Gut Hormones as Potential New Targets for Appetite Regulation and the Treatment of Obesity
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LEADING ARTICLE
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Gut Hormones as Potential New Targets for Appetite Regulation and the Treatment of Obesity Benjamin C.T. Field,1 Alison M. Wren,1 Dunstan Cooke2 and Stephen R. Bloom1,2 1 2
Department of Metabolic Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK Thiakis Limited, Imperial Bioincubator, London, UK
Abstract
Food intake and bodyweight are tightly regulated by the brainstem, hypothalamus and reward circuits. These centres integrate diverse cognitive inputs with humoral and neuronal signals of nutritional status. Our knowledge of the role of gut hormones in this complex homeostatic system has expanded enormously in recent years. This review discusses both the role of gut hormones in appetite regulation, and the current state of development of gut hormone-based obesity therapies, with a particular focus on pancreatic polypeptide, peptide YY, amylin, glucagon-like peptide-1, oxyntomodulin, cholecystokinin and ghrelin. Several gut hormone-based treatments for obesity are under investigation in phase II and III clinical trials, and many more are in the pipeline.
1. Obesity Obesity is a condition that predisposes individuals to hypertension, ischaemic heart disease, stroke, obstructive sleep apnoea, osteoarthritis, several common cancers and, above all, to diabetes mellitus, with its attendant risks of blindness, kidney failure and limb amputation.[1] The magnitude of the effect cannot be trivialized. In a prospective cohort study of 114 281 women, the risk of developing type 2 diabetes increased exponentially with body mass index (BMI) [calculated as weight in kilograms divided by the square of height in metres]. After 14 years of follow-up, women in the highest BMI group were 93 times more likely to develop diabetes than those in the lowest group.[2] Over the last 30 years, the prevalence of obesity has dramatically increased, not only in industrial-
ized nations but throughout the world.[3-7] Children, as well as adults, are affected, and the complications of obesity are occurring at ever younger ages.[8,9] For example, the incidence of end-stage renal failure secondary to type 2 diabetes in 30- to 44-year-old Europeans, Canadians and Australians increased by 16% each year from 1998 to 2002.[10] Although obesity may be successfully treated by changes to diet and physical activity habits, it is unusual for affected individuals to alter their lifestyles on a permanent basis. Current pharmacological therapies are limited in their efficacy and hampered by significant adverse effects.[11] Of all the medical interventions currently available for morbid obesity, only bariatric surgery, with all its risks, offers the prospect of substantial, permanent weight loss.
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2. Gut Hormones and Satiety The most common bariatric surgical procedures in current use are the adjustable gastric band and the Roux-en-Y gastric bypass. The adjustable gastric band consists of a silastic ring, sutured in place around the upper por
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