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Copyright 2006 by The Endocrine Society Gut Peptides in the Regulation of Food Intake and
Energy Homeostasis
Kevin G. Murphy, Waljit S. Dhillo, and Stephen R. Bloom Department of Metabolic Medicine, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 ONN,United Kingdom Gut hormones signal to the central nervous system to influ-
represent important pharmaceutical targets for potential anti-
ence energy homeostasis. Evidence supports the existence of
obesity therapies. Our laboratory investigates the role of gut
a system in the gut that senses the presence of food in the
hormones in energy homeostasis and has a particular interest in
gastrointestinal tract and signals to the brain via neural and
this field of translational research. In this review we describe
endocrine mechanisms to regulate short-term appetite and
our initial studies and the results of more recent investigations
satiety. Recent evidence has shown that specific gut hor-
into the effects of the gastric hormone ghrelin and the intestinal
mones administered at physiological or pathophysiological
hormones peptide YY, pancreatic polypeptide, glucagon-like
concentrations can influence appetite in rodents and humans.
peptide-1, and oxyntomodulin on energy homeostasis. We also
Gut hormones therefore have an important physiological role
speculate on the role of gut hormones in the future treatment of
in postprandial satiety, and gut hormone signaling systems
obesity. (Endocrine Reviews 27: 719 –727, 2006)
signals are thought to be the hypothalamus and the brain stem.
II. Gastrointestinal Hormones and Energy Homeostasis In particular, the hypothalamus interprets neural and humoral inputs and integrates these data to provide a picture of the body’s state of energy balance, which is then used to coordinate feeding and energy expenditure. Many of the long-term signals communicating information regarding the body’s energy stores, endocrine status, and general health appear to be hu- moral, in particular the adipose hormone leptin and the pan-creatic hormone insulin. It is believed that short-term signals,including gut hormones and neural signals from higher brain I. Introduction
centers and the gut, regulate meal initiation and termination.
THEGASTROINTESTINALTRACTisthelargestendocrine Both short-term and long-term signals can also affect energy organ in the body and an important source of regulatory expenditure via sympathetic nervous efferents to brown adi- peptide hormones. The gut peptide secretin was the first sub- pose tissue and by effecting the secretion of various pituitary stance given the name “hormone.” Early studies into the gut endocrine system focused on the role of gut hormones in the The mechanisms that regulate short-term, postprandial sa- peripheral regulation of gastrointestinal function, for example, tiety are still being established. Evidence supports the existence secretin on pancreatic secretion, cholecystokinin on gall bladder of a system in the gut that senses the presence of food in the contraction, and gastrin on gastric acid release. It was not until gastrointestinal tract and signals to the brain via neural and the 1970s, a period during which a number of novel gut hor- endocrine mechanisms to regulate short-term appetite and sa- mones were identified, that it became clear that gut hormones tiety. The gut releases more than 20 peptide hormones in re- signaled to the central nervous system (CNS), often in profound sponse to specific stimuli, and the release of a number of these and subtle ways. In 1973, cholecystokinin became the first gut hormones is sensitive to changes in gut nutrient content. Recent hormone demonstrated to influence appetite, paving the way evidence has shown that specific gut hormones administered at for many seminal studies into the role of the brain-gut axis in physiological or pathophysiological concentrations can influ- ence appetite in rodents and humans (3–8). Gut hormones The most important CNS target centers for these peripheral therefore have an important physiological role in postprandialsatiety, and gut hormone signaling systems represent impor-tant pharmaceutical targets for potential antiobesity therapies.
First Published Online October 31, 2006
Abbreviations: AgRP, Agouti-related protein; CNS, central nervous
system; CTA, conditioned taste aversion; GHS-R, GH secretagogue re- II. Gastrointestinal Hormones and Energy
ceptor; GLP-1, glucagon-like peptide-1; NPY, neuropeptide Y; NTS, Homeostasis
nucleus of the solitary tract; PP, pancreatic polypeptide; PPY, peptideYY; PWS, Prader-Willi syndrome.
Endocrine Reviews is published by The Endocrine Society (http://
www.endo-society.org), the foremost professional society serving the
Ghrelin is a circulating peptide hormone derived predom- endocrine community.
inantly from the stomach. It is the endogenous ligand for the Endocrine Reviews, December 2006, 27(7):719 –727 Murphy et al. • Gut Hormones and Appetite GH secretagogue receptor (GHS-R), and the only peripher- different roles in the regulation of food intake and energy ally active orexigenic hormone discovered to date. Ghrelin is expenditure, which might explain the equivocal effects of 28 amino acids long and exists in a form with an acyl side central and peripheral administration of exogenous ghrelin.
chain attached to the serine found at position 3. This acyl Further ambiguity is conferred to the investigation of group appears vital to the binding of ghrelin to the GHS-R ghrelin physiology by the existence of different forms of and to its subsequent orexigenic effects (9).
ghrelin that have been reported to have different effects.
After its discovery in 1999 (9), it was found that ghrelin Although des-acylated ghrelin does not bind to the GHS-R could stimulate appetite (3, 10, 11). We demonstrated that and does not increase food intake, it may have other bio- peripheral administration of acylated ghrelin potently stim- logical roles, possibly mediated by as yet undiscovered ulated feeding in rodents. This effect appeared to be medi- GHS-R subtypes (21). It has been reported that intracerebro- ated via the hypothalamus, because administration of ghre- ventricular and peripheral administration of des-acylated lin into the third cerebral ventricle also stimulated feeding ghrelin reduces food intake in fasted mice (22). However, we (3). Chronic intracerebroventricular administration of ghre- have found ip injection of des-acylated ghrelin to have no effect lin increased body weight and adiposity in rats (12). Excit- on food intake in fed or fasted mice (23). Interestingly, it has ingly, ghrelin also increases appetite in humans. In a ran- recently been reported that the gene that codes for ghrelin also domized double-blind crossover study, iv infusion of ghrelin codes for another peptide, named “obestatin,” which reduces in healthy volunteers, at 5 pmol/kg⅐min (to achieve circu- food intake (24). Further studies are necessary to understand the lating levels similar to those observed after a 24-h fast), relative roles of the different forms of ghrelin and how ghrelin increased food intake at a free-choice buffet by almost 30% signaling is integrated with obestatin signaling.
and significantly increased appetite. Ghrelin had no effect on The reported inimical effects of acylated and des-acylated gastric emptying at this dose, and this, in conjunction with forms of ghrelin on food intake mean that the ability to measure the rodent data, suggested that its effects are centrally me- specific forms of ghrelin is particularly vital to such studies. We diated rather than secondary to effects on the stomach (4).
have recently found evidence that suggests that the majority of Because iv administration is an impractical route for poten- circulating acylated ghrelin is bound to larger molecules, tial pharmaceutical agents, we have since demonstrated that whereas des-acylated ghrelin circulates as free peptide (25).
a bolus sc injection of 3.6 nmol/kg ghrelin can also increase These data emphasize the importance of assay specificity and food intake and induce appetite to a similar degree (13).
suggest that assays measuring specific forms of ghrelin will be The mechanism or mechanisms by which ghrelin stimulates more useful in determining its physiological role than those that feeding are contentious. There is evidence that ghrelin signals detect both acylated and des-acylated forms.
via the hypothalamus. In particular, an important role has been Ghrelin has also been reported to play a role in glucose suggested for the hypothalamic arcuate nucleus. Ghrelin has a homeostasis and adipocyte function. We have found that acy- particularly potent effect on feeding after administration into lated ghrelin potentiates insulin-induced glucose uptake in adi- the arcuate nucleus (12), which is in accord with neuronal ac- pocytes from specific fat depots, but the relevance of this effect tivation data after central administration of ghrelin in rats (11).
in normal physiology remains to be determined (26).
Orexigenic neuropeptide Y (NPY) and agouti-related protein The factors regulating plasma ghrelin levels can provide (AgRP)-expressing neurons in the arcuate nucleus may play an vital evidence as to the physiological role of peripheral important role. Central injection of ghrelin activates NPY/ ghrelin. Circulating ghrelin concentrations rise with fasting AgRP neurons and NPY and AgRP antibodies, and NPY an- and fall after a meal (27). This primary regulation by food tagonists block the orexigenic actions of ghrelin (11). Ghrelin intake is in accord with the suggested role of ghrelin as a does not stimulate food intake in NPY and AgRP double knock- “hunger hormone” (10). Although calorie intake appears to out mice (14). We have demonstrated that transgenic mice with be the primary regulator of plasma ghrelin levels, the exact postembryonic ablation of NPY/AgRP neurons do not respond mechanisms mediating ghrelin release are unknown. Dex- to ghrelin, suggesting that the desensitization to ghrelin in trose and parenteral nutrition infusions decrease ghrelin lev- NPY/AgRP embryonic knockouts is not due to developmental els but do not reduce hunger, suggesting that the role of changes (15). In agouti mice, ectopic production of agouti pro- ghrelin may be more complex (28). Intraduodenal infusion of tein antagonizes central melanocortin 4 receptors. We have long-chain fatty acids suppresses circulating ghrelin levels, shown that ghrelin does not increase food intake in these mice, although not in the presence of a lipase inhibitor, suggesting demonstrating that disrupting the hypothalamic melanocortin that fat digestion is required to influence ghrelin release (29).
system can cause ghrelin resistance (16).
The length of the fatty acid chain also appears to be important There is also strong evidence that the vagus nerve is re- to ghrelin secretion, because intraduodenal infusion of do- quired to mediate the orexigenic effects of ghrelin. Vagotomy decanoic acid, a fatty acid containing 12 carbon atoms, de- abolishes ghrelin-stimulated feeding in animal models (17, creases plasma ghrelin, but infusion of decanoic acid, which 18). We have found that ghrelin does not stimulate appetite only contains 10 carbon atoms, does not (30).
in humans after surgical procedures involving vagotomy Circulating ghrelin concentrations are also regulated by (19). Ghrelin may therefore signal to the hypothalamus via longer term changes in energy homeostasis. Ghrelin levels the vagus and the brain stem. Interestingly, ghrelin expres- are lower in humans with higher body weight and rise after sion has been detected in neurons adjacent to the third ven- diet-induced weight loss (31). The usual postprandial fall in tricle (20). The importance of these neurons in energy ho- plasma ghrelin is absent or attenuated in the obese, suggest- meostasis is currently unknown. However, it is possible that ing that ghrelin may be involved in the pathophysiology of endogenous central and peripheral ghrelin signaling play obesity (32, 33). We have shown that iv ghrelin administra- Murphy et al. • Gut Hormones and Appetite Endocrine Reviews, December 2006, 27(7):719 –727 tion stimulates appetite in obese humans, suggesting that though it is interesting to note that lipid digestion is required they are not ghrelin resistant (34).
to generate the lipid-induced rise in circulating PP (29). As Prader-Willi syndrome (PWS) is a genetic syndrome char- early as 1977, it was demonstrated that PP could reduce food acterized by severe hyperphagia, short stature, and mental intake in mice (55). However, it was not until 2003 that we retardation. PWS patients are hypogonadal and have GH demonstrated that iv infusion of PP at 10 pmol/kg⅐min levels deficiency. The PWS phenotype is thought to be a conse- to healthy human volunteers reduced food intake (7). We quence of hypothalamic developmental abnormalities. In- have since found that infusions at half this dose can also terestingly, fasting and postprandial ghrelin levels are higher significantly reduce food intake (our unpublished data). The relative to obesity in PWS patients (35–37). However, soma- precise mechanism by which the anorectic effect of PP is tostatin infusion in PWS patients does reduce ghrelin with- mediated is unknown. PP signals via the Y family of recep- out influencing appetite. This implies that factors besides tors and binds with greatest affinity to the Y4 and Y5 recep- ghrelin may be responsible for PWS hyperphagia, although tors. PP may directly activate neurons in the area postrema, it is also possible that concomitant reductions in anorectic gut where Y4 receptors are highly expressed (56).
hormones compensate for the reduction in ghrelin (38).
It has been suggested that the anorectic effects of iv PP The years since the discovery of ghrelin have seen the administration in humans are secondary to delayed gastric emergence of a considerable research literature on this hor- emptying. We found that infusing bovine PP at 2 pmol/ mone. Ghrelin antagonists have been touted as potential kg⅐min to achieve levels twice those observed after a normal obesity drugs. Ghrelin and GHS-R knockout mice were mixed breakfast in man had no effect on gastric emptying found not to have profoundly altered food intake or body (57). Similarly, infusion of human PP at 10 pmol/kg⅐min weight on a normal diet (39, 40). Subsequently, it has been significantly inhibited food intake in man with no detectable shown that GHS-R knockout mice are resistant to diet-in- effect on gastric emptying (7). However, others have found duced obesity (41, 42) and favor fat as a metabolic substrate that human PP inhibits gastric emptying of solid food at when on a high-fat diet (43). GHS-R antagonists may there- infusion rates as low as 0.75 or 2.25 pmol/kg⅐min (58). These fore have beneficial effects in obese humans. Knockout mod- discrepancies may reflect the different forms of the hormone els have also provided further evidence for the role of ghrelin used or the different infusion protocols. The presence of PP in glucose homeostasis. Diabetic ghrelin knockout mice show binding sites and the activation of neurons in the area pos- less dramatic hyperphagia than controls (44), and ablating trema after PP administration suggests that PP is having a ghrelin attenuates diabetes in the ob/ob obese mouse (45).
central effect, but it is currently unknown whether this cen- In addition to the therapeutic potential of blocking ghrelin tral activity is directly regulating food intake (56).
signaling, a number of patient groups would benefit from the In animal models, peripheral PP administration increases development of appetite-inducing therapies.
energy expenditure in addition to its effects on food intake Intensive care unit patients have been shown to have re- (59). Chronic administration of PP to obese mice slows body duced ghrelin levels compared with healthy controls (46).
weight gain, and peripheral overexpression of PP reduces This is despite weight loss and reduced food intake, which food intake and body weight (60). In our human study, a would normally increase plasma ghrelin levels (27, 31, 47). It 90-min infusion of PP significantly reduced not only acute is therefore possible that changes in ghrelin may be partly food intake at a buffet meal 2 h after the infusion but also responsible for the loss of appetite and weight often observed reduced food intake for the following 24 h (7). PP therefore in these patients. If reduced ghrelin levels are even partially appears to have the potential to act as a long-term appetite responsible for the loss of appetite in certain patient groups, suppressor and thus may be a suitable target for antiobesity ghrelin administration would be an apposite appetite-induc- ing treatment. We have demonstrated that iv ghrelin canincrease food intake and meal appreciation in cancer patients with reported loss of appetite (48) and that sc ghrelin ad-ministration increases short-term food intake in dialysis pa- PYY is a 36-amino acid peptide structurally related to PP tients (49). Ghrelin also increases gastric emptying in patients and NPY and was first isolated and characterized in 1980 with diabetic gastroparesis, independent of vagal tone, sug- (61). PYY is found throughout the human small intestine at gesting that it may be a potential prokinetic agent in such tissue concentrations that increase distally, with the highest patients (50). The ghrelin system therefore may prove to have levels detected in the colon and rectum (62). Peripheral ad- clinical utility in a number of important diseases.
ministration of full-length PYY has several biological effects,including delayed gastric emptying and reduced gastric se-cretion in man (63, 64).
PYY is released postprandially (62) from the L cells of the PP is a 36-amino acid peptide released from the endocrine gut, where it is co-stored with glucagon-like peptide-1 pancreas. Soon after it was first identified, we discovered that (GLP-1) (65). However, the major form of PYY stored in the PP was released into the circulation after a meal (51, 52). PP gut and found in the circulation is the N-terminally truncated has a number of reported peripheral effects on the gastro- PYY3–36 (66). The different forms of PYY have different re- intestinal tract. Our early experiments established the phar- ceptor affinities, reflecting their different biological effects.
macodynamics of PP in man (53) and its effects on pancreatic Although full-length PYY binds with similar affinity to all of the members of the Y receptor family, PYY3–36 has high PP is released in proportion to meal calorie content, al- affinity only for the Y2 and a lesser affinity for Y1 and Y5 Endocrine Reviews, December 2006, 27(7):719 –727 Murphy et al. • Gut Hormones and Appetite receptors. In 2002, we published data demonstrating that result in circulating levels of PYY within the physiological peripheral administration of PYY3–36 at physiological doses range reduce food intake in humans without causing nausea significantly reduced food intake in rodents and man (5).
or any other ill effects (5, 6). Others have found that phar- Although there was initial contention regarding the effects of macological doses of PYY3–36 are required to reduce food PYY3–36 on appetite (5, 67), a number of groups have now intake and that nausea can occur at high doses (75). In recent conclusively demonstrated that PYY3–36 reduces food intake studies, we found that high doses of PYY3–36 were associated in rodents, primates, and man (68 –75). Handling, acclima- with nausea in humans (our unpublished data). This is un- tization, and habituation of rodents to experimental condi- surprising. Hunger, satiety, and nausea may be points along tions are vital to the success of PYY3–36 feeding studies (76, the same physiological spectrum (86). Nausea is associated 77). PYY knockout mice show disrupted regulation of energy with high-dose administration of several satiety-inducing homeostasis. However, the phenotype is not straightfor- gut hormones and their analogs, including cholecystokinin ward. Aged female mice lacking PYY have increased body (86), GLP-1 (87), exenatide (88, 89), and oxyntomodulin (90).
weight and fat mass. Male knockout mice are resistant to Interestingly, we found no greater inhibition of food intake obesity but have higher fat mass and lower glucose tolerance at supraphysiological plasma PYY levels than at lower doses than wild types when fed a high-fat diet. These findings previously investigated (our unpublished data; also, Refs. 5 suggest that PYY is important in energy and glucose ho- and 6). It is possible that PYY acts at physiological levels to meostasis. The sexual dimorphism observed has been sug- mediate postprandial satiety and only causes nausea at gested to be due to differences in the hypothalamo-pituitary pathophysiological levels. Fasting levels of PYY are chron- somatotrophic axis between the sexes (78). Another study ically elevated in several gastrointestinal diseases associated found no differences in food intake and body weight be- with appetite loss (91). It is possible that the reduced gastric tween wild-type and PYY knockout mice. However, these emptying and delayed gastrointestinal transit described after mice also lacked PP, which may have implications for the administration of PYY3–36 (64, 92) are responses designed to development of the energy homeostatic system (79).
reduce the nutrient load on the diseased small intestine while increasing transit and, hence, absorption time. Similarly, the 3–36 may be less responsible for the postprandial re- duction in food intake than regulating the size or timing of nausea reported in response to high levels of PYY3–36 may be subsequent meals. Plasma levels of endogenous PYY peak in an adaptation to reduce further stress on the gut in specific the second hour after a meal (5, 6, 62). In our studies, PYY pathophysiological states. It has been suggested that PYY reduced food intake 2 h after the infusion had stopped, when might act as an endogenous defense against diarrhea (93).
circulating PYY had returned to basal levels, and continued Very high levels of PYY3–36 may therefore have powerful to reduce food intake for the subsequent 12 h (5).
aversive effects to avoid further stress on the gut, but these effects may not be responsible for the normal PYY duced reduction of food intake. In our recent study, we found 3–36 is thought to act via the Y2 receptor. Ad- that the subjective feeling of nausea was short-lived and 3–36 does not reduce appetite in Y2 knockout mice (5), and the anorectic effects of PYY lasted for no more than 30 min. Interestingly, PYY rats by the coadministration of a specific Y2 antagonist (80). We duced food intake after nausea levels had returned to base- line, suggesting an independent effect (our unpublished 3–36 activated anorectic proopiomelanocortin (POMC) expressing neurons in the arcuate nucleus. Certainly, data). Similarly, recent work by others has shown that al- rats (5). However, it has been reported subsequently that doses can reduce food intake without causing CTA (94).
PYY3–36 inhibits both POMC and NPY neurons, suggesting thatit may be via reduced NPY signaling that PYY3–36 exerts its D. Glucagon-like peptide-1 (GLP-1) effects (81). This is in accord with results showing that themelanocortin system is not essential for the anorectic actions of GLP-1 is a neuropeptide hormone produced by posttrans- PYY3–36 (16, 68, 77). The anorectic effects of PYY3–36 may also be lational processing of the preproglucagon gene in the CNS partly mediated via the vagal nerve (82).
and the gut. We were the first to demonstrate the potent PYY3–36 may have utility as an obesity therapy. Circulating anorectic effects of intracerebroventricular administration of PYY levels are lower in the obese, suggesting that low PYY GLP-1 in rodents. GLP-1 neurons in the nucleus of the sol- levels may have a causative role in the development of obe- itary tract (NTS) extend to regions of the hypothalamus im- sity (6, 66). We and others have found food intake and body portant in the regulation of food intake (95). In 1988, we weight to be reduced in animals chronically treated with identified high-affinity binding sites for GLP-1 in the hypo- peripheral PYY3–36 (5, 72, 83). Importantly, PYY3–36 can re- thalamus and the brain stem (96). Subsequently, we found duce food intake in obese volunteers, suggesting that obesity that GLP-1 reduced food intake in fasted rats and activated neurons in the arcuate and paraventricular nuclei of the There is debate as to whether PYY3–36 reduces food intake hypothalamus, and that blocking GLP-1 receptor signaling by activating physiological food reduction circuits or by hav- with the GLP-1 receptor antagonist, exendin (9 –39), doubled ing an aversive effect. Different groups have published con- food intake in satiated rats. Our findings suggested that tradictory data as to whether PYY3–36 causes conditioned central GLP-1 could induce satiety (97) and might also in- taste aversion (CTA) in rodents, and thus whether the effects crease energy expenditure by raising body temperature (98).
of PYY3–36 on food intake are secondary to unpleasant side Repeated intracerebroventricular injection of GLP-1 reduced effects (84, 85). We have found that doses of PYY3–36 that food intake and body weight in rats. Conversely, blocking Murphy et al. • Gut Hormones and Appetite Endocrine Reviews, December 2006, 27(7):719 –727 endogenous GLP-1 signaling by repeated central adminis- Originally characterized as an inhibitor of gastric acid se- tration of exendin (9 –39) increased food intake and body cretion, like GLP-1, oxyntomodulin also reduces food intake weight, providing further evidence that GLP-1 is a physio- when administered centrally to rodents or peripherally to Leptin may signal in part through the central GLP-1 system.
Oxyntomodulin binds to the GLP-1 receptor. However, We demonstrated that the long isoform leptin receptor was although the affinity of oxyntomodulin for the GLP-1 recep- expressed in GLP-1 neurons extending from the NTS and that tor is much lower than that of GLP-1, oxyntomodulin and exendin (9–39) blocked the effects of leptin on food intake and GLP-1 are equally efficacious at inhibiting food intake. Oxyn- body weight (100). In subsequent experiments, we showed that tomodulin may reduce food intake via a different pathway intracerebroventricular leptin administration prevents the re- to GLP-1 (119). However, both oxyntomodulin and GLP-1 duction in hypothalamic GLP-1 peptide content observed in have been shown to cause similar patterns of neuronal ac- pair-fed food-restricted rats, and peripheral leptin increases tivation after peripheral administration (105). Oxyntomodu- hypothalamic GLP-1 peptide in food-restricted mice (101).
lin has been suggested to bind to a specific oxyntomodulin However, leptin does reduce food intake in GLP-1 receptor receptor. However, the anorectic effects of oxyntomodulin knockout mice (102), demonstrating that GLP-1 signaling is not are blocked by exendin (9 –39) (122) and abolished in GLP-1 necessary to mediate the biological effects of leptin. Leptin is receptor knockout mice (105). Although it is possible that known to act via a number of central neuropeptide signals (2, developmental changes in the GLP-1 receptor knockout 103, 104). Whether the efficacy of leptin in the GLP-1 receptor mouse affect the functioning of another discrete oxynto- knockout mouse is maintained because of developmental com- modulin receptor, and that exendin (9 –39) also binds to this pensation or because of the ability of the mature energy ho- putative oxyntomodulin receptor, it seems more likely that meostasis circuitry to signal via alternative routes is unknown.
oxyntomodulin does reduce food intake via the GLP-1 re- Peripheral GLP-1 can also influence glucose and energy ho- ceptor. GLP-1 receptors are found in the brainstem and the meostasis. It is therefore difficult to tease apart peripheral and arcuate nucleus. The different biological effects of oxynto- central GLP-1 signaling pathways. It has been reported that modulin and GLP-1 may therefore be due to differences in both peripheral and central GLP-1 administration activate neu- local breakdown, tissue penetration, or possibly context-de- rons in the arcuate nucleus, the hypothalamic paraventricular pendent changes in receptor signaling, such as the receptor nucleus, NTS, and area postrema (82, 95, 105, 106). How the activity modifying proteins that regulate the specificity of the central and peripheral GLP-1 systems interact and are inte- calcitonin receptor-like receptor (123). The GLP-1 receptor grated into the bodywide energy homeostasis is unknown.
agonist exenatide has recently been approved for the treat- GLP-1 is released into the circulation after a meal, and ment of type 2 diabetes mellitus in the United States, and proglucagon expression is decreased in the small intestine by exenatide treatment is associated with weight loss (116 –118).
fasting (107). The physical form of a meal appears to have a However, it is possible that peptide analogs based on the greater influence on GLP-1 release than its fat content (108).
structure of oxyntomodulin will prove more efficacious at We discovered that GLP-1 acts as a physiological incretin promoting weight loss than those based on GLP-1.
(109, 110) and suppressor of gastric acid secretion (111) in Preliminary data suggest that oxyntomodulin may prove man. Administration of exendin-4 reduces fasting and post- useful as an obesity drug. Chronic central or peripheral ad- prandial glucose in humans (112). We were the first group to ministration of oxyntomodulin reduces weight gain in rats investigate the effects of chronic sc GLP-1 treatment in type (119, 120). Intravenous infusion of oxyntomodulin to sup- 2 diabetes mellitus. Three weeks of sc GLP-1 treatment sig- raphysiological levels reduces food intake in humans (8).
nificantly improved postprandial glycemic control in pa- Further work is required to elucidate the physiological sig- tients with poorly controlled type 2 diabetes mellitus (113, nificance of oxyntomodulin in human appetite, but it is in- 114). Peripheral GLP-1 infusion has been reported to cause teresting to note that oxyntomodulin levels are, like PYY, a dose-dependent reduction in food intake in humans (115).
increased in particular pathophysiological conditions asso- We confirmed that peripheral administration of the GLP-1 receptor agonist, exendin-4, significantly reduced food in- We have recently performed studies demonstrating that take in healthy volunteers (112). Clinical trials have shown oxyntomodulin can cause weight loss in humans. In a 4-wk that exenatide, a long-acting agonist of the GLP-1 receptor, study in which overweight and obese volunteers self-admin- is useful in the regulation of glucose homeostasis in type 2 istered oxyntomodulin or saline three times daily, the oxynto- diabetes mellitus. Interestingly, exenatide does not only en- modulin-treated group ate significantly less. This substantial hance insulin secretion and suppress glucagon release. In reduction in appetite was well-maintained over the 4-wk study 30-wk phase 3 clinical trials, it also reduced body weight period. Oxyntomodulin treatment also resulted in significant (116 –118). Not all patients showed weight loss, and ex- weight loss of an additional 0.45-kg weight loss per week com- enatide is not approved as an obesity treatment. However, pared with saline, accompanied by changes in the levels of these results do demonstrate that gut hormone systems have adipose hormones consistent with a loss of body fat (90).
the potential to reduce body weight.
Rats chronically treated with oxyntomodulin lose more weight than pair-fed controls, suggesting that oxyntomodulinmay also increase energy expenditure (120). Excitingly, the re- sults of our latest human oxyntomodulin study suggested that Like GLP-1, oxyntomodulin is a product of the prepro- oxyntomodulin also promotes energy expenditure in humans.
glucagon gene released into the circulation postprandially.
Overweight and obese volunteers again self-administered Endocrine Reviews, December 2006, 27(7):719 –727 Murphy et al. • Gut Hormones and Appetite oxyntomodulin, although this time for only four days. Energy Acknowledgments
expenditure was measured by indirect calorimetry and com-bined heart rate and movement monitoring, and food intake Address all correspondence and requests for reprints to: Prof. S. R.
was assessed by a test meal. Oxyntomodulin administration Bloom, Department of Metabolic Medicine, Imperial College Faculty of significantly reduced energy intake at the study meal and in- Medicine, Hammersmith Campus, Du Cane Road, London W12 ONN,United Kingdom. E-mail: [email protected] creased activity-related energy expenditure by more than 25% Disclosure Statement: S.R.B. is a director of Thiakis, a new company (125). Oxyntomodulin is thus the first therapy shown to sup- interested in exploiting the use of oxyntomodulin and PYY in the treat- press appetite and concurrently increase spontaneous activity.
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culating levels of GLP-1, oxyntomodulin, and PYY are ele- tide reduces appetite and food intake in humans. J Clin Endocrinol vated after Roux-en-Y gastric bypass in humans and jejunointestinal bypass in rodents (126, 127).
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Source: http://www-3.unipv.it/dsffcm/pagine/labs/perin/oldstuff/kiro/GEP2.pdf