• amylin;
  • cholecystokinin;
  • ghrelin;
  • glucagon-like peptide-1;
  • obesity;
  • oxyntomodulin;
  • pancreatic polypeptide;
  • peptide YY


  1. Top of page
  2. Abstract
  3. GLP-1
  4. Oxyntomodulin
  5. Peptide YY
  6. Cholecystokinin
  7. Pancreatic polypeptide
  8. Amylin
  9. Ghrelin
  10. Conclusions
  11. Competing interests

Our knowledge of the complex mechanisms underlying energy homeostasis has expanded enormously in recent years. Food intake and body weight are tightly regulated by the hypothalamus, brainstem and reward circuits, on the basis both of cognitive inputs and of diverse humoral and neuronal signals of nutritional status. Several gut hormones, including cholecystokinin, glucagon-like peptide-1, peptide YY, oxyntomodulin, amylin, pancreatic polypeptide and ghrelin, have been shown to play an important role in regulating short-term food intake. These hormones therefore represent potential targets in the development of novel anti-obesity drugs. This review focuses on the role of gut hormones in short- and long-term regulation of food intake, and on the current state of development of gut hormone-based obesity therapies.

Obesity is classified by the World Health Organization as one of the eight principal causes of preventable chronic disease worldwide [1]. Recent, dramatic increases in its prevalence have resulted in a major burden on healthcare resources in many industrialized countries [2–5]. Obesity substantially increases an individual's risk of cardiovascular disease, stroke, peripheral vascular disease, renal failure, cancer, osteoarthritis and Type 2 diabetes mellitus [6, 7]. Indeed, a prospective cohort study of 114 281 women revealed an exponential relationship between body mass index (BMI) and risk of developing Type 2 diabetes mellitus, with those in the group with highest BMI being 93 times more likely to develop diabetes than those in the lowest group, after 14 years of follow-up [8].

Treatment options for obesity are limited. A combination of dieting and increased physical activity is effective only for as long as it is adhered to, a challenge even for participants in randomized trials [9]. Currently available medications are hampered by significant adverse effects and are only moderately effective, with weight loss persisting only for as long as treatment is continued [10]. In contrast, bariatric surgery routinely results in substantial, permanent weight loss and, despite significant perioperative risks, is the only treatment modality shown to reduce mortality in severe obesity [11, 12].

The two most commonly performed bariatric procedures are gastric banding and Roux-en-Y gastric bypass (RYGB). Unlike gastric banding, a solely restrictive procedure, RYGB combines gastric restriction with diversion of food away from the gastric fundus and proximal small bowel. Although RYGB is therefore a more complicated procedure, it generally produces greater weight loss and more rapid resolution of diabetes than gastric banding [13–15]. It is likely that this superiority results, at least in part, from altered patterns of secretion of several gut hormones, including peptide YY (PYY), glucagon-like peptide-1 (GLP-1) and oxyntomodulin, which occur after RYGB but not after purely restrictive procedures [16–18]. Similar patterns of secretion are observed in previously healthy people who lose weight following small bowel resections [19]. These and other observations have encouraged research into the role of gut hormones in regulating appetite and body weight, and into the possibility that they could represent valuable new targets in the development of anti-obesity medications.


  1. Top of page
  2. Abstract
  3. GLP-1
  4. Oxyntomodulin
  5. Peptide YY
  6. Cholecystokinin
  7. Pancreatic polypeptide
  8. Amylin
  9. Ghrelin
  10. Conclusions
  11. Competing interests

Of all the known gut hormones, GLP-1 has proved to be the most amenable target for drug development to date. One of several cleavage products of the proglucagon precursor, GLP-1 is secreted by L-cells located predominantly in the distal intestine [20]. Release nevertheless occurs rapidly after eating, in proportion to food intake, under the control of the vagus nerve, enteric nervous system, other circulating gut peptides and the direct effect of nutrients on L-cells [21–25].

GLP-1 acts by binding to the GLP-1 receptor (GLP-1R), a seven trans-membrane domain, G-protein-coupled receptor [26]. Ligand binding stimulates adenylate cyclase activity and increases the influx of extracellular Ca2+ ions [26, 27]. The GLP-1R is expressed in many tissues, including pancreatic islets, lung, brain, stomach, kidney and heart [26, 28]. The function of GLP-1 in several of these sites is not yet understood. However, in pancreatic islets, it functions as an incretin hormone, i.e. as a physiological, glucose-dependent, insulin secretagogue, the action of which is to potentiate postprandial insulin release [25]. In rodents, GLP-1 also increases β-cell mass [29]. It is a matter of conjecture as to whether a similar process may occur in humans. GLP-1 also inhibits glucagon secretion, delays gastric emptying [30, 31], and inhibits food intake in rats, after administration either systemically or directly into the central nervous system (CNS) [32–34]. In humans, acute intravenous (i.v.) infusion reduces energy intake at a subsequent ad libitum meal [35], whereas chronic subcutaneous infusion to patients with Type 2 diabetes mellitus results in weight loss and improved glycaemic control [36].

It is likely that the satiating effect of GLP-1 is due not only to delayed gastric emptying but also to direct effects in the CNS, since peripherally administered GLP-1 causes neuronal activation in the arcuate nucleus [37], whereas administration into the CNS causes neuronal activation in the paraventricular nucleus, nucleus of the tractus solitarius and area postrema [38, 39]. Furthermore, GLP-1R gene expression is altered in the hypothalamus and brainstem by fasting and refeeding [40]. It is also possible that GLP-1 acts via the vagus nerve, since GLP-1R gene expression occurs in the nodose ganglion of the vagus nerve [41], and the effect of peripherally administered GLP-1 on both energy intake and activation of arcuate nucleus neurons is attenuated by either bilateral sub-diaphragmatic truncal vagotomy or bilateral transections of the brainstem–hypothalamus pathway [37].

Recognition of the incretin and satiety-inducing properties of GLP-1 has made it a prime target for the development of treatments for diabetes and obesity. However, GLP-1 is not itself suitable for use as a drug, owing to the rapidity with which it is inactivated and cleared from the circulation, both by the action of dipeptidyl peptidase-IV (DPP-4) and by renal clearance [42–44]. This problem has been circumvented by the development of injectable, DPP-4-resistant incretin mimetics (i.e. GLP-1R agonists) and of orally available DPP-4 inhibitors. Examples of both these classes are currently licensed for the treatment of Type 2 diabetes mellitus. However, in contrast to the incretin mimetics, DPP-4 inhibitors have not consistently caused weight loss in Phase III clinical trials. This may be because DPP-4 does not function solely as an inactivator of GLP-1 but, rather, modifies a multitude of peptides, including cytokines [45].

The first available incretin mimetic is exenatide (Byetta; Amylin/Eli Lilly, Basingstoke, UK), this being the pharmaceutical name for exendin-4, a naturally occurring potent GLP-1R agonist that is resistant to DPP-4-mediated degradation [46, 47]. Exenatide is administered by twice-daily subcutaneous injection for the treatment of Type 2 diabetes mellitus, as an adjunct to metformin and/or sulphonylureas. A long-acting version is in development that could allow once-weekly dosing [48, 49]. Phase III trials of short-acting exenatide in patients with Type 2 diabetes showed not only that it improves glycaemic control but also that it significantly reduces body weight [50–55]. Nausea occurs very commonly, although its incidence declines with duration of treatment [50, 51]. It has been claimed that weight loss during exenatide treatment is not a consequence of nausea [50, 51]. Recent reports have given rise to the concern that exenatide use might increase the risk of developing acute pancreatitis [56, 57]. However, an analysis of health insurance claims in the USA suggests that this risk may in fact be no greater than that for patients started on other antidiabetic medications [58].

It has been hypothesized that exenatide could be used as a treatment for obesity in patients without diabetes. However, although trials are in progress, sparse peer-reviewed data have been published as yet. The exception is a small-scale, open-label study conducted in obese, nondiabetic women with polycystic ovary syndrome. The authors reported that exenatide and metformin in combination had beneficial effects on menstrual cyclicity, rate of ovulation, body weight and insulin sensitivity, and that these effects were more marked than treatment with either exenatide or metformin alone. There were no reported instances of hypoglycaemia [59].

Several other incretin mimetics are in development at present. Liraglutide (Victoza; Novo Nordisk, Crawley, UK) is an analogue of GLP-1(7-37) that received a licence for use in the treatment of Type 2 diabetes mellitus earlier this year. Its half-life is prolonged by albumin binding, which results from the addition of a side chain, comprising a glutamic acid residue coupled to a palmitoyl group, to lysine at position 26 [60]. In human studies, liraglutide has been shown to improve glycaemic control in association with weight loss [61–64]. As with exenatide, the major adverse effect is nausea. There are no published data regarding the effect of liraglutide on body weight in nondiabetic individuals as yet. Other molecules, including taspoglutide (Roche, Welwyn Garden City, UK) and albiglutide (GlaxoSmithKline, Brentford, UK), are at earlier stages of development but may have half-lives sufficient for weekly dosing [65, 66].


  1. Top of page
  2. Abstract
  3. GLP-1
  4. Oxyntomodulin
  5. Peptide YY
  6. Cholecystokinin
  7. Pancreatic polypeptide
  8. Amylin
  9. Ghrelin
  10. Conclusions
  11. Competing interests

Like GLP-1, oxyntomodulin is released postprandially from intestinal L-cells, in proportion to energy intake [67, 68]. Its actions include inhibition of gastric acid and pancreatic exocrine secretion, and prolongation of gastric emptying [68–73]. When administered to rats by either intracerebroventricular or peripheral injection, oxyntomodulin reduces food intake, increases energy expenditure and reduces the rate of increase in body weight [74–77]. In humans, i.v. infusion of oxyntomodulin reduces food intake [78], while repeated subcutaneous injection increases energy expenditure and causes weight loss in obese volunteers [79, 80].

Oxyntomodulin is another product of tissue-specific cleavage of the proglucagon precursor, comprising the entire 29-amino-acid sequence of glucagon with a C-terminal octapeptide extension [81–83]. It is an agonist at both the glucagon receptor (GLU-R) and the GLP-1R [74], but its anorectic effect is probably mediated via the latter receptor, since co-administration of exendin-(9-39), a specific GLP-1R antagonist, restores food intake to that of controls [74, 75]. Furthermore, whereas the anorectic effect of oxyntomodulin is maintained in mice lacking the GLU-R, it is absent in those lacking the GLP-1R [74].

Although oxyntomodulin is a GLP-1R agonist, several strands of evidence point to it having functions that are distinct from those of GLP-1. First, the affinity of oxyntomodulin for the GLP-1R is about fivefold less than that of GLP-1, yet the two hormones are virtually identical in their anorectic effect in rodents [75]. Second, injection of exendin-(9-39) into the arcuate nucleus prevents oxyntomodulin, but not GLP-1, from reducing food intake after intraperitoneal (i.p.) injection [77]. Third, functional imaging studies using manganese-enhanced magnetic resonance in mice show that oxyntomodulin and GLP-1 differ substantially in their effects on hypothalamic neuronal activity [84, 85]. These findings suggest that there may be an unknown oxyntomodulin-specific receptor, and/or that there may be differences between oxyntomodulin and GLP-1 in regional uptake within the CNS.

Like GLP-1, oxyntomodulin is inactivated by DPP-4 and neprilysin [86, 87] and cleared rapidly from the circulation [79]. This laboratory has used oxyntomodulin analogues to investigate the contribution of different regions of the molecule to its function and its sensitivity to proteolytic degradation [86]. An analogue of oxyntomodulin synthesized as part of this programme was developed by Thiakis and is now being evaluated by Wyeth Pharmaceuticals as a potential therapy for obesity.

Peptide YY

  1. Top of page
  2. Abstract
  3. GLP-1
  4. Oxyntomodulin
  5. Peptide YY
  6. Cholecystokinin
  7. Pancreatic polypeptide
  8. Amylin
  9. Ghrelin
  10. Conclusions
  11. Competing interests

Another product of intestinal L-cells, PYY is co-secreted with GLP-1 and oxyntomodulin after meals, in proportion to the calories consumed, with protein providing a greater stimulus to its release than fat [68, 88–90]. Plasma PYY concentration reaches a peak 1–2 h after each meal [90]. The hormone exists in two major forms in the circulation: PYY1-36, which has agonist activity at the Y1, Y2 and Y5 receptors (Y1R, Y2R, Y5R), and PYY3-36, which is a selective Y2R agonist [91, 92]. The predominant circulating moiety, PYY3-36, is formed by DPP-4-mediated proteolysis of the full-length peptide [93, 94].

PYY was originally described as being an appetite stimulant because of its potent effect when administered by intracerebroventricular injection [95]. However, autoradiographic studies show that radiolabelled PYY3-36 binds only at the area postrema, subfornical organ and median eminence in the CNS after peripheral administration [96]. Thus, the effect of intracerebroventricular PYY is unlikely to be representative of the physiological properties of circulating PYY.

Far from being an appetite stimulant, PYY3-36 is now thought to be a satiety-inducing hormone [97]. Several facts suggest that this satiating effect is mediated via Y2R in the arcuate nucleus. First, food intake in rodents is reduced by injection of PYY3-36 directly into the arcuate nucleus [97]. Second, peripheral injection of PYY3-36 increases c-fos expression, a marker of neuronal activation, in the arcuate nucleus [97]. Third, PYY3-36 has no effect on food intake in Y2R-knockout mice [97]. Fourth, prior administration of a selective Y2R antagonist, either by intra-arcuate injection [98] or by i.p. injection [99], prevents inhibition of food intake by i.p. PYY3-36.

However, PYY3-36 may exert effects on food intake not only at the arcuate nucleus but also via the vagus–brainstem–hypothalamic pathway. The Y2R is expressed in the nodose ganglion [100] and vagal ligation studies show that Y2R are transported to the peripheral terminals of vagal afferent neurons [101]. This is reflected in the fact that i.v. PYY3-36 causes afferent vagal discharges [101], while disruption of the vagus–brainstem–hypothalamus pathway, either by subdiaphragmatic truncal vagotomy or by bilateral midbrain transections rostral to the nucleus of the tractus solitarius, abolishes the satiating effect of i.p. PYY3-36[37, 101]. Subdiaphragmatic truncal vagotomy also prevents c-fos expression in the arcuate nucleus in response to PYY3-36 administered by i.p. injection [101].

The first report of the anorectic and weight loss-inducing effects of PYY3-36[97] was questioned by a number of other research groups, who were unable to demonstrate any reduction in food intake, either acute or chronic, in rodents [102, 103]. Since then, further studies in mice, rats, pigs, rhesus monkeys and humans have confirmed the acute anorectic properties of PYY3-36[98, 99, 104–118]. Several studies have also confirmed the ability of chronic PYY3-36 administration to cause weight loss in animal models of obesity [119–124]. It is possible that the failure of several groups to replicate the anorectic effects of PYY3-36 in rodents was due to inadequate acclimatization of the animals to study conditions [125]. Nevertheless, an attempt to use intranasally-delivered PYY3-36 as a treatment for obesity has foundered after significant problems with nausea and vomiting were encountered during a Phase II clinical trial [126].


  1. Top of page
  2. Abstract
  3. GLP-1
  4. Oxyntomodulin
  5. Peptide YY
  6. Cholecystokinin
  7. Pancreatic polypeptide
  8. Amylin
  9. Ghrelin
  10. Conclusions
  11. Competing interests

Cholecystokinin (CCK) is released postprandially by endocrine I-cells in the small intestine [127, 128]. Several cleavage products of the pro-CCK gene circulate in plasma, the minimal epitope for receptor binding being a carboxy-terminal-amidated, tyrosyl O-sulphated heptapeptide [129]. CCK-8, the shortest bioactive form, functions as a neurotransmitter, binding to both CCK1 (also known as CCK-A) and CCK2 (CCK-B) receptors in the CNS [130, 131]. In the gastrointestinal tract, CCK acts via the CCK1 receptor [132, 133] with several effects, including gallbladder contraction, sphincter of Oddi relaxation, pancreatic enzyme release and somatostatin release [134].

Peripheral administration of CCK causes early meal termination in rats, reducing short-term food intake [135]. This satiating effect is abolished by truncal vagotomy or capsaicin-induced afferent fibre ablation, suggesting that it is mediated by the vagus [136–139]. Human food intake may also be reduced acutely by administration of CCK [140–144]. However, early satiety at each meal does not necessarily translate into reduced long-term appetite. Indeed, in a clinical trial of a CCK1 receptor agonist developed by GlaxoSmithKline, mean body weight was similar in placebo- and drug-treated groups after 24 weeks' treatment [145]. This finding is reflected in rodent studies showing that tolerance to a continuous i.p. infusion of CCK develops within 24 h [146], and that reduced meal size during repeated CCK injection is compensated for by increased meal frequency [147]. Nevertheless, daily CCK injections enhance the effect of continuous intracerebroventricular infusion of leptin on body weight in rats [148], possibly by increasing the rate of leptin transport across the blood–brain barrier [149]. Further studies are required to investigate whether co-administration with leptin or other hormones may provide a role for CCK1 receptor agonists in the treatment of human obesity.

Pancreatic polypeptide

  1. Top of page
  2. Abstract
  3. GLP-1
  4. Oxyntomodulin
  5. Peptide YY
  6. Cholecystokinin
  7. Pancreatic polypeptide
  8. Amylin
  9. Ghrelin
  10. Conclusions
  11. Competing interests

Pancreatic polypeptide (PP) shares a hairpin-fold tertiary structure, known as the PP-fold, with PYY and neuropeptide Y [150]. The product of pancreatic islet PP-cells, it is secreted postprandially in proportion to the calorie content of ingested food [151–153]. Secretion is under vagal control, and is reduced by either atropine or vagotomy [154]. PP is a high-affinity agonist at the Y4 receptor (Y4R) but is also able to bind to the Y1R and Y5R [155]. As with PYY, the effect of exogenous PP on rodent food intake depends on route of administration, with the intracerebroventricular route resulting in an increase in food intake [156–158] but i.p. administration having the opposite effect [156, 159, 160]. Autoradiographic studies show that, after peripheral administration, 125I-labelled PP uptake occurs only in the area postrema, suggesting that the effect of intracerebroventricular PP is unlikely to be physiological [161].

Early animal studies showed that chronic administration of PP by i.p. injection reduces food intake and weight gain in ob/ob mice [160]. In New Zealand obese mice, similar treatment reduces hyperglycaemia, hyperinsulinaemia and weight gain [162]. More recent studies have shown that mice with selective transgenic overexpression of PP in pancreatic islets, resulting in a 20-fold increase in plasma PP concentration, are lean and hypophagic in comparison with controls [163]. Furthermore, this phenotype is reversed by administration of anti-PP antiserum [163]. Indirect calorimetry has been used to show that weight loss in ob/ob mice receiving PP is likely to occur both through a reduction in food intake and also through an increase in energy expenditure [159].

The effect of PP on human food intake was first studied in children with Prader-Willi syndrome, following the observation that meal-stimulated PP secretion is attenuated in this condition [164, 165]. In an initial study, i.v. infusion of extracted bovine PP did not affect measured food intake, but several parents noticed that their children had eaten less than usual after returning home from study infusions [166]. A second study was therefore performed, with a more prolonged infusion protocol, resulting in a 12% decrease in food intake [167]. More recently, human sequence PP has also been shown to reduce food intake in lean human volunteers [168, 169], and to delay gastric emptying [170]. However, since PP is degraded rapidly in the circulation [171], it is likely that its use as a treatment for obesity will depend on the development of long-acting Y4R agonists.


  1. Top of page
  2. Abstract
  3. GLP-1
  4. Oxyntomodulin
  5. Peptide YY
  6. Cholecystokinin
  7. Pancreatic polypeptide
  8. Amylin
  9. Ghrelin
  10. Conclusions
  11. Competing interests

Amylin is co-secreted with insulin by pancreatic islet β-cells and binds to a receptor complex that comprises the calcitonin receptor coupled to receptor activity-modifying proteins [172–176]. Peripheral administration of amylin in rats retards gastric emptying [177] and reduces food intake [178]. The anorectic effect is probably mediated via the area postrema, since it is abolished by experimental lesions in this area [179]. Furthermore, neuronal activation in the area postrema may be demonstrated by c-fos immunocytochemistry after peripheral administration of amylin [180].

A stable analogue of amylin, named pramlintide (Symlin; Amylin Pharmaceuticals, San Diego, CA, USA), is licensed in the USA for use as an adjunct to insulin treatment in both Type 1 and Type 2 diabetes mellitus, and its use in patients with these diseases is associated with modest weight loss [181–184]. In addition, small-scale trials of its efficacy as an obesity treatment have demonstrated that it may also be of use in patients without diabetes, both as monotherapy and in combination with a leptin receptor agonist [185, 186].


  1. Top of page
  2. Abstract
  3. GLP-1
  4. Oxyntomodulin
  5. Peptide YY
  6. Cholecystokinin
  7. Pancreatic polypeptide
  8. Amylin
  9. Ghrelin
  10. Conclusions
  11. Competing interests

Ghrelin is an octanoylated peptide, secreted by endocrine cells in the gastric fundus, that activates the growth hormone secretagogue receptor (GHS-R1a) [187, 188]. In contrast to other gut hormones, it is a potent orexigenic agent, causing hyperphagia after acute administration in humans [189, 190] and weight gain during repeated administration to rodents [191, 192]. Furthermore, chronic treatment with an orally available GHS-R1a agonist causes weight gain in humans [193].

Despite the negative correlation between ghrelin levels and BMI, a study of the effect of ghrelin infusion on acute food intake has shown that obese individuals may be more sensitive to the orexigenic effects of ghrelin than lean individuals [190]. In addition, obesity is associated with attenuation of the usual postprandial fall in ghrelin levels [194]. Furthermore, the GHS-R1a exhibits constitutive activity, suggesting that an inverse agonist may have greater anorectic effect than an antagonist [195]. These factors suggest that disruption of ghrelin signalling may prove useful for treating obesity.

Various approaches have been used to block ghrelin activity, including GHS-R1a antagonists [196, 197], RNA Spiegelmers [198–200], anti-ghrelin vaccines [201, 202] and use of somatostatin to inhibit endogenous ghrelin release [203–205]. A number of orally available GHS-R1a antagonists have also been developed, the most promising of which have been shown in rodents to cause reductions in food intake and body weight and to improve glucose tolerance [206, 207]. However, a viable treatment for human obesity has yet to emerge from any of these strategies.


  1. Top of page
  2. Abstract
  3. GLP-1
  4. Oxyntomodulin
  5. Peptide YY
  6. Cholecystokinin
  7. Pancreatic polypeptide
  8. Amylin
  9. Ghrelin
  10. Conclusions
  11. Competing interests

Satiety in humans is experienced as a spectrum that ranges from extreme hunger at one end, through the onset of satiation during a meal, to feelings of fullness and then nausea at the other end. Gut hormones play an important role in generating satiety, alongside neuronal afferent pathways and blood-borne humoral and nutrient signals. However, clinical trial experience has shown that enhanced satiety alone may not be sufficient to cause weight loss during chronic treatment [145]. Put another way, using gut hormone-based treatment to advance the onset of satiety at each meal may not necessarily lead to alterations in either long-term food intake or energy expenditure. Thus one of the major challenges in this field is to improve understanding of the physiological role of each gut hormone, integrating this knowledge into a comprehensive model of energy homeostasis.

As new peripheral targets for anti-obesity drug development, gut hormones also pose several other challenges. Amongst the greatest of these are that the native hormones are not orally available, and that they are cleared rapidly from the circulation, rendering their use by subcutaneous infusion or injection uneconomic. Various approaches have been proposed to circumvent these issues, including the use of other routes of administration, e.g. intranasal, inhalational or transdermal, the modification of peptide structures to render them resistant to proteolysis and clearance, and the synthesis of small molecule agonists. Each approach has its merits, but success may be most likely when the resulting treatment has a smooth pharmacokinetic profile, reducing the risk of nausea that may occur at high plasma concentrations.

Nausea has proved to be a very common adverse effect of treatment with exenatide, and it also occurs during administration of liraglutide, oxyntomodulin, pramlintide, CCK and PYY3-36. Studies in human volunteers of the anorectic effects of infusions of CCK-8 and PYY3-36 suggest that the presence or absence of nausea does not influence the extent of reduction of food intake [113, 208]. Furthermore, there is some evidence that the extent of weight loss with exenatide treatment is not related to the incidence of nausea [50, 51]. Although these findings suggest that maximal anorectic effects may be achieved without inducing nausea, it also seems likely that therapeutic windows may be narrow.

After RYGB, the physiological secretion of several hormones, including GLP-1, oxyntomodulin and PYY3-36, is increased. Although nausea is common in patients who have undergone RYGB, it tends only to occur postprandially, and is rarely severe enough to warrant reversal of the procedure. This gives rise to the hypothesis that treatment with multiple gut hormones could be better tolerated, and more effective, than single hormone treatment. Support for this hypothesis is available from small-scale studies of acute food intake in rodents and humans [99, 116], although not all combinations have proven effective [209, 210]. However, if nausea occurs not simply as a result of excessive satiety but also as a specific, independent side effect, it might be avoided, and weight loss maximized, by co-administration of non-nauseating doses of several hormones.

In summary, gut hormones present many opportunities for anti-obesity drug development. As peripheral targets, they may have relatively few nonspecific side effects compared with centrally acting drugs. Furthermore, it may be possible in the future, through judicious use of combination treatment, to mimic the physiological effect of RYGB and hence to cause a similar degree of weight loss without the perioperative risk. An ambitious goal? Yes, but one worth striving for.

Competing interests

  1. Top of page
  2. Abstract
  3. GLP-1
  4. Oxyntomodulin
  5. Peptide YY
  6. Cholecystokinin
  7. Pancreatic polypeptide
  8. Amylin
  9. Ghrelin
  10. Conclusions
  11. Competing interests

B.C.T.F. and O.B.C. have no financial interests to declare. S.R.B. is an inventor of United Kingdom patent application nos. PCT/GB02/04082 and PCT/GB/04/00017 and is a consultant for Thiakis, a subsidiary of Wyeth Pharmaceuticals.

B.C.T.F. and O.B.C. are recipients of NIHR Clinical Lectureships. We are very grateful to Dr Niamh Martin for her generous help with the preparation of this manuscript.


  1. Top of page
  2. Abstract
  3. GLP-1
  4. Oxyntomodulin
  5. Peptide YY
  6. Cholecystokinin
  7. Pancreatic polypeptide
  8. Amylin
  9. Ghrelin
  10. Conclusions
  11. Competing interests
  • 1
    WHO Global Infobase team. The suRF Report 2. Surveillance of Chronic Disease Risk Factors: Country-Level Data and Comparable Estimates. Geneva: World Health Organisation, 2007.
  • 2
    Katzmarzyk PT, Ardern CI. Overweight and obesity mortality trends in Canada, 1985–2000. Can J Public Health 2004; 95: 1620.
  • 3
    Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999–2000. JAMA 2002; 288: 17237.
  • 4
    De Looper M, Bhatia K. Australian Health Trends 2001. AIHW Cat. No. PHE 24. Canberra: Australian Institute of Health and Welfare, 2001.
  • 5
    National Audit Office. Tackling obesity in England. Report by the Comptroller and Auditor General. London: The Stationery Office, 2001.
  • 6
    Prospective Studies Collaboration, Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, Halsey J, Qizilbash N, Collins R, Peto R. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet 2009; 373: 108396.
  • 7
    Kopelman PG. Obesity as a medical problem. Nature 2000; 404: 63543.
  • 8
    Colditz GA, Willett WC, Rotnitzky A, Manson JE. Weight gain as a risk factor for clinical diabetes mellitus in women. Ann Intern Med 1995; 122: 4816.
  • 9
    Dansinger ML, Gleason JA, Griffith JL, Selker HP, Schaefer EJ. Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial. JAMA 2005; 293: 4353.
  • 10
    Padwal RS, Majumdar SR. Drug treatments for obesity: orlistat, sibutramine, and rimonabant. Lancet 2007; 369: 717.
  • 11
    Adams TD, Gress RE, Smith SC, Halverson RC, Simper SC, Rosamond WD, LaMonte MJ, Stroup AM, Hunt SC. Long-term mortality after gastric bypass surgery. N Engl J Med 2007; 357: 75361.
  • 12
    Sjöström L, Narbro K, Sjöström CD, Karason K, Larsson B, Wedel H, Lystig T, Sullivan M, Bouchard C, Carlsson B, Bengtsson C, Dahlgren S, Gummesson A, Jacobson P, Karlsson J, Lindroos A-K, Lönroth H, Näslund I, Olbers T, Stenlöf K, Torgerson J, Ågren G, Carlsson LMS. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007; 357: 74152.
  • 13
    Cottam DR, Atkinson J, Anderson A, Grace B, Fisher B. A case-controlled matched-pair cohort study of laparoscopic Roux-en-Y gastric bypass and Lap-Band patients in a single US center with three-year follow-up. Obes Surg 2006; 16: 53440.
  • 14
    Bowne WB, Julliard K, Castro AE, Shah P, Morgenthal CB, Ferzli GS. Laparoscopic gastric bypass is superior to adjustable gastric band in super morbidly obese patients: a prospective, comparative analysis. Arch Surg 2006; 141: 6839.
  • 15
    Sjöström L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, Dahlgren S, Larsson B, Narbro K, Sjöström CD, Sullivan M, Wedel H; Swedish Obese Subjects Study Scientific Group. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004; 351: 268393.
  • 16
    Kellum JM, Kuemmerle JF, O'Dorisio TM, Rayford P, Martin D, Engle K, Wolf L, Sugerman HJ. Gastrointestinal hormone responses to meals before and after gastric bypass and vertical banded gastroplasty. Ann Surg 1990; 211: 76370.
  • 17
    Le Roux CW, Aylwin SJB, Batterham RL, Borg CM, Coyle F, Prasad V, Shurey S, Ghatei MA, Patel AG, Bloom SR. Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters. Ann Surg 2006; 243: 10814.
  • 18
    Morínigo R, Moizé V, Musri M, Lacy AM, Navarro S, Marín JL, Delgado S, Casamitjana R, Vidal J. Glucagon-like peptide-1, peptide YY, hunger, and satiety after gastric bypass surgery in morbidly obese subjects. J Clin Endocrinol Metab 2006; 91: 173540.
  • 19
    Andrews NJ, Irving MH. Human gut hormone profiles in patients with short bowel syndrome. Dig Dis Sci 1992; 37: 72932.
  • 20
    Varndell IM, Bishop AE, Sikri KL, Uttenthal LO, Bloom SR, Polak JM. Localization of glucagon-like peptide (GLP) immunoreactants in human gut and pancreas using light and electron microscopic immunocytochemistry. J Histochem Cytochem 1985; 33: 10806.
  • 21
    Jang HJ, Kokrashvili Z, Theodorakis MJ, Carlson OD, Kim B-J, Zhou J, Kim HH, Xu X, Chan SL, Juhaszova M, Bernier M, Mosinger B, Margolskee RF, Egan JM. Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1. Proc Natl Acad Sci USA 2007; 104: 1506974.
  • 22
    Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M, Sugimoto Y, Miyazaki S, Tsujimoto G. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med 2005; 11: 904.
  • 23
    Rocca AS, Brubaker PL. Role of the vagus nerve in mediating proximal nutrient-induced glucagon-like peptide-1 secretion. Endocrinology 1999; 140: 168794.
  • 24
    Herrmann C, Göke R, Richter G, Fehmann HC, Arnold R, Göke B. Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients. Digestion 1995; 56: 11726.
  • 25
    Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet 1987; 2: 13004.
  • 26
    Thorens B. Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci USA 1992; 89: 86415.
  • 27
    Lu M, Wheeler MB, Leng XH, Boyd AE III. The role of the free cytosolic calcium level in beta-cell signal transduction by gastric inhibitory polypeptide and glucagon-like peptide I(7-37). Endocrinology 1993; 132: 94100.
  • 28
    Wei Y, Mojsov S. Tissue-specific expression of the human receptor for glucagon-like peptide-I: brain, heart and pancreatic forms have the same deduced amino acid sequences. FEBS Lett 1995; 358: 21924.
  • 29
    Perfetti R, Zhou J, Doyle ME, Egan JM. Glucagon-like peptide-1 induces cell proliferation and pancreatic-duodenum homeobox-1 expression and increases endocrine cell mass in the pancreas of old, glucose-intolerant rats. Endocrinology 2000; 141: 46005.
  • 30
    Willms B, Werner J, Holst JJ, Ørskov C, Creutzfeldt W, Nauck MA. Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7-36) amide in type 2 (noninsulin-dependent) diabetic patients. J Clin Endocrinol Metab 1996; 81: 32732.
  • 31
    Gutniak M, Ørskov C, Holst JJ, Ahrén B, Efendic S. Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus. N Engl J Med 1992; 326: 131622.
  • 32
    Larsen PJ, Fledelius C, Knudsen LB, Tang-Christensen M. Systemic administration of the long-acting GLP-1 derivative NN2211 induces lasting and reversible weight loss in both normal and obese rats. Diabetes 2001; 50: 25309.
  • 33
    Turton MD, O'Shea D, Gunn I, Beak SA, Edwards CMB, Meeran K, Choi SJ, Taylor GM, Heath MM, Lambert PD, Wilding JPH, Smith DM, Ghatei MA, Herbert J, Bloom SR. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 1996; 379: 6972.
  • 34
    Tang-Christensen M, Larsen PJ, Göke R, Fink-Jensen A, Jessop DS, Møller M, Sheikh SP. Central administration of GLP-1-(7-36) amide inhibits food and water intake in rats. Am J Physiol 1996; 271: R84856.
  • 35
    Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest. 1998; 101: 51520.
  • 36
    Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 2002; 359: 82430.
  • 37
    Abbott CR, Monteiro M, Small CJ, Sajedi A, Smith KL, Parkinson JRC, Ghatei MA, Bloom SR. The inhibitory effects of peripheral administration of peptide YY(3-36) and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagal-brainstem-hypothalamic pathway. Brain Res 2005; 1044: 12731.
  • 38
    Rowland NE, Crews EC, Gentry RM. Comparison of Fos induced in rat brain by GLP-1 and amylin. Regul Pept 1997; 71: 1714.
  • 39
    Larsen PJ, Tang-Christensen M, Jessop DS. Central administration of glucagon-like peptide-1 activates hypothalamic neuroendocrine neurons in the rat. Endocrinology 1997; 138: 444555.
  • 40
    Zhou J, Roane DS, Xi X, Bogacka I, Li B, Ryan DH, Martin RJ. Short-term food restriction and refeeding alter expression of genes likely involved in brain glucosensing. Exp Biol Med 2003; 228: 94350.
  • 41
    Nakagawa A, Satake H, Nakabayashi H, Nishizawa M, Furuya K, Nakano S, Kigoshi T, Nakayama K, Uchida K. Receptor gene expression of glucagon-like peptide-1, but not glucose-dependent insulinotropic polypeptide, in rat nodose ganglion cells. Auton Neurosci 2004; 110: 3643.
  • 42
    Mentlein R, Gallwitz B, Schmidt WE. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem 1993; 214: 82935.
  • 43
    Kieffer TJ, McIntosh CH, Pederson RA. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 1995; 136: 358596.
  • 44
    Simonsen L, Holst JJ, Deacon CF. Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs. Diabetologia 2006; 49: 70612.
  • 45
    De Meester I, Lambeir AM, Proost P, Scharpé S. Dipeptidyl peptidase IV substrates. An update on in vitro peptide hydrolysis by human DPPIV. Adv Exp Med Biol 2003; 524: 317.
  • 46
    Thum A, Hupe-Sodmann K, Göke R, Voigt K, Göke B, McGregor GP. Endoproteolysis by isolated membrane peptidases reveal metabolic stability of glucagon-like peptide-1 analogs, exendins-3 and -4. Exp Clin Endocrinol Diabetes 2002; 110: 1138.
  • 47
    Eng J, Kleinman WA, Singh L, Singh G, Raufman JP. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem 1992; 267: 74025.
  • 48
    Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, Porter L. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 2008; 372: 124050.
  • 49
    Kim D, MacConell L, Zhuang D, Kothare PA, Trautmann M, Fineman M, Taylor K. Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type 2 diabetes. Diabetes Care 2007; 30: 148793.
  • 50
    Ratner RE, Maggs D, Nielsen LL, Stonehouse AH, Poon T, Zhang B, Bicsak TA, Brodows RG, Kim DD. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab 2006; 8: 41928.
  • 51
    Riddle MC, Henry RR, Poon TH, Zhang B, Mac SM, Holcombe JH, Kim DD, Maggs DG. Exenatide elicits sustained glycaemic control and progressive reduction of body weight in patients with type 2 diabetes inadequately controlled by sulphonylureas with or without metformin. Diabetes Metab Res Rev 2006; 22: 48391.
  • 52
    Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (Exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004; 27: 262835.
  • 53
    DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (Exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005; 28: 1092100.
  • 54
    Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, Baron AD. Effects of exenatide (Exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 2005; 28: 108391.
  • 55
    Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med 2005; 143: 55969.
  • 56
    Denker PS, Dimarco PE. Exenatide (exendin-4)-induced pancreatitis: a case report. Diabetes Care 2006; 29: 471.
  • 57
    Ahmad SR, Swann J. Exenatide and rare adverse events. N Engl J Med 2008; 358: 19701.
  • 58
    Dore DD, Seeger JD, Arnold CK. Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide. Curr Med Res Opin 2009; 25: 101927.
  • 59
    Elkind-Hirsch K, Marrioneaux O, Bhushan M, Vernor D, Bhushan R. Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab 2008; 93: 26708.
  • 60
    Russell-Jones D. Molecular, pharmacological and clinical aspects of liraglutide, a once-daily human GLP-1 analogue. Mol Cell Endocrinol 2009; 297: 13740.
  • 61
    Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, Zdravkovic M, Düring M, Matthews DR. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009; 32: 8490.
  • 62
    Zinman B, Gerich J, Buse JB, Lewin A, Schwartz S, Raskin P, Hale PM, Zdravkovic M, Blonde L. Efficacy and safety of the human GLP-1 analog liraglutide in combination with metformin and TZD in patients with type 2 diabetes mellitus (LEAD-4 Met+TZD). Diabetes Care 2009; 32: 122430.
  • 63
    Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, Hale PM, Zdravkovic M, Bode B. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 2009; 373: 47381.
  • 64
    Marre M, Shaw J, Brändle M, Bebakar WM, Kamaruddin NA, Strand J, Zdravkovic M, Le Thi TD, Colagiuri S. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). Diabet Med 2009; 26: 26878.
  • 65
    Nauck MA, Ratner RE, Kapitza C, Berria R, Boldrin M, Balena R. Treatment with the human once-weekly GLP-1 analogue taspoglutide in combination with metformin improves glycemic control and lowers body weight in patients with type 2 diabetes mellitus inadequately controlled with metformin alone: a double-blind placebo-controlled study. Diabetes Care 2009; 32: 123743.
  • 66
    Matthews JE, Stewart MW, De Boever EH, Dobbins RL, Hodge RJ, Walker SE, Holland MC, Bush MA. Pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in patients with type 2 diabetes. J Clin Endocrinol Metab 2008; 93: 48107.
  • 67
    Mojsov S, Heinrich G, Wilson IB, Ravazzola M, Orci L, Habener JF. Preproglucagon gene expression in pancreas and intestine diversifies at the level of post-translational processing. J Biol Chem 1986; 261: 118809.
  • 68
    Ghatei MA, Uttenthal LO, Christofides ND, Bryant MG, Bloom SR. Molecular forms of human enteroglucagon in tissue and plasma: plasma responses to nutrient stimuli in health and in disorders of the upper gastrointestinal tract. J Clin Endocrinol Metab 1983; 57: 48895.
  • 69
    Le QA, Kervran A, Blache P, Ciurana AJ, Bataille D. Oxyntomodulin-like immunoreactivity: diurnal profile of a new potential enterogastrone. J Clin Endocrinol Metab 1992; 74: 14059.
  • 70
    Schjoldager B, Mortensen PE, Myhre J, Christiansen J, Holst JJ. Oxyntomodulin from distal gut. Role in regulation of gastric and pancreatic functions. Dig Dis Sci 1989; 34: 14119.
  • 71
    Biedzinski TM, Bataille D, Devaux MA, Sarles H. The effect of oxyntomodulin (glucagon-37) and glucagon on exocrine pancreatic secretion in the conscious rat. Peptides 1987; 8: 96772.
  • 72
    Dubrasquet M, Bataille D, Gespach C. Oxyntomodulin (glucagon-37 or bioactive enteroglucagon): a potent inhibitor of pentagastrin-stimulated acid secretion in rats. Biosci Rep 1982; 2: 3915.
  • 73
    Bataille D, Gespach C, Coudray AM, Rosselin G. Enteroglucagon’: a specific effect on gastric glands isolated from the rat fundus. Evidence for an ‘oxyntomodulin’ action. Biosci Rep 1981; 1: 1515.
  • 74
    Baggio LL, Huang Q, Brown TJ, Drucker DJ. Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology 2004; 127: 54658.
  • 75
    Dakin CL, Gunn I, Small CJ, Edwards CMB, Hay DL, Smith DM, Ghatei MA, Bloom SR. Oxyntomodulin inhibits food intake in the rat. Endocrinology 2001; 142: 424450.
  • 76
    Dakin CL, Small CJ, Park AJ, Seth A, Ghatei MA, Bloom SR. Repeated ICV administration of oxyntomodulin causes a greater reduction in body weight gain than in pair-fed rats. Am J Physiol Endocrinol Metab 2002; 283: E11737.
  • 77
    Dakin CL, Small CJ, Batterham RL, Neary NM, Cohen MA, Patterson M, Ghatei MA, Bloom SR. Peripheral oxyntomodulin reduces food intake and body weight gain in rats. Endocrinology 2004; 145: 268795.
  • 78
    Cohen MA, Ellis SM, Le Roux CW, Batterham RL, Park A, Patterson M, Frost GS, Ghatei MA, Bloom SR. Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin Endocrinol Metab 2003; 88: 4696701.
  • 79
    Wynne K, Park AJ, Small CJ, Patterson M, Ellis SM, Murphy KG, Wren AM, Frost GS, Meeran K, Ghatei MA, Bloom SR. Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial. Diabetes 2005; 54: 23905.
  • 80
    Wynne K, Park AJ, Small CJ, Meeran K, Ghatei MA, Frost GS, Bloom SR. Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: a randomised controlled trial. Int J Obes (Lond) 2006; 30: 172936.
  • 81
    Bataille D, Tatemoto K, Gespach C, Jornvall H, Rosselin G, Mutt V. Isolation of glucagon-37 (bioactive enteroglucagon/oxyntomodulin) from porcine jejuno-ileum. Characterization of the peptide. FEBS Lett 1982; 146: 7986.
  • 82
    Bell GI, Santerre RF, Mullenbach GT. Hamster preproglucagon contains the sequence of glucagon and two related peptides. Nature 1983; 302: 7168.
  • 83
    Bell GI, Sanchez-Pescador R, Laybourn PJ, Najarian RC. Exon duplication and divergence in the human preproglucagon gene. Nature 1983; 304: 36871.
  • 84
    Chaudhri OB, Parkinson JR, Kuo Y-T, Druce MR, Herlihy AH, Bell JD, Dhillo WS, Stanley SA, Ghatei MA, Bloom SR. Differential hypothalamic neuronal activation following peripheral injection of GLP-1 and oxyntomodulin in mice detected by manganese-enhanced magnetic resonance imaging. Biochem Biophys Res Commun 2006; 350: 298306.
  • 85
    Parkinson JRC, Chaudhri OB, Kuo YT, Field BCT, Herlihy AH, Dhillo WS, Ghatei MA, Bloom SR, Bell JD. Differential patterns of neuronal activation in the brainstem and hypothalamus following peripheral injection of GLP-1, oxyntomodulin and lithium chloride in mice detected by manganese-enhanced magnetic resonance imaging (MEMRI). NeuroImage 2009; 44: 102231.
  • 86
    Druce MR, Minnion JS, Field BCT, Patel SR, Shillito JC, Tilby M, Beale KE, Murphy KG, Ghatei MA, Bloom SR. Investigation of structure–activity relationships of oxyntomodulin (oxm) using oxm analogs. Endocrinology 2009; 150: 171222.
  • 87
    Zhu L, Tamvakopoulos C, Xie D, Dragovic J, Shen X, Fenyk-Melody JE, Schmidt K, Bagchi A, Griffin PR, Thornberry NA, Sinha Roy R. The role of dipeptidyl peptidase IV in the cleavage of glucagon family peptides: in vivo metabolism of pituitary adenylate cyclase activating polypeptide-(1-38). J Biol Chem 2003; 278: 2241823.
  • 88
    Batterham RL, Heffron H, Kapoor S, Chivers JE, Chandarana K, Herzog H, Le Roux CW, Thomas EL, Bell JD, Withers DJ. Critical role for peptide YY in protein-mediated satiation and body-weight regulation. Cell Metab 2006; 4: 22333.
  • 89
    Pedersen-Bjergaard U, Høst U, Kelbaek H, Schifter S, Rehfeld JF, Faber J, Christensen NJ. Influence of meal composition on postprandial peripheral plasma concentrations of vasoactive peptides in man. Scand J Clin Lab Invest 1996; 56: 497503.
  • 90
    Adrian TE, Ferri GL, Bacarese-Hamilton AJ, Fuessl HS, Polak JM, Bloom SR. Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology 1985; 89: 10707.
  • 91
    Nygaard R, Nielbo S, Schwartz TW, Poulsen FM. The PP-fold solution structure of human polypeptide YY and human PYY3-36 as determined by NMR. Biochem 2006; 45: 83507.
  • 92
    Grandt D, Schimiczek M, Beglinger C, Layer P, Goebell H, Eysselein VE, Reeve JR Jr. Two molecular forms of peptide YY (PYY) are abundant in human blood: characterization of a radioimmunoassay recognizing PYY 1-36 and PYY 3-36. Regul Pept 1994; 51: 1519.
  • 93
    Eberlein GA, Eysselein VE, Schaeffer M, Layer P, Grandt D, Goebell H, Niebel W, Davis M, Lee TD, Shively JE, Reeve JR Jr. A new molecular form of PYY: structural characterization of human PYY(3-36) and PYY(1-36). Peptides 1989; 10: 797803.
  • 94
    Mentlein R, Dahms P, Grandt D, Kruger R. Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV. Regul Pept 1993; 49: 13344.
  • 95
    Morley JE, Levine AS, Grace M, Kneip J. Peptide YY (PYY), a potent orexigenic agent. Brain Res 1985; 341: 2003.
  • 96
    Dumont Y, Moyse E, Fournier A, Quirion R. Distribution of peripherally injected peptide YY ([125I] PYY (3-36)) and pancreatic polypeptide ([125I] hPP) in the CNS: enrichment in the area postrema. J Mol Neurosci 2007; 33: 294304.
  • 97
    Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA, Dakin CL, Wren AM, Brynes AE, Low MJ, Ghatei MA, Cone RD, Bloom SR. Gut hormone PYY(3-36) physiologically inhibits food intake. Nature 2002; 418: 6504.
  • 98
    Abbott CR, Small CJ, Kennedy AR, Neary NM, Sajedi A, Ghatei MA, Bloom SR. Blockade of the neuropeptide Y Y2 receptor with the specific antagonist BIIE0246 attenuates the effect of endogenous and exogenous peptide YY(3-36) on food intake. Brain Res 2005; 1043: 13944.
  • 99
    Talsania T, Anini Y, Siu S, Drucker DJ, Brubaker PL. Peripheral exendin-4 and peptide YY(3-36) synergistically reduce food intake through different mechanisms in mice. Endocrinology 2005; 146: 374856.
  • 100
    Ghilardi JR, Allen CJ, Vigna SR, McVey DC, Mantyh PW. Cholecystokinin and neuropeptide Y receptors on single rabbit vagal afferent ganglion neurons: site of prejunctional modulation of visceral sensory neurons. Brain Res 1994; 633: 3340.
  • 101
    Koda S, Date Y, Murakami N, Shimbara T, Hanada T, Toshinai K, Niijima A, Furuya M, Inomata N, Osuye K, Nakazato M. The role of the vagal nerve in peripheral PYY3-36-induced feeding reduction in rats. Endocrinology 2005; 146: 236975.
  • 102
    Boggiano MM, Chandler PC, Oswald KD, Rodgers RJ, Blundell JE, Ishii Y, Beattie AH, Holch P, Allison DB, Schindler M, Arndt K, Rudolf K, Mark M, Schoelch C, Joost HG, Klaus S, Thöne-Reineke C, Benoit SC, Seeley RJ, Beck-Sickinger AG, Koglin N, Raun K, Madsen K, Wulff BS, Stidsen CE, Birringer M, Kreuzer OJ, Deng XY, Whitcomb DC, Halem H, Taylor J, Dong J, Datta R, Culler M, Ortmann S, Castañeda TR, Tschöp M. PYY3-36 as an anti-obesity drug target. Obes Rev 2005; 6: 30722.
  • 103
    Tschöp M, Castañeda TR, Joost HG, Thöne-Reineke C, Ortmann S, Klaus S, Hagan MM, Chandler PC, Oswald KD, Benoit SC, Seeley RJ, Kinzig KP, Moran TH, Beck-Sickinger AG, Koglin N, Rodgers RJ, Blundell JE, Ishii Y, Beattie AH, Holch P, Allison DB, Raun K, Madsen K, Wulff BS, Stidsen CE, Birringer M, Kreuzer OJ, Schindler M, Arndt K, Rudolf K, Mark M, Deng XY, Whitcomb DC, Halem H, Taylor J, Dong J, Datta R, Culler M, Craney S, Flora D, Smiley D, Heiman ML. Physiology: does gut hormone PYY3-36 decrease food intake in rodents? Nature 2004; 430. doi:10.1038/nature02665.
  • 104
    Asakawa A, Uemoto M, Ueno N, Katagi M, Fujimiya M, Fujino K, Kodoma N, Nanba H, Sakamaki R, Shinfuku N, Meguid MM, Inui A. Peptide YY3-36 and pancreatic polypeptide suppress food intake. J Gastroenterol Hepatol 2006; 21: 15012.
  • 105
    Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, Ghatei MA, Bloom SR. Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med 2003; 349: 9418.
  • 106
    Batterham RL, Ffytche DH, Rosenthal JM, Zelaya FO, Barker GJ, Withers DJ, Williams SCR. PYY modulation of cortical and hypothalamic brain areas predicts feeding behaviour in humans. Nature 2007; 450: 1069.
  • 107
    Challis BG, Pinnock SB, Coll AP, Carter RN, Dickson SL, O'Rahilly S. Acute effects of PYY3-36 on food intake and hypothalamic neuropeptide expression in the mouse. Biochem Biophys Res Commun 2003; 311: 9159.
  • 108
    Challis BG, Coll AP, Yeo GS, Pinnock SB, Dickson SL, Thresher RR, Dixon J, Zahn D, Rochford JJ, White A, Oliver RL, Millington G, Aparicio SA, Colledge WH, Russ AP, Carlton MB, O'Rahilly S. Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY(3-36). Proc Natl Acad Sci USA 2004; 101: 4695700.
  • 109
    Chelikani PK, Haver AC, Reidelberger RD. Intravenous infusion of peptide YY(3-36) potently inhibits food intake in rats. Endocrinology 2005; 146: 87988.
  • 110
    Degen L, Oesch S, Casanova M, Graf S, Ketterer S, Drewe J, Beglinger C. Effect of peptide YY3-36 on food intake in humans. Gastroenterology 2005; 129: 14306.
  • 111
    Ito T, Thidarmyint H, Murata T, Inoue H, Neyra RM, Kuwayama H. Effects of peripheral administration of PYY3-36 on feed intake and plasma acyl-ghrelin levels in pigs. J Endocrinol 2006; 191: 1139.
  • 112
    Le Roux CW, Batterham RL, Aylwin SJ, Patterson M, Borg CM, Wynne KJ, Kent A, Vincent RP, Gardiner J, Ghatei MA, Bloom SR. Attenuated peptide YY release in obese subjects is associated with reduced satiety. Endocrinology 2006; 147: 38.
  • 113
    Le Roux CW, Borg CM, Murphy KG, Vincent RP, Ghatei MA, Bloom SR. Supraphysiological doses of intravenous PYY3-36 cause nausea, but no additional reduction in food intake. Ann Clin Biochem 2008; 45: 935.
  • 114
    Martin NM, Small CJ, Sajedi A, Patterson M, Ghatei MA, Bloom SR. Pre-obese and obese agouti mice are sensitive to the anorectic effects of peptide YY(3-36) but resistant to ghrelin. Int J Obes Relat Metab Disord 2004; 28: 88693.
  • 115
    Moran TH, Smedh U, Kinzig KP, Scott KA, Knipp S, Ladenheim EE. Peptide YY(3-36) inhibits gastric emptying and produces acute reductions in food intake in rhesus monkeys. Am J Physiol Regul Integr Comp Physiol 2005; 288: R3848.
  • 116
    Neary NM, Small CJ, Druce MR, Park AJ, Ellis SM, Semjonous NM, Dakin CL, Filipsson K, Wang F, Kent AS, Frost GS, Ghatei MA, Bloom SR. Peptide YY3-36 and glucagon-like peptide-17-36 inhibit food intake additively. Endocrinology 2005; 146: 51207.
  • 117
    Roth JD, Coffey T, Jodka CM, Maier H, Athanacio JR, Mack CM, Weyer C, Parkes DG. Combination therapy with amylin and peptide YY[3-36] in obese rodents: anorexigenic synergy and weight loss additivity. Endocrinology 2007; 148: 605461.
  • 118
    Unniappan S, McIntosh CH, Demuth HU, Heiser U, Wolf R, Kieffer TJ. Effects of dipeptidyl peptidase IV on the satiety actions of peptide YY. Diabetologia 2006; 49: 191523.
  • 119
    Chelikani PK, Haver AC, Reidelberger RD. Intermittent intraperitoneal infusion of peptide YY(3-36) reduces daily food intake and adiposity in obese rats. Am J Physiol Regul Integr Comp Physiol 2007; 293: R3946.
  • 120
    Adams SH, Lei C, Jodka CM, Nikoulina SE, Hoyt JA, Gedulin B, Mack CM, Kendall ES. PYY[3-36] administration decreases the respiratory quotient and reduces adiposity in diet-induced obese mice. J Nutr 2006; 136: 195201.
  • 121
    Chelikani PK, Haver AC, Reeve JR Jr, Keire DA, Reidelberger RD. Daily, intermittent intravenous infusion of peptide YY(3-36) reduces daily food intake and adiposity in rats. Am J Physiol Regul Integr Comp Physiol 2006; 290: R298305.
  • 122
    Koegler FH, Enriori PJ, Billes SK, Takahashi DL, Martin MS, Clark RL, Evans AE, Grove KL, Cameron JL, Cowley MA. Peptide YY(3-36) inhibits morning, but not evening, food intake and decreases body weight in rhesus macaques. Diabetes 2005; 54: 3198204.
  • 123
    Pittner RA, Moore CX, Bhavsar SP, Gedulin BR, Smith PA, Jodka CM, Parkes DG, Paterniti JR, Srivastava VP, Young AA. Effects of PYY[3-36] in rodent models of diabetes and obesity. Int J Obes Relat Metab Disord 2004; 28: 96371.
  • 124
    Sileno AP, Brandt GC, Spann BM, Quay SC. Lower mean weight after 14 days intravenous administration peptide YY3-36 (PYY3-36) in rabbits. Int J Obes (Lond) 2006; 30: 6872.
  • 125
    Abbott CR, Small CJ, Sajedi A, Smith KL, Parkinson JR, Broadhead LL, Ghatei MA, Bloom SR. The importance of acclimatisation and habituation to experimental conditions when investigating the anorectic effects of gastrointestinal hormones in the rat. Int J Obes (Lond) 2006; 30: 28892.
  • 126
    Gantz I, Erondu N, Mallick M, Musser B, Krishna R, Tanaka WK, Snyder K, Stevens C, Stroh MA, Zhu H, Wagner JA, MacNeil DJ, Heymsfield SB, Amatruda JM. Efficacy and safety of intranasal peptide YY3-36 for weight reduction in obese adults. J Clin Endocrinol Metab 2007; 92: 17547.
  • 127
    Polak JM, Bloom SR, Rayford PL, Pearse AG, Buchan AM, Thompson JC. Identification of cholecystokinin-secreting cells. Lancet 1975; 2: 10168.
  • 128
    Liddle RA, Goldfine ID, Rosen MS, Taplitz RA, Williams JA. Cholecystokinin bioactivity in human plasma. Molecular forms, responses to feeding, and relationship to gallbladder contraction. J Clin Invest 1985; 75: 114452.
  • 129
    Rehfeld JF, Sun G, Christensen T, Hillingsø JG. The predominant cholecystokinin in human plasma and intestine is cholecystokinin-33. J Clin Endocrinol Metab 2001; 86: 2518.
  • 130
    Hutchison JB, Dimaline R, Dockray GJ. Neuropeptides in the gut: quantification and characterization of cholecystokinin octapeptide-, bombesin- and vasoactive intestinal polypeptide-like immunoreactivities in the myenteric plexus of the guinea-pig small institute. Peptides 1981; 2: 2330.
  • 131
    Barden N, Merand Y, Rouleau D, Moore S, Dockray GJ, Dupont A. Regional distributions of somatostatin and cholecystokinin-like immunoreactivities in rat and bovine brain. Peptides 1981; 2: 299302.
  • 132
    Kopin AS, Mathes WF, McBride EW, Nguyen M, Al-Haider W, Schmitz F, Bonner-Weir S, Kanarek R, Beinborn M. The cholecystokinin-A receptor mediates inhibition of food intake yet is not essential for the maintenance of body weight. J Clin Invest 1999; 103: 38391.
  • 133
    Beglinger C, Degen L, Matzinger D, D'Amato M, Drewe J. Loxiglumide, a CCK-A receptor antagonist, stimulates calorie intake and hunger feelings in humans. Am J Physiol Regul Integr Comp Physiol 2001; 280: R114954.
  • 134
    Dufresne M, Seva C, Fourmy D. Cholecystokinin and gastrin receptors. Physiol Rev 2006; 86: 80547.
  • 135
    Gibbs J, Young RC, Smith GP. Cholecystokinin decreases food intake in rats. J Comp Physiol Psychol 1973; 84: 48895.
  • 136
    Ritter RC, Ladenheim EE. Capsaicin pretreatment attenuates suppression of food intake by cholecystokinin. Am J Physiol 1985; 248: R5014.
  • 137
    MacLean DB. Abrogation of peripheral cholecystokinin-satiety in the capsaicin treated rat. Regul Pept 1985; 11: 32133.
  • 138
    Asin KE, Gore PA Jr, Bednarz L, Holladay M, Nadzan AM. Effects of selective CCK receptor agonists on food intake after central or peripheral administration in rats. Brain Res 1992; 571: 16974.
  • 139
    Moran TH, Baldessarini AR, Salorio CF, Lowery T, Schwartz GJ. Vagal afferent and efferent contributions to the inhibition of food intake by cholecystokinin. Am J Physiol 1997; 272: R124551.
  • 140
    Kissileff HR, Pi-Sunyer FX, Thornton J, Smith GP. C-terminal octapeptide of cholecystokinin decreases food intake in man. Am J Clin Nutr 1981; 34: 15460.
  • 141
    Pi-Sunyer X, Kissileff HR, Thornton J, Smith GP. C-terminal octapeptide of cholecystokinin decreases food intake in obese men. Physiol Behav 1982; 29: 62730.
  • 142
    Lieverse RJ, Jansen JB, Van De Zwan A, Samson L, Masclee AA, Lamers CB. Effects of a physiological dose of cholecystokinin on food intake and postprandial satiation in man. Regul Pept 1993; 43: 839.
  • 143
    Lieverse RJ, Jansen JB, Masclee AM, Lamers CB. Satiety effects of cholecystokinin in humans. Gastroenterology 1994; 106: 14514.
  • 144
    Lieverse RJ, Jansen JB, Masclee AA, Lamers CB. Satiety effects of a physiological dose of cholecystokinin in humans. Gut 1995; 36: 1769.
  • 145
    Jordan J, Greenway FL, Leiter LA, Li Z, Jacobson P, Murphy K, Hill J, Kler L, Aftring RP. Stimulation of cholecystokinin-A receptors with GI181771X does not cause weight loss in overweight or obese patients. Clin Pharmacol Ther 2008; 83: 2817.
  • 146
    Crawley JN, Beinfeld MC. Rapid development of tolerance to the behavioural actions of cholecystokinin. Nature 1983; 302: 7036.
  • 147
    West DB, Fey D, Woods SC. Cholecystokinin persistently suppresses meal size but not food intake in free-feeding rats. Am J Physiol 1984; 246: R77687.
  • 148
    Matson CA, Reid DF, Ritter RC. Daily CCK injection enhances reduction of body weight by chronic intracerebroventricular leptin infusion. Am J Physiol Regul Integr Comp Physiol 2002; 282: R136873.
  • 149
    Merino B, Cano V, Guzman R, Somoza B, Ruiz-Gayo M. Leptin-mediated hypothalamic pathway of cholecystokinin (CCK-8) to regulate body weight in free-feeding rats. Endocrinology 2008; 149: 19942000.
  • 150
    Glover I, Haneef I, Pitts J, Wood S, Moss D, Tickle I, Blundell T. Conformational flexibility in a small globular hormone: x-ray analysis of avian pancreatic polypeptide at 0.98-Å resolution. Biopolymers 1983; 22: 293304.
  • 151
    Adrian TE, Bloom SR, Bryant MG, Polak JM, Heitz PH, Barnes AJ. Distribution and release of human pancreatic polypeptide. Gut 1976; 17: 9404.
  • 152
    Larsson LI, Sundler F, Håkanson R. Immunohistochemical localization of human pancreatic polypeptide (HPP) to a population of islet cells. Cell Tissue Res 1975; 156: 16771.
  • 153
    Track NS, McLeod RS, Mee AV. Human pancreatic polypeptide: studies of fasting and postprandial plasma concentrations. Can J Physiol Pharmacol 1980; 58: 14849.
  • 154
    Schwartz TW, Holst JJ, Fahrenkrug J, Lindkær Jensen S, Nielsen OV, Rehfeld JF, Schaffalitzky de Muckadell OB, Stadil F. Vagal, cholinergic regulation of pancreatic polypeptide secretion. J Clin Invest 1978; 61: 7819.
  • 155
    Berglund MM, Hipskind PA, Gehlert DR. Recent developments in our understanding of the physiological role of PP-fold peptide receptor subtypes. Exp Biol Med (Maywood) 2003; 228: 21744.
  • 156
    Asakawa A, Inui A, Ueno N, Fujimiya M, Fujino MA, Kasuga M. Mouse pancreatic polypeptide modulates food intake, while not influencing anxiety in mice. Peptides 1999; 20: 14458.
  • 157
    Campbell RE, Smith MS, Allen SE, Grayson BE, Ffrench-Mullen JM, Grove KL. Orexin neurons express a functional pancreatic polypeptide Y4 receptor. J Neurosci 2003; 23: 148797.
  • 158
    Clark JT, Kalra PS, Crowley WR, Kalra SP. Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 1984; 115: 4279.
  • 159
    Asakawa A, Inui A, Yuzuriha H, Ueno N, Katsuura G, Fujimiya M, Fujino MA, Niijima A, Meguid MM, Kasuga M. Characterization of the effects of pancreatic polypeptide in the regulation of energy balance. Gastroenterology 2003; 124: 132536.
  • 160
    Malaisse-Lagae F, Carpentier JL, Patel YC, Malaisse WJ, Orci L. Pancreatic polypeptide: a possible role in the regulation of food intake in the mouse. Hypothesis. Experientia 1977; 33: 9157.
  • 161
    Whitcomb DC, Taylor IL, Vigna SR. Characterization of saturable binding sites for circulating pancreatic polypeptide in rat brain. Am J Physiol 1990; 259: G68791.
  • 162
    Gates RJ, Lazarus NR. The ability of pancreatic polypeptides (APP and BPP) to return to normal the hyperglycaemia, hyperinsulinaemia and weight gain of New Zealand obese mice. Horm Res 1977; 8: 189202.
  • 163
    Ueno N, Inui A, Iwamoto M, Kaga T, Asakawa A, Okita M, Fujimiya M, Nakajima Y, Ohmoto Y, Ohnaka M, Nakaya Y, Miyazaki JI, Kasuga M. Decreased food intake and body weight in pancreatic polypeptide-overexpressing mice. Gastroenterology 1999; 117: 142732.
  • 164
    Zipf WB, O'Dorisio TM, Cataland S, Sotos J. Blunted pancreatic polypeptide responses in children with obesity of Prader-Willi syndrome. J Clin Endocrinol Metab 1981; 52: 12646.
  • 165
    Zipf WB, O'Dorisio TM, Cataland S, Dixon K. Pancreatic polypeptide responses to protein meal challenges in obese but otherwise normal children and obese children with Prader-Willi syndrome. J Clin Endocrinol Metab 1983; 57: 107480.
  • 166
    Zipf WB, O'Dorisio TM, Berntson GG. Short-term infusion of pancreatic polypeptide: effect on children with Prader-Willi syndrome. Am J Clin Nutr 1990; 51: 1626.
  • 167
    Berntson GG, Zipf WB, O'Dorisio TM, Hoffman JA, Chance RE. Pancreatic polypeptide infusions reduce food intake in Prader-Willi syndrome. Peptides 1993; 14: 497503.
  • 168
    Batterham RL, Le Roux CW, Cohen MA, Park AJ, Ellis SM, Patterson M, Frost GS, Ghatei MA, Bloom SR. Pancreatic polypeptide reduces appetite and food intake in humans. J Clin Endocrinol Metab 2003; 88: 398992.
  • 169
    Jesudason DR, Monteiro MP, McGowan BMC, Neary NM, Park AJ, Philippou E, Small CJ, Frost GS, Ghatei MA, Bloom SR. Low-dose pancreatic polypeptide inhibits food intake in man. Br J Nutr 2007; 97: 4269.
  • 170
    Schmidt PT, Näslund E, Grybäck P, Jacobsson H, Holst JJ, Hilsted L, Hellström PM. A role for pancreatic polypeptide in the regulation of gastric emptying and short-term metabolic control. J Clin Endocrinol Metab 2005; 90: 52416.
  • 171
    Adrian TE, Greenberg GR, Besterman HS, Bloom SR. Pharmacokinetics of pancreatic polypeptide in man. Gut 1978; 19: 9079.
  • 172
    Butler PC, Chou J, Carter WB, Wang YN, Bu BH, Chang D, Chang JK, Rizza RA. Effects of meal ingestion on plasma amylin concentration in NIDDM and nondiabetic humans. Diabetes 1990; 39: 7526.
  • 173
    Moore CX, Cooper GJ. Co-secretion of amylin and insulin from cultured islet beta-cells: modulation by nutrient secretagogues, islet hormones and hypoglycemic agents. Biochem Biophys Res Commun 1991; 179: 19.
  • 174
    Chen WJ, Armour S, Way J, Chen G, Watson C, Irving P, Cobb J, Kadwell S, Beaumont K, Rimele T, Kenakin T. Expression cloning and receptor pharmacology of human calcitonin receptors from MCF-7 cells and their relationship to amylin receptors. Mol Pharmacol 1997; 52: 116475.
  • 175
    McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, Foord SM. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 1998; 393: 3339.
  • 176
    Christopoulos G, Perry KJ, Morfis M, Tilakaratne N, Gao Y, Fraser NJ, Main MJ, Foord SM, Sexton PM. Multiple amylin receptors arise from receptor activity-modifying protein interaction with the calcitonin receptor gene product. Mol Pharmacol 1999; 56: 23542.
  • 177
    Young AA, Gedulin BR, Rink TJ. Dose-responses for the slowing of gastric emptying in a rodent model by glucagon-like peptide (7-36) NH2, amylin, cholecystokinin, and other possible regulators of nutrient uptake. Metabolism 1996; 45: 13.
  • 178
    Lutz TA, Geary N, Szabady MM, Del Prete E, Scharrer E. Amylin decreases meal size in rats. Physiol Behav 1995; 58: 1197202.
  • 179
    Lutz TA, Senn M, Althaus J, Del Prete E, Ehrensperger F, Scharrer E. Lesion of the area postrema/nucleus of the solitary tract (AP/NTS) attenuates the anorectic effects of amylin and calcitonin gene-related peptide (CGRP) in rats. Peptides 1998; 19: 30917.
  • 180
    Riediger T, Schmid HA, Lutz T, Simon E. Amylin potently activates AP neurons possibly via formation of the excitatory second messenger cGMP. Am J Physiol Regul Integr Comp Physiol 2001; 281: R183343.
  • 181
    Whitehouse F, Kruger DF, Fineman M, Shen L, Ruggles JA, Maggs DG, Weyer C, Kolterman OG. A randomized study and open-label extension evaluating the long-term efficacy of pramlintide as an adjunct to insulin therapy in type 1 diabetes. Diabetes Care 2002; 25: 72430.
  • 182
    Hollander PA, Levy P, Fineman MS, Maggs DG, Shen LZ, Strobel SA, Weyer C, Kolterman OG. Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care 2003; 26: 78490.
  • 183
    Ratner RE, Dickey R, Fineman M, Maggs DG, Shen L, Strobel SA, Weyer C, Kolterman OG. Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in Type 1 diabetes mellitus: a 1-year, randomized controlled trial. Diabet Med 2004; 21: 120412.
  • 184
    Edelman S, Garg S, Frias J, Maggs D, Wang Y, Zhang B, Strobel S, Lutz K, Kolterman O. A double-blind, placebo-controlled trial assessing pramlintide treatment in the setting of intensive insulin therapy in type 1 diabetes. Diabetes Care 2006; 29: 218995.
  • 185
    Smith SR, Aronne LJ, Burns CM, Kesty NC, Halseth AE, Weyer C. Sustained weight loss following 12-month pramlintide treatment as an adjunct to lifestyle intervention in obesity. Diabetes Care 2008; 31: 181623.
  • 186
    Roth JD, Roland BL, Cole RL, Trevaskis JL, Weyer C, Koda JE, Anderson CM, Parkes DG, Baron AD. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc Natl Acad Sci USA 2008; 105: 725762.
  • 187
    Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402: 65660.
  • 188
    Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Suganuma T, Matsukura S, Kangawa K, Nakazato M. Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 2000; 141: 425561.
  • 189
    Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatei MA, Bloom SR. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 2001; 86: 59925.
  • 190
    Druce MR, Wren AM, Park AJ, Milton JE, Patterson M, Frost G, Ghatei MA, Small C, Bloom SR. Ghrelin increases food intake in obese as well as lean subjects. Int J Obes (Lond) 2005; 29: 11306.
  • 191
    Tschöp M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature 2000; 407: 90813.
  • 192
    Wren AM, Small CJ, Abbott CR, Dhillo WS, Seal LJ, Cohen MA, Batterham RL, Taheri S, Stanley SA, Ghatei MA, Bloom SR. Ghrelin causes hyperphagia and obesity in rats. Diabetes 2001; 50: 25407.
  • 193
    Nass R, Pezzoli SS, Oliveri MC, Patrie JT, Harrell FE Jr, Clasey JL, Heymsfield SB, Bach MA, Vance ML, Thorner MO. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Ann Intern Med 2008; 149: 60111.
  • 194
    English PJ, Ghatei MA, Malik IA, Bloom SR, Wilding JP. Food fails to suppress ghrelin levels in obese humans. J Clin Endocrinol Metab 2002; 87: 29847.
  • 195
    Holst B, Cygankiewicz A, Jensen TH, Ankersen M, Schwartz TW. High constitutive signaling of the ghrelin receptor—identification of a potent inverse agonist. Mol Endocrinol 2003; 17: 220110.
  • 196
    Asakawa A, Inui A, Kaga T, Katsuura G, Fujimiya M, Fujino MA, Kasuga M. Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut 2003; 52: 94752.
  • 197
    Beck B, Richy S, Stricker-Krongrad A. Feeding response to ghrelin agonist and antagonist in lean and obese Zucker rats. Life Sci 2004; 76: 4738.
  • 198
    Helmling S, Maasch C, Eulberg D, Buchner K, Schröder W, Lange C, Vonhoff S, Wlotzka B, Tschöp MH, Rosewicz S, Klussmann S. Inhibition of ghrelin action in vitro and in vivo by an RNA-Spiegelmer. Proc Natl Acad Sci USA 2004; 101: 131749.
  • 199
    Kobelt P, Helmling S, Stengel A, Wlotzka B, Andresen V, Klapp BF, Wiedenmann B, Klussmann S, Mönnikes H. Anti-ghrelin Spiegelmer NOX-B11 inhibits neurostimulatory and orexigenic effects of peripheral ghrelin in rats. Gut 2006; 55: 78892.
  • 200
    Shearman LP, Wang SP, Helmling S, Stribling DS, Mazur P, Ge L, Wang L, Klussmann S, MacIntyre E, Howard AD, Strack AM. Ghrelin neutralization by a ribonucleic acid-SPM ameliorates obesity in diet-induced obese mice. Endocrinology 2006; 147: 151726.
  • 201
    Zorrilla EP, Iwasaki S, Moss JA, Chang J, Otsuji J, Inoue K, Meijler MM, Janda KD. Vaccination against weight gain. Proc Natl Acad Sci USA 2006; 103: 1322631.
  • 202
    Vizcarra JA, Kirby JD, Kim SK, Galyean ML. Active immunization against ghrelin decreases weight gain and alters plasma concentrations of growth hormone in growing pigs. Domest Anim Endocrinol 2007; 33: 17689.
  • 203
    Tan TM, Vanderpump M, Khoo B, Patterson M, Ghatei MA, Goldstone AP. Somatostatin infusion lowers plasma ghrelin without reducing appetite in adults with Prader-Willi syndrome. J Clin Endocrinol Metab 2004; 89: 41625.
  • 204
    Broglio F, Koetsveld PP, Benso A, Gottero C, Prodam F, Papotti M, Mucciolo G, Gauna C, Hofland L, Deghenghi R, Arvat E, Van Der Lely AJ, Ghigo E. Ghrelin secretion is inhibited by either somatostatin or cortistatin in humans. J Clin Endocrinol Metab 2002; 87: 482932.
  • 205
    Nørrelund H, Hansen TK, Ørskov H, Hosoda H, Kojima M, Kangawa K, Weeke J, Møller N, Christiansen JS, Jørgensen JOL. Ghrelin immunoreactivity in human plasma is suppressed by somatostatin. Clin Endocrinol (Oxf) 2002; 57: 53946.
  • 206
    Esler WP, Rudolph J, Claus TH, Tang W, Barucci N, Brown SE, Bullock W, Daly M, Decarr L, Li Y, Milardo L, Molstad D, Zhu J, Gardell SJ, Livingston JN, Sweet LJ. Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss. Endocrinology 2007; 148: 517585.
  • 207
    Rudolph J, Esler WP, O'Connor S, Coish PD, Wickens PL, Brands M, Bierer DE, Bloomquist BT, Bondar G, Chen L, Chuang CY, Claus TH, Fathi Z, Fu W, Khire UR, Kristie JA, Liu XG, Lowe DB, McClure AC, Michels M, Ortiz AA, Ramsden PD, Schoenleber RW, Shelekhin TE, Vakalopoulos A, Tang W, Wang L, Yi L, Gardell SJ, Livingston JN, Sweet LJ, Bullock WH. Quinazolinone derivatives as orally available ghrelin receptor antagonists for the treatment of diabetes and obesity. J Med Chem 2007; 50: 520216.
  • 208
    Greenough A, Cole G, Lewis J, Lockton A, Blundell J. Untangling the effects of hunger, anxiety, and nausea on energy intake during intravenous cholecystokinin octapeptide (CCK-8) infusion. Physiol Behav 1998; 65: 30310.
  • 209
    Gutzwiller JP, Degen L, Matzinger D, Prestin S, Beglinger C. Interaction between GLP-1 and CCK-33 in inhibiting food intake and appetite in men. Am J Physiol Regul Integr Comp Physiol 2004; 287: R5627.
  • 210
    Neary NM, McGowan BM, Monteiro MP, Jesudason DR, Ghatei MA, Bloom SR. No evidence of an additive inhibitory feeding effect following PP and PYY 3-36 administration. Int J Obes (Lond) 2008; 32: 143840.