SECTION III

Can Gut Control Appetite and Prevent Obesity?

OWAIS B. CHAUDHRI, PHD ters are the subject of some contention. KATIE WYNNE, PHD The proximity of both the STEPHEN R. BLOOM, MD, DSC and brainstem to structures with a relative deficiency of blood-brain barrier (the me- dian eminence in the case of the hypothal- The current obesity epidemic is fuelled by the availability of highly palatable, calorie-dense food, amus and the in respect of and the low requirement for physical activity in our modern environment. If energy intake the brainstem) may allow circulating fac- exceeds energy use, the excess calories are stored as body fat. Although the body has mechanisms tors direct access to CNS neurons. There that act to maintain body weight over time, they primarily defend against starvation and are less is a growing body of evidence, however, robust in preventing the development of obesity. Knowledge of this homeostatic system that that points to the vagus nerve as a primary controls body weight has increased exponentially over the last decade and has revealed new site of action of some appetite-modulating possibilities for the treatment of obesity and its associated comorbidities. One therapeutic target is the development of agents based on the gastrointestinal hormones that control appetite. This hormones (11–15). From a therapeutic review discusses the hormones , YY, -like peptide 1, pancreatic perspective, targeting the interaction of polypeptide, and and their emerging potential as anti-obesity treatments. appetite signals with their receptors in the vagal nerve offers the potential advantage Care 31 (Suppl. 2):S284–S289, 2008 of being able to manipulate appetite at a site distant from the CNS. he grave personal, societal, and eco- lay information to important CNS cen- nomic consequences presaged by ters, including the hypothalamus and the GUT HORMONES — The GI-pan- T the continued worldwide rise in the brainstem (7). These CNS structures have creatic complex is the largest endocrine prevalence of obesity are well docu- extensive reciprocal connections and organ in the body and a source of impor- mented (1,2). Currently, licensed non- both receive neuronal input from the pe- tant regulatory . surgical interventions are of limited riphery, with the brainstem-vagus nerve was the first to be implicated in the short- efficacy (3–6). This relative failure of complex being of particular significance term control of food intake (16), and available therapies has imparted impetus in the control of feeding (8–10). other appetite-regulating hormones have to work directed at harnessing the physi- Neuronal activity in hypothalamic subsequently been characterized. Of ological mechanisms of appetite control. and brainstem nuclei is susceptible to in- these, ghrelin is the only known orexi- The pursuit of the body’s own satiety sig- fluence by circulating hormones. In the genic gut , whereas a number of nals as therapeutic targets promises effec- hypothalamic arcuate nucleus (Arc), sig- satiety factors exist, including glucagon- tive reductions in body weight with nals from the periphery result in changes like peptide (GLP)-1, oxyntomodulin minimum disruption to other systems, in the relative activity of two subpopula- (OXM), peptide YY (PYY), and pancreatic avoiding the side effects that occur as an tions of neurons: an orexigenic popula- polypeptide (PP) (7). Unlike , unwanted consequence of therapies tar- tion co-expressing the neurotransmitters which is thought to signal longer-term en- geting ubiquitous neurotransmitter and Y and agouti-related pep- ergy status, these gut hormones appear to complexes. tide and an anorexigenic population co- act as meal initiators and terminators. Al- expressing pro-opiomelanocortin and terations in levels of gut hormones after THE GUT-BRAIN AXIS — The cocaine- and amphetamine-regulated bariatric surgery may contribute to the lines of communication between the gas- transcript. Alterations in the release of appetite suppression and sustained trointestinal (GI) tract and central ner- these affect feeding behav- weight loss seen in patients undergoing vous system (CNS) form a key component ior and energy expenditure, resulting in this procedure and supports the develop- in a recently established model of appetite the maintenance of energy homeostasis. ment of these hormones as therapeutic regulation. This gut-brain axis has both The mechanisms by which hor- targets (17,18). neural and humoral components that re- mones interact with CNS appetite cen- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From the Department of Metabolic Medicine, Imperial College London, Hammersmith Hospital, London, Ghrelin U.K. This28–aminoacidpeptideissynthe- Address correspondence and reprint requests to Professor S.R. Bloom, Department of Metabolic Medicine, sized principally in the (19). It Imperial College London, 6th Floor Commonwealth Building, Hammersmith Hospital, Du Cane Rd., Lon- acts via the secretagogue don W12 0NN, U.K. E-mail: [email protected]. receptor to increase food intake in rodents S.R.B. is on the board of and holds stock in Thiakis. O.B.C. and K.W. declare no relevant conflict of interest. (20) and also acts to stimulate food intake This article is based on a presentation at the 1st World Congress of Controversies in Diabetes, Obesity and in humans (21,22). Clinical studies have Hypertension (CODHy). The Congress and the publication of this article were made possible by unrestricted thus far concentrated on its use as an educational grants from MSD, Roche, sanofi-aventis, Novo Nordisk, Medtronic, LifeScan, World Wide, Eli orexigenic agent in conditions character- Lilly, Keryx, Abbott, Novartis, Pfizer, Generx Biotechnology, Schering, and Johnson & Johnson. Abbreviations: CNS, central nervous system; DPP-IV, dipetidyl peptidase IV; GI, gastrointestinal; GLP, ized by and cachexia (23–26). glucagon-like peptide; OXM, oxyntomodulin; PYY, peptide YY. Antagonists to ghrelin have been used in DOI: 10.2337/dc08-s269 preclinical studies, however, paving the © 2008 by the American Diabetes Association.

S284 DIABETES CARE, VOLUME 31, SUPPLEMENT 2, FEBRUARY 2008 Chaudhri, Wynne, and Bloom way for possible future evaluation as a However, like GLP-1, dose-limiting side latter scenario is intriguing, since it of- therapy for obesity in humans (27). effects of nausea and vomiting define the fers another possible point for thera- maximal tolerated dose (35). The use of peutic intervention. GLP-1 is also associated with hypogly- Like GLP-1, OXM is inactivated in A product of cleavage, cemia, although this occurs predomi- large part by DPP-IV, and its advance- GLP-1 is released from the L-cells of the nantly in patients receiving the drug in ment as a clinically useful treatment will GI tract postprandially in proportion to combination with another hypoglycemic be reliant on the development of a the calories ingested. GLP-1 and longer- agent (36). It has been reported that up to breakdown-resistant analog. Thiakis acting GLP-1 receptor , such as 30% of patients taking exenatide develop and Imperial Innovations (London, exendin-4, reduce food intake in rodents antibodies to this foreign peptide, al- U.K.) are in the process of developing when injected into the CNS (28) or pe- though the clinical significance of this re- novel analogs of oxyntomodulin for the ripherally (12,29). Given the observation mains unclear (33). treatment of obesity. of reduced circulating levels of GLP-1 and an attenuated postprandial response in Oxyntomodulin the obese (30), it is not unreasonable to Another product of the tissue-specific dif- Inhibitors of DPP-IV hypothesize that restoration of satiety ferential cleavage of proglucagon, OXM, In the quest for an effective anti-obesity through the use of exogenous GLP-1 re- is co-secreted with GLP-1 and PYY3–36 treatment, some researchers have ceptor agonists might result in weight into the circulation by intestinal L-cells adopted the approach of augmenting the loss. To date, clinical development has fo- after nutrient ingestion (37). OXM is a effectiveness of endogenous gut peptides. cused on its strong effect and its satiety signal and administration reduces Multiple DPP-IV inhibitors have been resultant use as an anti-diabetic agent: a energy intake in both rodents and hu- tested in animals, and although they im- 6-week subcutaneous infusion of GLP-1 mans (38–42). Indeed, preprandial sub- prove glucose levels in rodent models of improved blood glucose levels in poorly cutaneous administration of OXM to , their effect on weight is controlled diabetic subjects (31). How- overweight and obese humans over a more equivocal (49–52). A number of ever, in contrast to , GLP-1 results 4-week period resulted in a significant re- DPP-IV inhibitors are at various stages of in a tendency to reduce body weight (32). duction in body weight of 2.3 kg, com- development as adjuvant therapy for use The advantages of a hypoglycemic agent pared with 0.5 kg for the placebo arm in type 2 diabetic subjects with poorly that also promotes weight loss are obvi- (42). In addition, OXM has been found to controlled blood glucose levels. Of these, ous. These results may also be encourag- have a beneficial effect on energy usage, (Januvia, Merck) was granted ing for the use of GLP-1 as an anti-obesity in that it increased activity levels back marketing approval by the Food and Drug therapy. toward normal in overweight and obese Administration in October 2006, and A major hurdle to the therapeutic use volunteers (43). Oxyntomodulin admin- (Glavus, Novartis) is cur- of native GLP-1, and one common to istration was well tolerated in these stud- rently undergoing Food and Drug Ad- many gut hormones, is its short half-life. ies. Longer-term trials are now required to The principle mediator of GLP-1 inactiva- determine whether its beneficial combi- ministration review. The evidence from tion is the enzyme dipetidyl peptidase IV nation of properties can be sustained. clinical trials to date suggests that these (DPP-IV). A number of DPP-IV–resistant Although direct comparisons have therapies were well tolerated with few ad- GLP-1 receptor agonists, including lira- not been made, OXM appears to cause verse effects, but also have little effect on glutide (Novo Nordisk, Denmark) and less nausea than GLP-1–based treatments weight (53). Longer-term safety and out- exenatide (Byetta, Pharmaceuti- and thus may prove a potentially reward- come data are awaited. cals, San Diego) have therefore been de- ing avenue of investigation. OXM is veloped. has been synthesized thought to act via the GLP-1 receptor Amylin using the GLP-1 sequence with the addi- (29). However, despite this common re- ␤ tion of an acyl side chain that allows for ceptor, there are biological differences be- Co-secreted with insulin from the -cells noncovalent binding to albumin and pro- tween the two hormones. There is of the , the peptide amylin forms longs its half-life in the circulation (33). evidence that OXM acts through different the basis of (Symlin; Amylin As an alternative strategy, exenatide (ex- CNS pathways (40,44) and has a weaker Pharmaceuticals), a novel treatment for endin-4) was extracted from the venom of incretin effect than GLP-1 (41,42,45). Its diabetes that has recently been granted the gila monster (Heloderma suspectum). It effect on food intake is more potent than Food and Drug Administration approval. potently binds to and activates the GLP-1 that of GLP-1 in humans (41,42). In ad- In addition to favorable effects on blood receptor and is resistant to DPP-IV break- dition, the increased activity levels ob- glucose, pramlintide reduces food intake down in the plasma. served during oxyntomodulin therapy and has been shown to result in a 1.8-kg Exenatide was recently licensed by (43) have not been demonstrated with reduction in body weight over 26 weeks the Food and Drug Administration for use GLP-1 treatment, whose effect on energy in overweight diabetic subjects (54). as an adjunctive therapy for suboptimal expenditure remains controversial (46– Phase 2 clinical trials of pramlintide for glucose control in type 2 diabetic patients 48). The reasons for these dissimilar ac- the treatment of obesity have shown and is now undergoing further clinical tri- tions awaits elucidation but may lie in weight loss of 3.5 kg over 16 weeks in 204 als to evaluate its utility specifically as a differential penetration of OXM and obese subjects (160 without diabetes and therapy for obesity. Initial data from GLP-1 into different areas of the CNS or 44 with non–insulin-treated type 2 diabe- open-label extension studies in diabetic modification of ligand binding to the tes). Further evaluation of this drug as a patients have shown that a weight loss of GLP-1 receptor in specific CNS regions therapy specifically for the treatment of 4.4 kg can be achieved by 82 weeks (34). by a receptor-associated protein. This obesity is awaited.

DIABETES CARE, VOLUME 31, SUPPLEMENT 2, FEBRUARY 2008 S285 Gut hormones in obesity

Peptide YY nasal spray for 6 days in 37 obese vol- Their use as a basis for therapy in obesity PYY3–36, the major circulating form of unteers was associated with significant therefore promises efficacy with minimal PYY, is co-secreted from intestinal L-cells reductions in daily caloric intake that adverse effects. with GLP-1 and OXM. Although there were sustained over the study period. Nevertheless, the therapeutic devel- was initially some contention regarding Thrice-daily administration of the pep- opment of gut peptides is not without its the effects of PYY3–36 on energy intake in tide yielded a reduction in caloric intake difficulties. As indicated above, the short animal models (55), a number of research of 2,713 kJ and weight loss of 0.6 kg half-life of many native gut peptides ne- groups have demonstrated that periph- after 6 days of treatment. The results of cessitates unwieldy and inconvenient ad- eral PYY3–36 inhibits food intake and re- more extensive trials are awaited. ministration regimens (42,76). The use of duces body weight gain in several species stable analogs and novel methods of drug (56–63). The minimization of stress, delivery, thus avoiding the need for sub- which can itself result in an inhibition of Sharing some common structural features cutaneous injection or infusion, are two food intake, is vital to observe the anorec- with PYY3–36, pancreatic polypeptide is means by which this issue may be circum- tic effect of PYY3–36 in rodents (27,64). principally secreted by a population of vented. The former is exemplified by the This has led some to question the utility of cells located at the periphery of pancreatic GLP-1 receptor agonists exenatide and li- PYY3–36 as a basis for human therapy islets. It is released into the circulation in raglutide and the latter by interest in nasal (55). However, the evidence from human a biphasic manner in response to nutrient delivery of PYY3–36. Orally stable prepa- studies to date is encouraging. ingestion and is subject to control by the rations of gut peptides remain some way In the first clinical study of the in- vagus nerve and a number of other factors off (77,78), although the development of travenous administration of PYY3–36, (67). nonpeptide receptor agonists offers a po- spontaneous food intake was reduced The role of pancreatic polypeptide in tentially fruitful alternative avenue. by 30% at plasma levels similar to those the regulation of energy balance is un- Several gut hormones cause nausea in seen physiologically (56). A further re- clear. Studies have shown that circulating a proportion of patients receiving ther- cent study observed a dose-dependent levels are reduced in the context of obe- apy, and this has limited the usefulness of reduction in appetite and food intake in sity, and there is a reduced second phase GLP-1–based therapies to some extent response to intravenous PYY3–36 admin- release after a meal (68), whereas in an- (35). Satiety and nausea likely lie at dif- istration in normal-weight volunteers, orexic patients, levels are elevated (69). ferent points along a spectrum of reac- although nausea occurred at higher However, these findings have not been tions to GI stimuli, and gut peptide– doses (63). universally replicated (70,71). regulated pathways may mediate aspects It has been suggested that obesity is a PP reduces food intake when admin- of both responses (79–81). Although PYY3–36–deficient state, with lower basal istered to rodents and humans (72–74). It problematical, the application of dose- levels and a blunted postprandial re- remains to be evaluated whether this ef- escalation regimes provides one possible sponse (65). PYY3–36 “replacement” fect is preserved in obese humans. Work solution and would not be dissimilar to would therefore seem an apposite therapy in individuals with Prader-Willi syn- the manner in which patients are com- for obesity, and there is evidence that drome, characterized by overeating and menced on other commonly used thera- obese individuals retain sensitivity to its morbid obesity, is encouraging (75), but pies such as . appetite-suppressant effects (58). How- not necessarily applicable to the more Perhaps a greater obstacle to the entry ever, the therapeutic potential of PYY3–36 general nonsyndromic obese population. of GI hormone–based therapies lies in as an anti-obesity treatment is currently However, the observation that a single in- considerations of efficacy. The regulation unknown, since there are limited data re- fusion of pancreatic polypeptide caused a of food intake is complex, and although garding the effect of repeated doses of measurable effect on food intake as long its role is significant, the gut-brain axis PYY3–36 on body weight in humans. as 24 h afterward in normal-weight vol- operates alongside other components in- Two drug companies are engaged in unteers (74) suggests that pancreatic cluding CNS reward pathways, input developing PYY3–36 for the treatment of polypeptide may have potential as a long- from higher centers, and societal and en- human obesity. term suppressor of appetite. vironmental influences. The homeostatic has completed Phase I trials of its investi- system has developed with a high degree gational compound AC162352, although CONCLUSIONS — Even the modest of in-built redundancy to guard against no data are in the public domain regard- weight loss resulting from the use of cur- starvation, and this is signified by the dis- ing its efficacy. Nastech Pharmaceutical rently available therapies, such as sibutra- continuation of development of the cho- Company (Bothell, WA), in collaboration mine, , and , can result lecystokinin receptor 181771 by with Merck (Whitehouse Station, NJ), has in improvements in health and life ex- GlaxoSmithKline (Brentford, Middlesex, recently completed Phase I trials of pectancy (4,6). However, projections of U.K.) after the results of clinical trials PYY3–36 delivered via the intranasal route. future trends in the prevalence of over- made it commercially nonviable. Similar Acutely, PYY3–36 caused significant re- weight and obesity underline the urgent concerns have been raised over PYY3–36 ductions in visual analog appetite scores, need for more effective treatments if the (55). and there was a trend toward a dose- attendant socioeconomic consequences However, individual gut peptides dependent reduction in food intake at a are to be lessened. are not released in isolation in response test meal (66). The most significant ad- The mechanisms of postprandial sati- to nutrient ingestion. Rather, there is a verse effect noted was nausea, but this was ety are still being characterized. Satiety coordinated release of a number of GI seen in those subjects with the highest factors secreted by the GI tract appear to hormones, which act additively in or- plasma levels of PYY3–36 after administra- occupy an important position in meal ter- chestrating efficient nutrient absorption tion. Furthermore, preprandial use of the mination and the limitation of meal size. and meal termination (22). It therefore

S286 DIABETES CARE, VOLUME 31, SUPPLEMENT 2, FEBRUARY 2008 Chaudhri, Wynne, and Bloom seems not unreasonable to propose that Physiol Rev 85:1131–1158, 2005 tide from stomach. Nature 402:656–660, in the therapeutic targeting of appetite 8. Schwartz GJ: Integrative capacity of the 1999 regulation, polypharmacy with a num- caudal brainstem in the control of food 20. Wren AM, Small CJ, Abbott CR, Dhillo ber of therapies might maximize clinical intake. Philos Trans R Soc Lond B Biol Sci WS, Seal LJ, Cohen MA, Batterham RL, effect while minimizing side effects, 361:1275–1280, 2006 Taheri S, Stanley SA, Ghatei MA, Bloom 9. Ellacott KL, Cone RD: The role of the cen- SR: Ghrelin causes hyperphagia and obe- mirroring trends in the management of tral system in the regulation sity in rats. Diabetes 50:2540–2547, 2001 other chronic conditions such as hyper- of food intake and energy homeostasis: 21. Wren AM, Seal LJ, Cohen MA, Brynes AE, tension (82). 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