| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Metabolic Medicine, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 ONN, United Kingdom
Correspondence: Address all correspondence and requests for reprints to: Prof. S. R. Bloom, Department of Metabolic Medicine, Imperial College Faculty of Medicine, Hammersmith Campus, Du Cane Road, London W12 ONN, United Kingdom. E-mail: s.bloom{at}imperial.ac.uk
 |
Abstract |
|---|
 Top Abstract I. IntroductionII. Gastrointestinal Hormones...III. The Future of...References |
|---|
|
I. Introduction |
|---|
|
TopAbstractI. IntroductionII. Gastrointestinal Hormones...III. The Future of...References |
|---|
The most important CNS target centers for these peripheral signals are thought to be the hypothalamus and the brain stem. 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 humoral, in particular the adipose hormone leptin and the pancreatic hormone insulin. It is believed that short-term signals, including gut hormones and neural signals from higher brain centers and the gut, regulate meal initiation and termination. Both short-term and long-term signals can also affect energy expenditure via sympathetic nervous efferents to brown adipose tissue and by effecting the secretion of various pituitary hormones (2).
The mechanisms that regulate short-term, postprandial satiety are still being established. Evidence supports the existence of a system in the gut that senses the presence of food in the gastrointestinal tract and signals to the brain via neural and endocrine mechanisms to regulate short-term appetite and satiety. The gut releases more than 20 peptide hormones in response to specific stimuli, and the release of a number of these hormones is sensitive to changes in gut nutrient content. Recent evidence has shown that specific gut hormones administered at physiological or pathophysiological concentrations can influence appetite in rodents and humans (3, 4, 5, 6, 7, 8). Gut hormones therefore have an important physiological role in postprandial satiety, and gut hormone signaling systems represent important pharmaceutical targets for potential antiobesity therapies.
|
II. Gastrointestinal Hormones and Energy Homeostasis |
|---|
|
TopAbstractI. IntroductionII. Gastrointestinal Hormones...III. The Future of...References |
|---|
After its discovery in 1999 (9), it was found that ghrelin could stimulate appetite (3, 10, 11). We demonstrated that peripheral administration of acylated ghrelin potently stimulated feeding in rodents. This effect appeared to be mediated via the hypothalamus, because administration of ghrelin into the third cerebral ventricle also stimulated feeding (3). Chronic intracerebroventricular administration of ghrelin increased body weight and adiposity in rats (12). Excitingly, ghrelin also increases appetite in humans. In a randomized double-blind crossover study, iv infusion of ghrelin in healthy volunteers, at 5 pmol/kg·min (to achieve circulating levels similar to those observed after a 24-h fast), increased food intake at a free-choice buffet by almost 30% and significantly increased appetite. Ghrelin had no effect on gastric emptying at this dose, and this, in conjunction with the rodent data, suggested that its effects are centrally mediated rather than secondary to effects on the stomach (4). Because iv administration is an impractical route for potential pharmaceutical agents, we have since demonstrated that a bolus sc injection of 3.6 nmol/kg ghrelin can also increase food intake and induce appetite to a similar degree (13).
The mechanism or mechanisms by which ghrelin stimulates feeding are contentious. There is evidence that ghrelin signals via the hypothalamus. In particular, an important role has been suggested for the hypothalamic arcuate nucleus. Ghrelin has a particularly potent effect on feeding after administration into the arcuate nucleus (12), which is in accord with neuronal activation data after central administration of ghrelin in rats (11). Orexigenic neuropeptide Y (NPY) and agouti-related protein (AgRP)-expressing neurons in the arcuate nucleus may play an important role. Central injection of ghrelin activates NPY/AgRP neurons and NPY and AgRP antibodies, and NPY antagonists block the orexigenic actions of ghrelin (11). Ghrelin does not stimulate food intake in NPY and AgRP double knockout mice (14). We have demonstrated that transgenic mice with postembryonic ablation of NPY/AgRP neurons do not respond to ghrelin, suggesting that the desensitization to ghrelin in NPY/AgRP embryonic knockouts is not due to developmental changes (15). In agouti mice, ectopic production of agouti protein antagonizes central melanocortin 4 receptors. We have shown that ghrelin does not increase food intake in these mice, demonstrating that disrupting the hypothalamic melanocortin system can cause ghrelin resistance (16).
There is also strong evidence that the vagus nerve is required to mediate the orexigenic effects of ghrelin. Vagotomy abolishes ghrelin-stimulated feeding in animal models (17, 18). We have found that ghrelin does not stimulate appetite in humans after surgical procedures involving vagotomy (19). Ghrelin may therefore signal to the hypothalamus via the vagus and the brain stem. Interestingly, ghrelin expression has been detected in neurons adjacent to the third ventricle (20). The importance of these neurons in energy homeostasis is currently unknown. However, it is possible that endogenous central and peripheral ghrelin signaling play different roles in the regulation of food intake and energy expenditure, which might explain the equivocal effects of central and peripheral administration of exogenous ghrelin.
Further ambiguity is conferred to the investigation of ghrelin physiology by the existence of different forms of ghrelin that have been reported to have different effects. Although des-acylated ghrelin does not bind to the GHS-R and does not increase food intake, it may have other biological roles, possibly mediated by as yet undiscovered GHS-R subtypes (21). It has been reported that intracerebroventricular and peripheral administration of des-acylated ghrelin reduces food intake in fasted mice (22). However, we have found ip injection of des-acylated ghrelin to have no effect on food intake in fed or fasted mice (23). Interestingly, it has recently been reported that the gene that codes for ghrelin also codes for another peptide, named "obestatin," which reduces food intake (24). Further studies are necessary to understand the relative roles of the different forms of ghrelin and how ghrelin signaling is integrated with obestatin signaling.
The reported inimical effects of acylated and des-acylated forms of ghrelin on food intake mean that the ability to measure specific forms of ghrelin is particularly vital to such studies. We have recently found evidence that suggests that the majority of circulating acylated ghrelin is bound to larger molecules, whereas des-acylated ghrelin circulates as free peptide (25). These data emphasize the importance of assay specificity and suggest that assays measuring specific forms of ghrelin will be more useful in determining its physiological role than those that detect both acylated and des-acylated forms.
Ghrelin has also been reported to play a role in glucose homeostasis and adipocyte function. We have found that acylated ghrelin potentiates insulin-induced glucose uptake in adipocytes from specific fat depots, but the relevance of this effect in normal physiology remains to be determined (26).
The factors regulating plasma ghrelin levels can provide vital evidence as to the physiological role of peripheral ghrelin. Circulating ghrelin concentrations rise with fasting and fall after a meal (27). This primary regulation by food intake is in accord with the suggested role of ghrelin as a "hunger hormone" (10). Although calorie intake appears to be the primary regulator of plasma ghrelin levels, the exact mechanisms mediating ghrelin release are unknown. Dextrose and parenteral nutrition infusions decrease ghrelin levels but do not reduce hunger, suggesting that the role of ghrelin may be more complex (28). Intraduodenal infusion of long-chain fatty acids suppresses circulating ghrelin levels, although not in the presence of a lipase inhibitor, suggesting that fat digestion is required to influence ghrelin release (29). The length of the fatty acid chain also appears to be important to ghrelin secretion, because intraduodenal infusion of dodecanoic acid, a fatty acid containing 12 carbon atoms, decreases plasma ghrelin, but infusion of decanoic acid, which only contains 10 carbon atoms, does not (30).
Circulating ghrelin concentrations are also regulated by longer term changes in energy homeostasis. Ghrelin levels are lower in humans with higher body weight and rise after diet-induced weight loss (31). The usual postprandial fall in plasma ghrelin is absent or attenuated in the obese, suggesting that ghrelin may be involved in the pathophysiology of obesity (32, 33). We have shown that iv ghrelin administration stimulates appetite in obese humans, suggesting that they are not ghrelin resistant (34).
Prader-Willi syndrome (PWS) is a genetic syndrome characterized by severe hyperphagia, short stature, and mental retardation. PWS patients are hypogonadal and have GH deficiency. The PWS phenotype is thought to be a consequence of hypothalamic developmental abnormalities. Interestingly, fasting and postprandial ghrelin levels are higher relative to obesity in PWS patients (35, 36, 37). However, somatostatin infusion in PWS patients does reduce ghrelin without influencing appetite. This implies that factors besides ghrelin may be responsible for PWS hyperphagia, although it is also possible that concomitant reductions in anorectic gut hormones compensate for the reduction in ghrelin (38).
The years since the discovery of ghrelin have seen the emergence of a considerable research literature on this hormone. Ghrelin antagonists have been touted as potential obesity drugs. Ghrelin and GHS-R knockout mice were found not to have profoundly altered food intake or body weight on a normal diet (39, 40). Subsequently, it has been shown that GHS-R knockout mice are resistant to diet-induced obesity (41, 42) and favor fat as a metabolic substrate when on a high-fat diet (43). GHS-R antagonists may therefore have beneficial effects in obese humans. Knockout models have also provided further evidence for the role of ghrelin in glucose homeostasis. Diabetic ghrelin knockout mice show less dramatic hyperphagia than controls (44), and ablating ghrelin attenuates diabetes in the ob/ob obese mouse (45).
In addition to the therapeutic potential of blocking ghrelin signaling, a number of patient groups would benefit from the development of appetite-inducing therapies.
Intensive care unit patients have been shown to have reduced ghrelin levels compared with healthy controls (46). This is despite weight loss and reduced food intake, which would normally increase plasma ghrelin levels (27, 31, 47). It is therefore possible that changes in ghrelin may be partly responsible for the loss of appetite and weight often observed in these patients. If reduced ghrelin levels are even partially responsible for the loss of appetite in certain patient groups, ghrelin administration would be an apposite appetite-inducing treatment. We have demonstrated that iv ghrelin can increase food intake and meal appreciation in cancer patients with reported loss of appetite (48) and that sc ghrelin administration increases short-term food intake in dialysis patients (49). Ghrelin also increases gastric emptying in patients with diabetic gastroparesis, independent of vagal tone, suggesting that it may be a potential prokinetic agent in such patients (50). The ghrelin system therefore may prove to have clinical utility in a number of important diseases.
B. Pancreatic polypeptide (PP)
PP is a 36-amino acid peptide released from the endocrine pancreas. Soon after it was first identified, we discovered that PP was released into the circulation after a meal (51, 52). PP has a number of reported peripheral effects on the gastrointestinal tract. Our early experiments established the pharmacodynamics of PP in man (53) and its effects on pancreatic and biliary output (54).
PP is released in proportion to meal calorie content, although it is interesting to note that lipid digestion is required to generate the lipid-induced rise in circulating PP (29). As early as 1977, it was demonstrated that PP could reduce food intake in mice (55). However, it was not until 2003 that we demonstrated that iv infusion of PP at 10 pmol/kg·min levels to healthy human volunteers reduced food intake (7). We have since found that infusions at half this dose can also significantly reduce food intake (our unpublished data). The precise mechanism by which the anorectic effect of PP is mediated is unknown. PP signals via the Y family of receptors and binds with greatest affinity to the Y4 and Y5 receptors. PP may directly activate neurons in the area postrema, where Y4 receptors are highly expressed (56).
It has been suggested that the anorectic effects of iv PP administration in humans are secondary to delayed gastric emptying. We found that infusing bovine PP at 2 pmol/kg·min to achieve levels twice those observed after a normal mixed breakfast in man had no effect on gastric emptying (57). Similarly, infusion of human PP at 10 pmol/kg·min significantly inhibited food intake in man with no detectable effect on gastric emptying (7). However, others have found that human PP inhibits gastric emptying of solid food at infusion rates as low as 0.75 or 2.25 pmol/kg·min (58). These discrepancies may reflect the different forms of the hormone used or the different infusion protocols. The presence of PP binding sites and the activation of neurons in the area postrema after PP administration suggests that PP is having a central effect, but it is currently unknown whether this central activity is directly regulating food intake (56).
In animal models, peripheral PP administration increases energy expenditure in addition to its effects on food intake (59). Chronic administration of PP to obese mice slows body weight gain, and peripheral overexpression of PP reduces food intake and body weight (60). In our human study, a 90-min infusion of PP significantly reduced not only acute food intake at a buffet meal 2 h after the infusion but also reduced food intake for the following 24 h (7). PP therefore appears to have the potential to act as a long-term appetite suppressor and thus may be a suitable target for antiobesity drug design.
C. Peptide YY (PYY)
PYY is a 36-amino acid peptide structurally related to PP and NPY and was first isolated and characterized in 1980 (61). PYY is found throughout the human small intestine at tissue concentrations that increase distally, with the highest levels detected in the colon and rectum (62). Peripheral administration of full-length PYY has several biological effects, including delayed gastric emptying and reduced gastric secretion in man (63, 64).
PYY is released postprandially (62) from the L cells of the gut, where it is co-stored with glucagon-like peptide-1 (GLP-1) (65). However, the major form of PYY stored in the gut and found in the circulation is the N-terminally truncated PYY3–36 (66). The different forms of PYY have different receptor affinities, reflecting their different biological effects. Although full-length PYY binds with similar affinity to all of the members of the Y receptor family, PYY3–36 has high affinity only for the Y2 and a lesser affinity for Y1 and Y5 receptors. In 2002, we published data demonstrating that peripheral administration of PYY3–36 at physiological doses significantly reduced food intake in rodents and man (5). Although there was initial contention regarding the effects of PYY3–36 on appetite (5, 67), a number of groups have now conclusively demonstrated that PYY3–36 reduces food intake in rodents, primates, and man (68, 69, 70, 71, 72, 73, 74, 75). Handling, acclimatization, and habituation of rodents to experimental conditions are vital to the success of PYY3–36 feeding studies (76, 77). PYY knockout mice show disrupted regulation of energy homeostasis. However, the phenotype is not straightforward. Aged female mice lacking PYY have increased body weight and fat mass. Male knockout mice are resistant to obesity but have higher fat mass and lower glucose tolerance than wild types when fed a high-fat diet. These findings suggest that PYY is important in energy and glucose homeostasis. The sexual dimorphism observed has been suggested to be due to differences in the hypothalamo-pituitary somatotrophic axis between the sexes (78). Another study found no differences in food intake and body weight between wild-type and PYY knockout mice. However, these mice also lacked PP, which may have implications for the development of the energy homeostatic system (79).
PYY3–36 may be less responsible for the postprandial reduction in food intake than regulating the size or timing of subsequent meals. Plasma levels of endogenous PYY peak in the second hour after a meal (5, 6, 62). In our studies, PYY3–36 reduced food intake 2 h after the infusion had stopped, when circulating PYY had returned to basal levels, and continued to reduce food intake for the subsequent 12 h (5).
The mechanism by which PYY3–36 reduces food intake is contentious. PYY3–36 is thought to act via the Y2 receptor. Administration of PYY3–36 does not reduce appetite in Y2 knockout mice (5), and the anorectic effects of PYY3–36 can be blocked in rats by the coadministration of a specific Y2 antagonist (80). We reported that PYY3–36 activated anorectic proopiomelanocortin (POMC) expressing neurons in the arcuate nucleus. Certainly, direct intra-arcuate injection of PYY3–36 reduces food intake in rats (5). However, it has been reported subsequently that PYY3–36 inhibits both POMC and NPY neurons, suggesting that it may be via reduced NPY signaling that PYY3–36 exerts its effects (81). This is in accord with results showing that the melanocortin system is not essential for the anorectic actions of PYY3–36 (16, 68, 77). The anorectic effects of PYY3–36 may also be partly mediated via the vagal nerve (82).
PYY3–36 may have utility as an obesity therapy. Circulating PYY levels are lower in the obese, suggesting that low PYY levels may have a causative role in the development of obesity (6, 66). We and others have found food intake and body weight to be reduced in animals chronically treated with peripheral PYY3–36 (5, 72, 83). Importantly, PYY3–36 can reduce food intake in obese volunteers, suggesting that obesity is not a PYY-resistant state (6).
There is debate as to whether PYY3–36 reduces food intake by activating physiological food reduction circuits or by having an aversive effect. Different groups have published contradictory data as to whether PYY3–36 causes conditioned taste aversion (CTA) in rodents, and thus whether the effects of PYY3–36 on food intake are secondary to unpleasant side effects (84, 85). We have found that doses of PYY3–36 that result in circulating levels of PYY within the physiological range reduce food intake in humans without causing nausea or any other ill effects (5, 6). Others have found that pharmacological doses of PYY3–36 are required to reduce food intake and that nausea can occur at high doses (75). In recent studies, we found that high doses of PYY3–36 were associated with nausea in humans (our unpublished data). This is unsurprising. Hunger, satiety, and nausea may be points along the same physiological spectrum (86). Nausea is associated with high-dose administration of several satiety-inducing gut hormones and their analogs, including cholecystokinin (86), GLP-1 (87), exenatide (88, 89), and oxyntomodulin (90).
Interestingly, we found no greater inhibition of food intake at supraphysiological plasma PYY levels than at lower doses previously investigated (our unpublished data; also, Refs. 5 and 6). It is possible that PYY acts at physiological levels to mediate postprandial satiety and only causes nausea at pathophysiological levels. Fasting levels of PYY are chronically elevated in several gastrointestinal diseases associated with appetite loss (91). It is possible that the reduced gastric emptying and delayed gastrointestinal transit described after administration of PYY3–36 (64, 92) are responses designed to reduce the nutrient load on the diseased small intestine while increasing transit and, hence, absorption time. Similarly, the nausea reported in response to high levels of PYY3–36 may be an adaptation to reduce further stress on the gut in specific pathophysiological states. It has been suggested that PYY might act as an endogenous defense against diarrhea (93). Very high levels of PYY3–36 may therefore have powerful aversive effects to avoid further stress on the gut, but these effects may not be responsible for the normal PYY3–36-induced reduction of food intake. In our recent study, we found that the subjective feeling of nausea was short-lived and lasted for no more than 30 min. Interestingly, PYY3–36 reduced food intake after nausea levels had returned to baseline, suggesting an independent effect (our unpublished data). Similarly, recent work by others has shown that although high doses of PYY3–36 cause CTA in rodents, lower doses can reduce food intake without causing CTA (94).
D. Glucagon-like peptide-1 (GLP-1)
GLP-1 is a neuropeptide hormone produced by posttranslational processing of the preproglucagon gene in the CNS and the gut. We were the first to demonstrate the potent anorectic effects of intracerebroventricular administration of GLP-1 in rodents. GLP-1 neurons in the nucleus of the solitary tract (NTS) extend to regions of the hypothalamus important in the regulation of food intake (95). In 1988, we identified high-affinity binding sites for GLP-1 in the hypothalamus and the brain stem (96). Subsequently, we found that GLP-1 reduced food intake in fasted rats and activated neurons in the arcuate and paraventricular nuclei of the hypothalamus, and that blocking GLP-1 receptor signaling with the GLP-1 receptor antagonist, exendin (9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39), doubled food intake in satiated rats. Our findings suggested that central GLP-1 could induce satiety (97) and might also increase energy expenditure by raising body temperature (98). Repeated intracerebroventricular injection of GLP-1 reduced food intake and body weight in rats. Conversely, blocking endogenous GLP-1 signaling by repeated central administration of exendin (9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39) increased food intake and body weight, providing further evidence that GLP-1 is a physiological mediator of appetite (99).
Leptin may signal in part through the central GLP-1 system. We demonstrated that the long isoform leptin receptor was expressed in GLP-1 neurons extending from the NTS and that exendin (9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39) blocked the effects of leptin on food intake and body weight (100). In subsequent experiments, we showed that intracerebroventricular leptin administration prevents the reduction in hypothalamic GLP-1 peptide content observed in pair-fed food-restricted rats, and peripheral leptin increases hypothalamic GLP-1 peptide in food-restricted mice (101). However, leptin does reduce food intake in GLP-1 receptor knockout mice (102), demonstrating that GLP-1 signaling is not necessary to mediate the biological effects of leptin. Leptin is known to act via a number of central neuropeptide signals (2, 103, 104). Whether the efficacy of leptin in the GLP-1 receptor knockout mouse is maintained because of developmental compensation or because of the ability of the mature energy homeostasis circuitry to signal via alternative routes is unknown.
Peripheral GLP-1 can also influence glucose and energy homeostasis. It is therefore difficult to tease apart peripheral and central GLP-1 signaling pathways. It has been reported that both peripheral and central GLP-1 administration activate neurons in the arcuate nucleus, the hypothalamic paraventricular nucleus, NTS, and area postrema (82, 95, 105, 106). How the central and peripheral GLP-1 systems interact and are integrated into the bodywide energy homeostasis is unknown.
GLP-1 is released into the circulation after a meal, and proglucagon expression is decreased in the small intestine by fasting (107). The physical form of a meal appears to have a greater influence on GLP-1 release than its fat content (108). We discovered that GLP-1 acts as a physiological incretin (109, 110) and suppressor of gastric acid secretion (111) in man. Administration of exendin-4 reduces fasting and postprandial glucose in humans (112). We were the first group to investigate the effects of chronic sc GLP-1 treatment in type 2 diabetes mellitus. Three weeks of sc GLP-1 treatment significantly improved postprandial glycemic control in patients with poorly controlled type 2 diabetes mellitus (113, 114). Peripheral GLP-1 infusion has been reported to cause a dose-dependent reduction in food intake in humans (115). We confirmed that peripheral administration of the GLP-1 receptor agonist, exendin-4, significantly reduced food intake in healthy volunteers (112). Clinical trials have shown that exenatide, a long-acting agonist of the GLP-1 receptor, is useful in the regulation of glucose homeostasis in type 2 diabetes mellitus. Interestingly, exenatide does not only enhance insulin secretion and suppress glucagon release. In 30-wk phase 3 clinical trials, it also reduced body weight (116, 117, 118). Not all patients showed weight loss, and exenatide is not approved as an obesity treatment. However, these results do demonstrate that gut hormone systems have the potential to reduce body weight.
E. Oxyntomodulin
Like GLP-1, oxyntomodulin is a product of the preproglucagon gene released into the circulation postprandially. Originally characterized as an inhibitor of gastric acid secretion, like GLP-1, oxyntomodulin also reduces food intake when administered centrally to rodents or peripherally to rodents or humans (8, 119, 120, 121).
Oxyntomodulin binds to the GLP-1 receptor. However, although the affinity of oxyntomodulin for the GLP-1 receptor is much lower than that of GLP-1, oxyntomodulin and GLP-1 are equally efficacious at inhibiting food intake. Oxyntomodulin may reduce food intake via a different pathway to GLP-1 (119). However, both oxyntomodulin and GLP-1 have been shown to cause similar patterns of neuronal activation after peripheral administration (105). Oxyntomodulin has been suggested to bind to a specific oxyntomodulin receptor. However, the anorectic effects of oxyntomodulin are blocked by exendin (9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39) (122) and abolished in GLP-1 receptor knockout mice (105). Although it is possible that developmental changes in the GLP-1 receptor knockout mouse affect the functioning of another discrete oxyntomodulin receptor, and that exendin (9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39) also binds to this putative oxyntomodulin receptor, it seems more likely that oxyntomodulin does reduce food intake via the GLP-1 receptor. GLP-1 receptors are found in the brainstem and the arcuate nucleus. The different biological effects of oxyntomodulin and GLP-1 may therefore be due to differences in local breakdown, tissue penetration, or possibly context-dependent changes in receptor signaling, such as the receptor activity modifying proteins that regulate the specificity of the calcitonin receptor-like receptor (123). The GLP-1 receptor agonist exenatide has recently been approved for the treatment of type 2 diabetes mellitus in the United States, and exenatide treatment is associated with weight loss (116, 117, 118). However, it is possible that peptide analogs based on the structure of oxyntomodulin will prove more efficacious at promoting weight loss than those based on GLP-1.
Preliminary data suggest that oxyntomodulin may prove useful as an obesity drug. Chronic central or peripheral administration of oxyntomodulin reduces weight gain in rats (119, 120). Intravenous infusion of oxyntomodulin to supraphysiological levels reduces food intake in humans (8). Further work is required to elucidate the physiological significance of oxyntomodulin in human appetite, but it is interesting to note that oxyntomodulin levels are, like PYY, increased in particular pathophysiological conditions associated with reduced appetite (124).
We have recently performed studies demonstrating that oxyntomodulin can cause weight loss in humans. In a 4-wk study in which overweight and obese volunteers self-administered oxyntomodulin or saline three times daily, the oxyntomodulin-treated group ate significantly less. This substantial reduction in appetite was well-maintained over the 4-wk study period. Oxyntomodulin treatment also resulted in significant weight loss of an additional 0.45-kg weight loss per week compared with saline, accompanied by changes in the levels of adipose hormones consistent with a loss of body fat (90).
Rats chronically treated with oxyntomodulin lose more weight than pair-fed controls, suggesting that oxyntomodulin may also increase energy expenditure (120). Excitingly, the results of our latest human oxyntomodulin study suggested that oxyntomodulin also promotes energy expenditure in humans. Overweight and obese volunteers again self-administered oxyntomodulin, although this time for only four days. Energy expenditure was measured by indirect calorimetry and combined heart rate and movement monitoring, and food intake was assessed by a test meal. Oxyntomodulin administration significantly reduced energy intake at the study meal and increased activity-related energy expenditure by more than 25% (125). Oxyntomodulin is thus the first therapy shown to suppress appetite and concurrently increase spontaneous activity. Normal dieting reduces energy expenditure, making it difficult to lose weight. Oxyntomodulin, in contrast, increases energy expenditure as it reduces energy intake. Long-term trials are now required to investigate the utility of oxyntomodulin as an obesity drug.
|
III. The Future of Obesity Treatment |
|---|
|
TopAbstractI. IntroductionII. Gastrointestinal Hormones...III. The Future of...References |
|---|
Gut hormones may represent a novel pathway by which to tackle the obesity crisis. In comparison with the drugs currently available and in development that influence central neurotransmitter systems to reduce appetite, pharmaceutical agents that hijack gut hormone signaling systems have several clear advantages. Gut hormone-based therapies would specifically target appetite circuits. If, as the evidence suggests, endogenous gut hormones regulate appetite physiologically, then one might expect fewer side effects. Although high doses of gut hormones may cause aversive effects, it may be possible to administer lower doses of gut hormones in combination. We have demonstrated that low doses of PYY3–36 and GLP-1 can additively reduce food intake in rodents and man (128). It may be that obesity treatment will rely on combination therapy, as does, for example, the treatment for hypertension. In addition, gut hormones are released on a daily basis throughout life, suggesting that tachyphylaxis may be less of a problem than with other drugs.
The major disadvantages of gut hormones are their relatively short half-lives and the fact that they cannot be orally administered. The design of breakdown-resistant analogs might increase the length of time such drugs would remain active in the circulation. Eventually, the hope is that new administration techniques could be developed, for example depot injections or nasal inhalers, and that small molecule mimetics could be designed for oral administration.
In conclusion, gut hormones physiologically regulate energy homeostasis, and commandeering gut hormone signaling systems provides a promising target for antiobesity therapies.
|
Footnotes |
|---|
First Published Online October 31, 2006
Abbreviations: AgRP, Agouti-related protein; CNS, central nervous system; CTA, conditioned taste aversion; GHS-R, GH secretagogue receptor; GLP-1, glucagon-like peptide-1; NPY, neuropeptide Y; NTS, nucleus of the solitary tract; PP, pancreatic polypeptide; PPY, peptide YY; PWS, Prader-Willi syndrome.
|
References |
|---|
|
TopAbstractI. IntroductionII. Gastrointestinal Hormones...III. The Future of...References |
|---|
