Eleanor Spreckley & Kevin Murphy
Section of Investigative Medicine, Imperial College London, UK

https://doi.org/10.36866/pn.96.28

The regulation of body weight should be simple. Balancing energy intake with energy expenditure will result in a stable body weight. If body weight is too high, then all that is required is to reduce food intake and/or increase energy expenditure. And yet the majority of the UK population is overweight or obese, and the costs of treating the obese may, it has been proposed, bankrupt the National Health Service.

The regulation of appetite – of feelings of hunger and satiety – are governed by a complex combination of signalling systems, both in the brain and in the periphery, that have evolved to prevent starvation. It is thought that our ancestors had sporadic access to food, and that in response the human body evolved to store excess caloric intake as adipose tissue for use during times of limited food availability (Ulijaszek, 2002). However, in the modern Western world, food is cheap and plentiful and packed with energy, and developments in transport, entertainment and the work environment mean that more physically demanding energy-expending activities are no longer a fundamental part of everyday life. These factors together contribute to the current obesity pandemic. Obesity, defined as a body mass index (BMI) of 30 kg/m2 or higher, is now a condition which affects over 500 million adults worldwide (World Health Organisation, 2013).

Obesity is a damaging state. It is associated with increased risk of developing numerous comorbidities, including cardiovascular disease, type II diabetes mellitus, osteoarthritis, stroke and certain cancers, as well as with other factors that reduce quality of life, including underachievement at school, low self-esteem, and mental health disorders (World Health Organisation, 2013). In England, more than 60% of adults are overweight or obese, meaning that what was once considered a ‘normal’ healthy bodyweight is now no longer normal. Related health problems are costing the NHS over £5 billion a year, and the economy shoulders further, less easily calculated costs due to the associated sick leave and reductions in productivity (Public Health England, 2010).

Central to the problem of obesity is the relative ineffectiveness of most treatments. Calorie-controlled diet and exercise routines work well when adhered to, but compliance rates are low, and public health campaigns are generally unsuccessful. The systems regulating energy homeostasis appear very sensitive in response to energy deficits, but much less responsive to energy excess, and the reward and decision making circuitry of the brain’s mesocorticolimbic system predisposes us to weight gain in our ‘obesogenic’ environment. There is thus a need for other methods of weight control. Current treatment options include very limited pharmacological tools, and bariatric surgery, which produces sustained weight loss and health benefits, including improvements in glucose homeostasis in type II diabetics. Bariatric surgery is becoming more common in the UK and, having previously been reserved for use in the morbidly obese (BMI <40 kg/m2), newly proposed guidelines from the National Institute for Health and Care Excellence suggest considering it for all obese patients with type II diabetes. However, this proposal has significant resource implications and it appears impractical to perform surgery on the large numbers who might qualify. For those who need to lose weight but are unable or unwilling to have surgery, pharmacological therapy may be appropriate. Currently, there is only one prescription weight-loss medication available in the UK. Orlistat is a gastric and pancreatic lipase inhibitor that inhibits the digestion, and thus the absorption, of dietary fat. However, with less than 30% of patients achieving a weight-loss of 5% of their total body weight in 1 year, Orlistat is only modestly effective, highlighting the need for novel drugs or other approaches to address the growing incidence of obesity (Powell et al., 2011).

The central regulation of energy homeostasis involves a number of brain regions, including the hypothalamus, the brain stem, and the aforementioned mesocorticolimbic system. Research over the last two decades has greatly increased our understanding of the circuits controlling food intake, energy expenditure and body weight. Pharmacological manipulation of these circuits may facilitate the regulation of energy intake and thus of body weight. For example, hypothalamic proopiomelanocortin (POMC) neurons act to inhibit appetite and food intake, in part by releasing agonists of the melanocortin 4 receptor. A novel, highly selective melanocortin 4 receptor agonist in development has been shown to chronically reduce food intake in a non-human primate model of obesity, without the unwanted effects on heart rate or blood pressure that such agents are often associated with (Kievit et al., 2013). In addition, neurotransmitters including serotonin and the catecholamines are thought to act within appetite centres to modulate energy intake. In the USA, the Food and Drug Administration has recently approved two new centrally acting weight-loss drugs, Qsymia and Belviq, for use in adults with a BMI of over 30. Qsymia is a once-daily oral combination of phentermine, a sympathomimetic agent that antagonizes alpha-adrenergic receptors, and topiramate, an anti-epileptic agent believed to enhance the activity of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) on excitatory glutamate neurons. Qsymia has beneficial effects on BMI, but has been associated with teratogenicity and an elevated heart rate, and does not have marketing approval in the UK thus far. The active ingredient of Belviq, lorcaserin hydrochloride, is a selective agonist of serotonin 5HT2C receptors, which drives satiety through mechanisms which include stimulating POMC neurons (Heisler et al., 2003). However, the precise mechanisms of action of such centrally acting drugs are rarely clear, with many displaying undesirable side-effect profiles that reflect the fact that such signals do not usually exclusively control energy homeostasis. It is possible that following further assessment Qsymia and Belviq will be approved in Europe in the future. However, there are a number of other drug targets being investigated that may be useful in the long-term treatment of obesity.

Central and peripheral circuits work in tandem to tightly regulate energy homeostasis. The gut is the largest endocrine organ in the body, releasing over 20 peptide hormones which influence processes including gut motility, gastric acid secretion and energy intake. Sensing of macronutrients – fats, carbohydrates and lipids – in the gut modulates the secretion of appetite-regulating hormones which act via the vagus nerve or directly on the brain to alter food intake. These hormones include peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), which are synthesized by enteroendocrine L-cells in the distal intestine and co-secreted into the circulation following a meal, and which act on specific brain regions to influence feeding behaviour. In addition, GLP-1 also stimulates glucose-stimulated insulin release. Interestingly, raised levels of such anorectic hormones are observed following bariatric surgery, and have been suggested to be responsible for at least part of the weight loss associated with this surgery. Such hormones represent peripheral signals which influence a relatively specific set of biological functions, and may thus result in fewer side-effects than other centrally acting agents. However, they also have short circulating half-lives, and thus the molecules require modification to be therapeutically useful.

Long-acting agonists of the GLP-1 receptor, for example liraglutide, are currently approved for the treatment of type 2 diabetes in the UK and USA. However, in addition to beneficial effects on glucose homeostasis, treatment with GLP-1 receptor agonists also results in weight loss, leading to trials of such agents as anti-obesity drugs. Concerns regarding a possible association with pancreatitis and pancreatic cancer have led to caution regarding the expansion of the use of GLP-1 agonists, but the EMA and FDA have recently stated that such causal associations ‘are inconsistent with the current data’. Another possible use of GLP-1 agonists is to improve the targeting of other agents. Oestrogen is known to have beneficial metabolic effects in the brain, but also results in changes to reproductive organs when peripherally administered. A recent paper used a peripherally administered glucagon-like peptide-1 (GLP-1)–oestrogen conjugate to specifically deliver oestrogen to appetite-regulating regions of the brain, resulting in weight loss without the usual adverse effects on the reproductive system (Finan et al., 2012).

In addition, our own research group is interested in the use of gut hormone analogues that can be administered weekly to regulate body weight, and have agents now progressing into phase 1 human clinical trials. Therapies combining several gut hormones may also prove to be successful, as some have been shown to have additive anorectic effects (Neary et al., 2005). It may, for example, be possible to simulate some of the effects of bariatric surgery by infusing multiple gut hormones at the elevated levels observed following surgery, resulting in a so-called ‘medical bypass’.

Postprandial levels of anorectic hormones, including PYY and GLP-1, are affected by the macronutrient composition of a meal. The physiology of the various nutrient-sensing receptors in the gut is gradually being elucidated, with receptors for sugars, fatty acids and amino acids now identified (Janssen & Depoortere, 2013). These receptors may represent better therapeutic targets than the hormones themselves, and ‘functional foods’ or ‘nutraceuticals’ designed to target them may prove useful in body weight management. High-protein diets, for example, lead to weight loss and improve weight maintenance, though they can be difficult to adhere to. Amino acids, the products of protein digestion, can modulate gut hormone release and may drive the increased satiety observed following protein ingestion. High protein meals have been shown to elicit greater and a more sustained PYY release than high fat or carbohydrate meals (van der Klaauw et al., 2013) and specific amino acids may underlie these effects, with their administration in animal studies shown to reduce food intake and stimulate GLP-1 secretion (Fromentin et al., 2012). However, the precise receptors or other sensing mechanisms involved are yet to be established.

In addition to pharmacotherapy, the effects of novel procedures that aim to replicate some of the effects of bariatric surgery without surgery are being studied. Examples include EndoBarrier™, which involves the insertion of synthetic apparatus which reduces the contact of ingested nutrients with the lining of the small intestine, and Obalon™, in which a balloon is inflated within the stomach to mimic the gastric distention felt after eating (Espinet-Coll et al., 2012). Bariatric surgery also results in altered vagal signalling, and the vagus is known to play an important role in food intake, including communicating acute feelings of fullness to the brain. Severing the vagus leads to decreased food intake. Techniques in development, such as VBLOC, involve the implantation of electrodes intended to temporarily inhibit the transmission of hunger signals, decrease gastric distension and reduce secretion of enzymes, which it is hoped will lead to decreased nutrient absorption (EnteroMedics, 2014).

The methods mentioned above are thought to mainly act by reducing food intake or absorption, though some agents are also known to regulate energy expenditure. Brown adipose tissue (BAT), in comparison with the white adipose tissue that constitutes the majority of our fat reserves, is densely populated with mitochondria and heavily innervated by sympathetic nerve fibres. The ability to generate heat makes BAT important in non-shivering thermogenesis. Previously thought to be important only in newborn humans, BAT has recently been shown to be functional in adults, providing a new host of potential drug targets aimed at altering energy expenditure. Increasing BAT thermogenesis to burn off excess energy may present another mechanism of treating obesity, though further research is needed to determine the prevalence, distribution and functionality of BAT in obese humans, and the possible side effects of over-activating BAT (Tseng et al., 2010).

Altering the way a person thinks about food and eating using cognitive behavioural therapy may also be a practical way to support lifestyle changes by improving coping skills and changing a person’s perception of weight loss. With the continued and rapid development of technology, the trend of being permanently logged in to social media and documenting our day to day lives is increasingly prevalent. This has led to the development of hundreds of mobile ‘apps’ to complement dieting attempts, ranging from documenting food intake, receiving healthy living tips and offering self-support systems, to those purportedly providing on-the-go weight-loss hypnosis to those who require a little extra motivation to cut down their calorie intake.

Currently, successful lifestyle modification and education remain the most important factors in the management of obesity. However, they are ineffective in the majority of overweight and obese patients. The physiological systems that evolved in a very different environment to encourage excess energy storage appear difficult to manipulate in order to drive weight loss. Previously developed appetite-reducing agents have been fraught with safety issues, with a number of compounds withdrawn from the market. It is possible that targeting peripheral signalling systems, or more specific central circuits, may allow the development of drugs with improved safety profiles. Targeting multiple signals involved in energy homeostasis, similar to the way in which high blood pressure is often treated, may prove a promising tactic. It may be that a tailored programme of behavioural therapies, nutritional advice, functional foods and combination drug treatments is required to result in effective and sustained weight loss. While the development of such therapies is challenging, it is crucial to prevent the current obesity pandemic escalating even further out of control.

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