Blackwell Publishing LtdOxford, UKOBRObesity Reviews1467-7881© 2007 Queen’s Printer and Controller of HMSO; published with permission; Journal compilation © 2007 The International Association for the Study of Obesity? 20078••6365Review ArticleHormonal regulation of appetite S. Bloom

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Hormonal regulation of appetite S. Bloom

Department of Metabolic Medicine, Imperial

Keywords: Appetite regulation, gut hormone, hypothalamus, obesity.

College London, London, UK

Accepted 30 November 2006

Address for correspondence: Professor S Bloom, Department of Metabolic Medicine, 6th Floor Commonwealth Building, Division of Investigative Science, Hammersmith Hospital, Imperial College London, Du Cane Road, London W12 ONN, UK. E-mail: [email protected]

OnlineOpen: This article is available free online at www.blackwell-synergy.com

Background Is it the case that normal healthy people in a healthy environment will inevitably become fat? The author’s cynical view is that humans have been the dominant species for over a million years and throughout that time their numbers have been mainly limited by food supply. There has therefore been very strong evolutionary pressure to limit energy expenditure and increase food intake whenever possible. Those who survived the numerous episodes of famine did so because they had accumulated some fat and were intrinsically parsimonious about expending energy. This is now built into our physiology and psychology – we enjoy eating and tend to be physically lazy. Civilization has recently brought the provision of a secure food supply and also mechanization to dramatically limit the need for exercise. This has been described as the obesogenic environment and, with our intrinsic nature, such circumstances have led to mass obesity. So, we do not become obese because we are abnormal; indeed, it is a struggle to overcome our intrinsic nature and stay thin. We are designed to over-eat and limit exercise, but high-energy and convenience foods are now freely available and those in industry vie to make it more so. Exercise is difficult to provide in our city environment. We are dying of the consequential obesity, but no one has any good idea of how to stop it (1). It follows from this that obesity is not a disease to be cured but a maladaption to our current ‘civilized’ environment. ‘Treatment’ therefore either requires a readjustment

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of the environment or a means to change our physiological energy-balance set point.

The current medical position No one thinks that medical treatment of normal, healthy but overweight individuals is desirable. There is widespread consensus that behavioural and environmental change is more appropriate. Unfortunately, this approach, although adopted for many decades, has neither stopped nor apparently slowed the development of a major obesity epidemic in the UK. The scientific proof that this ‘societal approach’ might ever work is very weak or absent. There are four theoretical medical approaches to reducing adipose tissue: • Reduce calorie input (low-calorie foods, drugs to impair absorption, change of environment). • Reduce appetite (behaviour training, drugs and change in environment). • Increase energy expenditure by exercise and environmental change. No drugs are available for this, but the medical condition of thyrotoxicosis illustrates the principle that such drugs are possible. • Remove fat or impair its metabolism (current agents are toxic but do prove the principle). There are only two drugs that have been licensed for obesity over the last few years and both are feeble. Sibutramine (Reductil) reduces appetite, acting on the brain. It

This paper was commissioned by the Foresight programme of the Office of Science and Innovation, Department of Trade and Industry © 2007 Queen’s Printer and Controller of HMSO; published with permission Journal compilation © 2007 The International Association for the Study of Obesity. obesity reviews 8 (Suppl. 1), 63–65

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cannot be used in some overweight and obese subjects because of side effects (such as increasing heart rate and blood pressure). Orlistat (Xenical) impairs fat absorption from the gut and is advised for subjects who can demonstrate weight loss by diet alone prior to taking it (2,3). Neither sibutramine nor orlistat are very effective and both have significant side effects. Rimonabant is a new drug due to be marketed shortly that causes a small to medium reduction in body weight over 12 months but has significant side effects (nausea and depression). The only currently fully effective intervention is surgery. Bypass surgery gives a 50% weight loss sustained over 20 years but has a 2% mortality and upward of 40% readmission to hospital (4). It is expensive, at least initially. The cheaper and simpler gastric banding procedure does not produce as great or as sustained a weight loss.

What can current cutting-edge research in the area of hormonal appetite regulation tell us about obesity? Understanding the normal mechanisms controlling energy balance will lead to the knowledge required for the development of effective anti-obesity therapies. There are two main strands to the current investigation of the regulation of energy balance. First, there are the central nervous system mechanisms that regulate appetite (5). Two main centres are recognized: brain stem and hypothalamus. The brain stem receives signals from the blood stream via the area postrema and from the peripheral nervous system, particularly by the vagus. The dorsal vagal complex in the brain stem integrates the signals and passes them upwards, in particular to the hypothalamus. The hypothalamus receives signals from higher centres, the brain stem and directly from the bloodstream. For example, the fat hormone leptin penetrates, probably via the choroid plexus, to decrease food intake. A major site of action of leptin is in the arcuate nucleus of the hypothalamus, where it acts particularly on two cell types. The first makes two neurotransmitters, which increase food intake – neuropeptide Y and agouti-related protein. Leptin inhibits this neurone type (6). The second neurone cell type makes two neurotransmitters, which inhibit food intake – alpha melanocyte stimulating hormone and cocaine and amphetamine regulated transcript. Leptin stimulates this cell type (6). Both types of cell project to the paraventricular nucleus, another nucleus in the hypothalamus. This nucleus is responsible for decreasing the expenditure of energy and increasing food intake, or the reverse. This story is already known to be too simple and a number of other neurotransmitters and circuits are likely to play a role, particularly in special circumstances. The second strand to the current investigation of the regulation of energy balance is peripheral factors, which

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regulate appetite. Leptin is released from fat tissue and acts via the hypothalamus in the brain to inhibit food intake (6). Unfortunately, in obese subjects, leptin does not inhibit food intake, as these subjects are resistant to leptin’s actions on food intake. More recently, many other hormones released by fat (e.g. adiponectin) have also been shown to affect food intake and this group of hormones is called the ‘adipokines’ (7) (also see contribution by Trayhurn). These may prove to be targets for the development of anti-obesity agents in the future. Hormones produced by the gut have been shown to affect food intake (8,9). Glucagon-like peptide-1 (GLP-1) has been shown to inhibit food intake and stimulate insulin secretion. A modified form of GLP-1, exenatide (Byetta) (10), is now licensed for the treatment of diabetes and also causes weight loss. Other gut hormones such as peptide YY (11,12) and oxyntomodulin (13–15) have also been shown to powerfully reduce food intake These hormones are released in all of us following a meal and are thought to be the hormonal signal that tells the brain that we are full. As these hormones are released by normal individuals in response to a meal, they are promising potential targets for the development of effective anti-obesity agents, which will be efficacious with minimal side effects. Other hormones such as cholecystokinin, insulin and amylin (Pramlintide) have also been studied as appetite regulators, but it is the author’s view that these hormones are not important players.

How might research in this area change our understanding in the next 25 years? In the future, one could predict that there might be alterations in our environment in which better education will lead to an increase in exercise and improvements in our diet. However, for some, this will be inadequate, and a safe means of adjusting individual appetite will be required. In this respect, it will be similar to the need of people with high blood pressure and elevated cholesterol levels, that is, they require safe long-term medication. Research into the normal mechanisms controlling appetite and abnormalities in the systems that cause obesity are necessary for the development of novel anti-obesity drugs (16,17). During the last 25 years, our knowledge of the mechanisms controlling appetite has increased considerably, but we are only beginning to properly appreciate how very complex the system is and its main regulatory features. In the next 25 years, our understanding of which circuits control appetite will be established and we will begin to have an idea of how all of these pathways integrate to control body weight. This will provide the rationale to develop effective anti-obesity agents, which are free of side effects. It is likely to be some time before a totally safe way of adjusting our appetite and our energy expenditure to

This paper was commissioned by the Foresight programme of the Office of Science and Innovation, Department of Trade and Industry © 2007 Queen’s Printer and Controller of HMSO; published with permission Journal compilation © 2007 The International Association for the Study of Obesity. obesity reviews 8 (Suppl. 1), 63–65

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match the current obesogenic environment exists so as to prevent excessive storage of surplus energy as fat.

Conclusions There is no current acceptable and proven mass-population environmental change that would prevent obesity in the majority of the people. There is also no way yet found of permanently, or even temporarily, adjusting the UK population’s appetite and the propensity was for energy expenditure to match the current obesogenic environment. We are used to taking statins for hypercholesterolaemia and several agents for high blood pressure for many decades. Chronic medication for chronic conditions is therefore acceptable if the benefit is big enough and the side effects very minor. The development of similarly benign agents to limit appetite to that appropriate for our current conditions is feasible in the next decade and may offer the most immediate and most practical solution to the obesity problem.

Conflict of Interest Statement The author is a director and shareholder in Thiakis.

References 1. O’Brien PE, Brown WA, Dixon JB. Obesity, weight loss and bariatric surgery. Med J Aust 2005; 183: 310–314. 2. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature 2000; 404: 661–671. 3. Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, Ghatei MA, Bloom SR. Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med 2003; 349: 941– 948. 4. Small CJ, Bloom SR. Gut hormones as peripheral anti obesity targets. Curr Drug Targets 2004; 3: 379–388.

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5. Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA, Dakin CL, Wren AM, Brynes AE, Low MJ, Ghatei MA, Cone RD, Bloom SR. Gut hormone PYY (3–36) physiologically inhibits food intake. Nature 2002; 418: 650–654. 6. Kaplan LM. Pharmacological therapies for obesity. Gastroenterol Clin North Am 2005; 34: 91–104. 7. Wynne K, Park AJ, Small CJ, Meeran K, Ghatei MA, Frost GS, Bloom SR. Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: a randomised controlled trial. Int J Obes (London) 2006; 30: 1729–1736. 8. Bray GA. Risks of obesity. Endocrinol Metab Clin North Am 2003; 32: 787–804. 9. Edwards CMB, Stanley SA, Davis R, Brynes AE, Frost GSS, Seal LJ, Ghatei MA, Bloom SR. Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am J Physiol 2001; 281: E155–E161. 10. Wynne K, Park AJ, Small CJ, Patterson M, Ellis SM, Murphy KG, Wren AM, Frost GS, Meeran K, Ghatei MA, Bloom SR. Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial. Diabetes 2005; 54: 2390–2395. 11. Cohen MA, Ellis SM, le Roux CW, Batterham RL, Park A, Patterson M, Frost GS, Ghatei MA, Bloom SR. Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin Endocrinol Metab 2003; 88: 4696–4701. 12. Curran MP, Scott LJ. Orlistat: a review of its use in the management of patients with obesity. Drugs 2004; 64: 2845– 2864. 13. Foxcroft DR, Milne R. Orlistat for the treatment of obesity: rapid review and cost-effectiveness model. Obes Rev 2000; 1: 121–126. 14. Hukshorn CJ, van Dielen FM, Buurman WA, WesterterpPlantenga MS, Campfield LA, Saris WH. The effect of pegylated recombinant human leptin (PEG-OB) on weight loss and inflammatory status in obese subjects. Int J Obes Relat Metab Disord 2002; 26: 504–509. 15. Finer N. Pharmacotherapy of obesity. Best Pract Res Clin Endocrinol Metab 2002; 16: 717–742. 16. Stanley S, Wynne K, McGowan B, Bloom S. Hormonal regulation of food intake. Physiol Rev 2005; 85: 1131–1158. 17. Trayhurn P. Endocrine and signalling role of adipose tissue: new perspectives on fat. Acta Physiol Scand 2005; 184: 285–293.

This paper was commissioned by the Foresight programme of the Office of Science and Innovation, Department of Trade and Industry © 2007 Queen’s Printer and Controller of HMSO; published with permission Journal compilation © 2007 The International Association for the Study of Obesity. obesity reviews 8 (Suppl. 1), 63–65