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Can Gut Hormones Control Appetite and Prevent Obesity?

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Can Gut Hormones Control Appetite and Prevent Obesity? SECTION III Can Gut Hormones Control Appetite and Prevent Obesity? OWAIS B. CHAUDHRI, PHD ters are the subject of some contention. KATIE WYNNE, PHD The proximity of both the hypothalamus 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 area postrema 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 oxyntomodulin, peptide YY, glucagon-like peptide 1, pancreatic perspective, targeting the interaction of polypeptide, and ghrelin and their emerging potential as anti-obesity treatments. appetite signals with their receptors in the vagal nerve offers the potential advantage Diabetes 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 peptides. Cholecystokinin 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 hormone, 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 leptin, unwanted consequence of therapies tar- tion co-expressing the neurotransmitters which is thought to signal longer-term en- geting ubiquitous neurotransmitter and neuropeptide Y and agouti-related pep- ergy status, these gut hormones appear to receptor 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 neuropeptides 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 stomach (19). It Imperial College London, 6th Floor Commonwealth Building, Hammersmith Hospital, Du Cane Rd., Lon- acts via the growth hormone 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 anorexia 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 exenatide is also associated with hypogly- Like GLP-1, OXM is inactivated in A product of proglucagon 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 agonists, 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 incretin 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 type 2 diabetes, 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 insulin, 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, sitagliptin (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- vildagliptin (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.
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