation as coordinated L and β‑cell secretagogues, as discussed in more detail below. Both insulin and leptin also serve as GLP‑1 secreta gogues, with the effects of insulin seeming to form a positive feedback loop between the L cell and islet β cell.75,76 The concomitant findings that conditions of leptin and insulin resistance impair the L cell response to oral glucose are consistent with reports of reduced GLP‑1 levels in individuals with obesity and insulin resistance and/or type 2 diabetes mellitus, respectively,77–79 and indi cate that, like the X/A-like cell, the L cell is dysregulated by perturbations in nutrient homeostasis. Once released into the circulation, GLP‑1 and GLP‑2 are cleaved by dipeptidylpeptidase 4 (DPP‑4), render ing short bioactive half-lives of ~1–2 min and ~7 min, respectively. 53,80,81 Oxyntomodulin has intermediate susceptibility to degradation by DPP‑4, at least in vitro, and a DPP‑4-resistant analogue has been reported to demon trate enhanced bioactivity compared with the s native peptide in vivo.82,83 In the case of both GLP‑1 and GLP‑2, the cleavage product serves as a partial agonist or antagonist at the respective receptor,84,85 although trun cated GLP‑1 also seems to mediate some of the cardio protective actions of GLP‑1 through a yet-to-be-identified receptor.86 Finally, PYY is also degraded by DPP‑4,87,88 www.nature.com/nrgastro © 2012 Macmillan Publishers Limited. All rights reserved
- 5. REVIEWS with the half-lives of both PYY1–36NH2 and PYY3–36NH2 being ~13 min,89 but, in contrast to the inactivation of GLP‑1, GLP‑2 and oxynto odulin, DPP‑4-mediated cleavage of m PYY is actually required for its biological activity at the Y2 receptor.90 Thus, the truncated peptide, PYY3–36NH2, mediates the effects of PYY as a satiety factor.87 Together, therefore, GLP‑1, GLP‑2, oxyntomodulin and PYY are all released by the intestinal L cell. However, these L cell hormones have distinct profiles of biological actions, which ultimately integrate at the level of whole body nutrient homeostasis. GLP‑1 As a result of the widespread distribution of the GLP‑1 receptor, in both peripheral tissues and the CNS,91–93 cir culating GLP‑1 exerts a diverse array of effects on nutrient homeostasis. The major biological actions of GLP‑1 are antidiabetic, and are most notably exerted through the pancreatic β cell. Hence, GLP‑1 is an incretin that enhances glucose-dependent insulin secretion, as well as stimulat ing insulin biosynthesis and, in rodents, promoting β‑cell proliferation while inhibiting apoptosis.94,95 GLP‑1 also inhibits release of glucagon by pancreatic α cells, delays nutrient absorption through inhibition of gastric emptying and intestinal motility, and enhances insulin sensitivity at the level of both the liver and peripheral tissues—although the majority of its effects on glycaemia seem to be medi ated through changes in islet hormone secretion.96 The beneficial effects of circulating endogenous and exogenous GLP‑1 or its analogues on regulation of glucose have also been confirmed in studies using both antagonist and receptor knockout approaches.97,98 However, peripherally administered GLP‑1 and its analogues also have anorexi genic actions, inducing satiety and inhibiting food intake in normal and obese rodents and humans, as well as in patients with type 2 diabetes mellitus.99–102 As a consequence of the reported biological actions of GLP‑1, several long-acting, DPP‑4-resistant GLP‑1based drugs have now been licensed for clinical use in the treatment of type 2 diabetes mellitus, the major effects of which are a reduction in haemoglobin A1c (HbA1c, a glycated haemoglobin) levels in association with weight loss.103 Of note, although GLP‑1R agonists do induce weight loss in overweight and obese individuals with and without type 2 diabetes mellitus, the overall effect is fairly modest, averaging 2.9 kg.104 However, a GLP‑1– glucagon co-agonist that takes advantage of the inhibi tory effects of GLP‑1 on food intake and the stimulatory effects of glucagon on energy expenditure, while at the same time balancing the hypoglycaemic and hyper glycaemic effects of the two peptides, respectively, indi cates that novel approaches to the use of GLP‑1 could optimize its use in obesity. 105 Conversely, although DPP‑4 inhibitors are used clinically to increase circulat ing levels of endo enous GLP‑1, as well as of the other g major incretin, GIP, in patients with type 2 diabetes mel litus,103 the use of these agents is associated with reduced levels of HbA1c but not weight loss, the latter possibly owing to concomitantly reduced production of bioactive PYY3–36NH2, as discussed above. An alternative approach to the use of GLP‑1 in the treatment of patients with type 2 diabetes mellitus and/or obesity is enhancement of endogenous GLP‑1 secretion by activation of novel L cell secretory pathways and, in particular, those medi ating the responses to fatty acids, including GPR40 and GPR119.74,106 Such agents would have the advantage of concomitantly increasing the release of all of the L cell hormones, of which oxynto odulin and PYY3–36NH2 are m also anorexigenic (discussed in more detail below). Although GLP‑1 is released into the circulation as a hormone, its short half-life suggests that at least some of its physiological actions might be mediated indirectly, prob ably through the GLP‑1R expressed on afferent neurons. Hence, despite the well-established direct effects of GLP‑1 on β cells in vitro,107,108 the in vivo actions of GLP‑1 to stimulate insulin release have been reported to require afferent neurons.92 Indeed, GLP‑1 increases vagal afferent firing in rats.109 However, in direct comparative studies, the requirement for sensory afferents in the actions of GLP‑1 on both insulin release and food intake in mice was observed at low, but not high, doses of GLP‑1.110,111 Whether some of the anorexigenic actions of GLP‑1 are also mediated via suppression of gastric emptying remains unclear.112 Nonetheless, these findings collectively suggest that the physiological effects of endogenously secreted GLP‑1, which includes the actions of GLP‑1 in patients treated with DPP‑4 inhibitors, are mediated indirectly by local effects of GLP‑1 on its receptor expressed by gastro intestinal and/or vagal afferent neurons.113 By contrast, the pharmacologic actions of GLP‑1 and long-acting GLP‑1R agonists seem to be exerted, at least in part, through direct effects on the GLP‑1R in β cells and the brain. Genetic studies have demonstrated that poly morphisms in the voltage-gated K + channel gene, KCNQ1, are associated with reduced secretion of GLP‑1, whereas variants in the genes for the GLP‑1R, the β‑cell transcription factor, TCF7L2, and the neuroendocrine transmembrane protein, Wolfram syndrome 1, lead to reduced GLP‑1-stimulated insulin release.114–117 Hence, inter ndividual differences in GLP‑1 release or func i tion might be linked to alterations in the effectiveness of DPP‑4 inhibitors and GLP‑1R agonists, respectively, in patients with type 2 diabetes mellitus, a notion that has yet to be rigorously assessed. GLP‑2 In contrast to GLP‑1, the actions of GLP‑2 are more restricted owing to the highly concentrated expression of the GLP‑2R in the gastrointestinal tract; these receptors are expressed in only a few other tissues, including the vagus nerve and brain.118,119 GLP‑2 is, therefore, known foremost for its effects in the gastrointestinal tract. Both GLP‑2 and its degradation-resistant analogues increase small and large intestinal weight, crypt-villus height and mucosal surface area through stimulation of crypt cell proliferation and inhibition of epithelial cell apop tosis.120–122 GLP‑2 also enhances nutrient absorption through various actions, including increasing expression of digestive enzymes and nutrient transporters, as well as stimulating intestinal blood flow.120–122 Of note, although NATURE REVIEWS | GASTROENTEROLOGY HEPATOLOGY © 2012 Macmillan Publishers Limited. All rights reserved VOLUME 9 | DECEMBER 2012 | 709
- 6. REVIEWS GLP‑2 also inhibits gastric emptying, these effects are minor compared with the actions of GLP‑1 on gastric emptying.123 Furthermore, in a wide variety of animal models of intestinal damage and insufficiency, GLP‑2 exerts protective effects on the gastrointestinal epithelium by reducing inflammation and increasing barrier func tion, as well as by preventing and repairing damage.124–127 However, in contrast to the profound pharmacological actions of GLP‑2, the role of the endogenous hormone seems to be more limited, with only a small or no reduc tion in bowel size noted upon administration of a GLP‑2R antagonist and in GLP‑2R null mice.128,129 Nonetheless, endogenous GLP‑2 is required for the intestinal adaptive responses to nutrient ingestion after a prolonged fast, as well as for protection from chemically induced enteri tis.85,130 Importantly, the majority of the major findings on GLP‑2 in rodent models have also been confirmed in humans, most notably in patients with intestinal insuffi ciency owing to short bowel syndrome or damage associ ated with Crohn’s disease.131,132 Clinical trials are ongoing, and a long-acting analogue of GLP‑2 has been approved in Europe for use in patients with short bowel syndrome.133 Despite extensive characterization of the effects of GLP‑2, the mechanistic basis of the action of GLP‑2 is only poorly understood. The GLP‑2R is not localized to the major site of action of GLP‑2 (that is, intestinal epithelial cells) but rather it is localized to the intestinal subepithelial myofibroblasts, enteric nervous system and diffuse entero endocrine cells;122 the actions of GLP‑2 must therefore be exerted indirectly by the release of paracrine factors from these cells. Downstream players that have been identified to date include: insulin-like growth factor (IGF)‑1 and IGF‑2, and the ErbB network for crypt cell proliferation in the small and large intestine;130,134–136 keratinocyte growth factor, for large bowel growth;137 vasoactive intestinal poly peptide, for anti-inflammatory actions in the small and large intestine;138 and endothelial nitric oxide synthase, for intestinal blood flow.139 Finally, and again in contrast to the actions of GLP‑1, the known effects of GLP‑2 do not seem to be mediated through afferent pathways, as activa tion of this receptor is not linked to any change in vagal firing, and centrally administered but not peripherally administered GLP‑2 inhibits food intake.109,140,141 Oxyntomodulin Although oxyntomodulin was originally named for its inhibitory effects on gastric acid secretion,142 these actions are relatively weak compared with those exerted by other gut peptides, such as somatostatin.143 Hence, the biologi cal role of oxyntomodulin remained somewhat uncer tain until ~10 years ago, when it was reported to inhibit food intake in both rats and humans when administered exogenously.144,145 Indeed, a number of studies have now demonstrated that repeated peripheral administration of either oxyntomodulin or its long-acting analogues induces weight loss in obese rats, mice and humans, with this effect being mediated through both suppression of food intake and increased energy expenditure.146–148 Interestingly, early studies on oxyntomodulin and gastric acid secretion suggested the existence of a receptor 710 | DECEMBER 2012 | VOLUME 9 for this hormone through which glucagon might also act, although with less potency.142 Although no specific oxyntomodulin receptor has been identified to date, this hormone has been established to be an agonist for both the GLP‑1R and the glucagon receptor. Hence, oxynto modulin has EC50s (half maximal effective concentra tions) for the GLP‑1R and glucagon receptor that are approximately 100-fold and 10-fold greater than those of GLP‑1 and glucagon, respectively.144,149,150 Consistent with these findings, the actions of oxyntomodulin on the gastric glands are now known to be mediated through GLP‑1R, as are the effects of peripheral oxyntomodulin to suppress food intake.151,152 However, the stimulatory effect of oxyntomodulin on energy expenditure might also be dependent upon the glucagon receptor, as this is also a well-established effect of glucagon.153,154 Hence, not only DPP‑4-resistant analogues of oxyntomodulin, but also dual GLP‑1R/glucagon receptor oxyntomodulin analogues have been developed as possible thera eutic p agents for the treatment of obesity. 83,148,155 Notably, oxyntomodulin also improves glycaemic control, through GLP‑1R-dependent increase of glucose-stimulated insulin secretion.156 Although this effect might be expected to be counter-balanced by oxyntomodulin-induced activation of the glucagon receptor, the available data suggest that the anti-hyperglycaemic effects of oxyntomodulin prevail in the setting of dual receptor activation.153 Furthermore, the mechanism of action of oxyntomodulin also implies that polymorphisms in either the GLP-1R, the glucagon receptor and/or their signalling pathways might influence the effectiveness of these drugs.115–117,157 Finally, the cellular pathway(s) by which oxynto modulin inhibits food intake are thought to include both the CNS and the vagus nerve. Peripheral admin istration of oxynto odulin activates a variety of central m nuclei involved in feeding, including the arcuate nucleus that abuts areas of the hypothalamus characterized by a leaky blood–brain barrier.150,152 Oxyntomodulin also stimulates release of the anorexigenic neuropeptide, α‑melanocyte-stimulating hormone, from hypothalamic explants in vitro, which is consistent with possible direct effects on central feeding centers.152 However, activation of the nucleus of the solitary tract by peripheral oxynto modulin is also in keeping with a role for vagal sensing of this hormone.150 Although studies of oxyntomodulin actions on food intake following vagal disruption have yet to be conducted, the inhibitory actions of oxynto modulin on pancreatic exocrine secretion are abrogated in vagotomised rats, which indicates that signalling can occur through this peripheral neural pathway.158 PYY Which prohormone convertase cleaves proPYY to PYY1–36NH2 is not known, although it is presumed to be PC1/3 owing to the known actions of this enzyme on pro glucagon in the intestinal L cell.50 PYY1–36NH2 was first iden tified as a gut peptide with tyrosine (‘Y’) at its N‑terminal and C‑terminal ends, and was initially characterized as an inhibitor of both pancreatic exocrine secretion and intestinal motility.159,160 However, although PYY1–36NH2 www.nature.com/nrgastro © 2012 Macmillan Publishers Limited. 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- 7. REVIEWS binds to multiple receptors of the neuropeptide Y recep tor (YR) family, its cleavage by DPP‑4 in the circula tion converts it to a Y2-receptor-selective agonist.87,90 Thus, compared with both full-length PYY 1–36NH2 and neuropeptide Y, which stimulate food intake through the Y1R and possibly the Y5R, the Y2R-selectivity of PYY3–36NH2 and its agonists enables suppression of food intake through inhibition of neuropeptide Y release in the arcuate nucleus, while Y2R specific antagonists prevent the anorexigenic actions of PYY3–36NH2.161–164 Consistent with these findings, initial studies in mice have suggested that the actions of PYY3–36NH2 are not mediated by periph eral sensory afferent nerves such as the vagus.111 However, in the rat, the Y2R is expressed by the vagus nerve, and peripherally administered PYY3–36NH2 stimulates gastric vagal afferent firing, while vagotomy prevents the anorexi genic actions of PYY3–36NH2.165 Thus, the mechanism of action of PYY3–36NH2 might exhibit species- pecific dif s ferences. Alternatively, as the Y2R expressed by rat vagal afferent neurons is regulated by cholecystokinin in a nutri ent-dependent manner,166 experimental differences could also account for these apparent discrepancies. Although great interest was generated by the first reports of the anorexigenic actions of PYY3–36NH2 in rodents as well as normal-weight and obese humans,163,167 these findings have been the subject of some controversy in the literature, with both confirmatory and negative findings reported.111,168,169 The reason for these discrepant findings remains elusive. Nonetheless, both a rare PYY mutation and Y2R variants have been linked to altera tions in body weight in humans.170–172 Hence, long-acting PYY3–36NH2 analogues, as well as Y2R agonists, are cur rently under development for the treatment of obesity, and many clinical trials are ongoing. Combined effects Although the L cell hormones are co-secreted, few studies have examined the combined effects of simultaneous increased levels of these hormones. With respect to feed back suppression of food intake, additive and/or syner gistic effects of PYY3–36NH2 with oxyntomodulin, as well as of PYY3–36NH2 with GLP‑1 or its analogues have been reported.111,173–175 Furthermore, PYY3–36NH2 and GLP‑1 also have additive effects to delay gastric emptying.176 Finally, GLP‑1 and GLP‑2 do not demonstrate additive effects to suppress food intake,177 but do exert opposing effects on glucagon release, with the inhibitory effect of GLP‑1 predominating.178 No studies to date have examined the physiological consequences of increasing the levels of all four of these hormones, or of their effects when given in combination with all of the other gut hormones released by nutrient intake. Such investigations will clearly be nec essary to fully understand the integrated contribution of the L cell to nutrient homeostasis, particularly if L cell secretagogues are to be used for the treatment of type 2 diabetes mellitus and/or obesity, as discussed above. Clinical relevance Two successful, surgical treatments for obesity—Rouxen‑Y gastric bypass (RYGB) and sleeve gastrectomy—also improve or reverse the symptoms of type 2 diabetes mel litus. RYGB markedly reduces the size of the stomach and diverts ingested nutrients and pancreato-biliary flow directly to the distal small intestine, whereas sleeve gas trectomy introduces gastric restriction only.179 Despite the differences between these surgical interventions, the results of clinical trials indicate that both proce dures result in equivalent improvements in glycaemic control and identical weight loss 1 year after surgery.180,181 Remarkably, the reductions in glucose levels occur rapidly after surgery, often prior to the changes in body weight.182 The success of RYGB for both resolution of type 2 diabetes mellitus and weight loss has largely been attributed to an increase in the release of peptides from the L cells, with the effects to reduce ghrelin release being controversial.181,183–187 The concomitant diversion of bile flow to the distal small intestine might also contribute to the increase in L cell secretion following RYGB through activation of the L cell bile acid receptor, TGR5.69 Indeed, a study has demonstrated that enhanced release of GLP‑1 following gastric bypass in obese rats is responsible for the weight-loss-independent improvement in glucose tolerance associated with this procedure.188 By contrast, sleeve gastrectomy has been reported to cause greater decreases in ghrelin levels and increased cholecystokinin release than found with RYGB, in addition to increasing L cell secretion.181 Thus, although differing somewhat in their mechanisms of action, RYGB and sleeve gastrec tomy are unique approaches that manipulate the physio logical actions of the gut hormones to regulate nutrient homeostasis through their combined effects on gut nutrient handling, glucose tolerance and food intake. Conclusion This Review has focused on the hormones produced by the enteroendocrine X/A-like cell (ghrelin) and the L cell (GLP‑1, GLP‑2, oxyntomodulin and PYY). These peptides have key roles in the integration of food intake with metabolism, as well as providing feedback signals to the brain to induce satiety during feeding. However, it is recognized that the gastrointestinal tract releases many other hormones that also have important roles in nutri ent homeostasis including, most notably, GIP and chol ecystokinin. Elucidation of the combined actions of all of these hormones will be essential to develop a comprehen sive understanding of the integrative role that the gastro intestinal tract has in maintaining nutrient homeostasis during fasting and in response to feeding. Review criteria PubMed was searched for full-length articles using the keywords “ghrelin”, “GLP‑1”, “GLP‑2”, “oxyntomodulin”, “enteroglucagon” and “PYY”, alone and in combination with key author names and/or the keywords “secretion”, “food intake”, “obesity”, “insulin resistance”, “type 2 diabetes” and/or “review”; review articles were used to further search for original papers. All years were included in the search. Articles published in languages other than English were excluded from the analysis. NATURE REVIEWS | GASTROENTEROLOGY HEPATOLOGY © 2012 Macmillan Publishers Limited. All rights reserved VOLUME 9 | DECEMBER 2012 | 711
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