Obesity
Obesity is one of the major public health issues in the developed world. It can lead to increased risks of heart disease, type 2 diabetes and some cancers. The percentage of UK adults who are obese has increased by 50 per cent in the last decade, and obesity in children continues to grow at an alarming rate – current obesity trends suggest that one fifth of UK children will be overweight or obese by 2010. Obesity is responsible for 9,000 premature deaths each year in England, and reduces life expectancy by an average of nine years.
Obesity has substantial economic costs. It has been estimated that the cost of obesity to the NHS is approximately £1 billion a year, with an additional £2.3 to £2.6 billion per year to the economy as a whole. If the current trend is not halted, by 2010 the cost to the economy alone could be £3.6 billion a year, and by 2050 it could be £45 billion a year, according to experts.
The National Audit Office (NAO) has predicted that if one million fewer people in the UK were obese, there would be around 15,000 fewer people with coronary heart disease, 34,000 fewer people developing type 2 diabetes, and 99,000 fewer people with high blood pressure. Many kinds of cancer would also be prevented.
Although the rise in obesity cannot be attributed to any single factor, it is the simple imbalance between energy in (through the food choices we make) and energy out (mainly through physical activity) which is the cause. Despite belief to the contrary, there is no evidence that obese people have a slower metabolism and burn energy any less quickly than thin people – indeed the opposite is the case. MRC scientists have made a substantial contribution to the field by investigating and clarifying the details of energy balance, and identifying social, environmental, genetic and parental factors that influence it. They have also developed ideas for treatments and interventions and evaluated their impact.
Big problem
MRC scientists have been working on obesity for more than two decades. In the 1980s, people did not understand why obese people put on weight. Professor (Dr at the time) Andrew Prentice, at the MRC Dunn Nutrition Unit in Cambridge, worked with Dr Andy Coward to develop the ‘doubly-labelled water method’. This measures how much energy a person expends, using a harmless tracer that tracks the amount of carbon dioxide produced by the body as a by-product of energy generation.
Professor Prentice found that obese people had a higher metabolic rate than their lean counterparts, reflecting their larger body size – dispelling the myth that their obesity was caused by a metabolic or behavioural defect that resulted in reduced energy expenditure1. The team demonstrated that reports of low energy intake were spurious and obese people were eating more calories than previously thought.
Subsequent work by the same team brought attention to the importance of low levels of physical activity, based on the rise in car ownership, increase in labour-saving devices at home, increase in hours of TV watched, reduced distance that children were walking to school and a reduced proportion of people employed in manufacturing and farming. All of these factors increase the risk of overconsumption of calories2.
Professor Nick Wareham, Director of the MRC Epidemiology Unit in Cambridge, has produced detailed measures of physical activity in individuals, looking at both activity and sedentary behaviour such as watching TV3. Dr Ulf Ekelund at the MRC Epidemiology Unit in Cambridge tracked 2,000 children from different areas in Europe and found that the amount of physical activity is linked to long-term obesity-related effects on health4. Their work continues with interventions designed to increase physical activity and to monitor its impact on health.
Food for thought
At MRC Human Nutrition Research in Cambridge, Dr Susan Jebb leads a team studying the specific dietary factors which increase the risk of overeating. Their research has shown that humans have a weak innate ability to recognise foods with a high energy density and to reduce the bulk of food eaten to maintain energy balance5. For example, fast food generally has a high energy density, and people tend to consume similar volumes of this with little reference to calorie content. The team showed that an energy-dense, low fibre, high fat dietary pattern at five and seven years increases fatness in later childhood6. They are continuing to explore the impact of changes in dietary habits on the risk of obesity and related metabolic diseases.
The question of whether the body has any control over appetite has been debated by scientists for many years. In 1962, Dr James Neel proposed the ‘Thrifty Gene Hypothesis’7, which suggests that humans evolved genes for efficient food collection and fat deposition to survive periods of famine and, now that food is continuously available, these genes are disadvantageous because they make us obese in preparation for a famine that never comes.
Appetite is important in the regulation of weight by the body, because it affects and can limit how much energy is taken in. Scientists are investigating whether this mechanism is deficient in some forms of obesity, or whether it can be manipulated to alleviate obesity.
On the brain
Professor Steve Bloom at Imperial College London has found how energy balance can be restored by gut hormones8. These hormones are released when a person eats, acting as neurotransmitters to indicate to the brain to stop eating. Researchers believe these hormones may provide a solution to appetite suppression, by mimicking the body’s response to being full.
An MRC researcher at University College London, Dr Rachel Batterham, has discovered why a high protein diet can help weight loss9. The gut hormone peptide YY (PYY) helps to regulate appetite by sending signals to the brain indicating that the person is full. The team has found that eating high protein foods increases PYY levels and reduces hunger10.
Scientists can now measure hunger in mice by recording images from their brain cells11. MRC-funded researchers at Imperial College London used Magnetic Resonance Imaging (MRI) to show areas of the brain that were more active during hunger. These areas of the brain became less active after administering the hormone PYY, and more active with ghrelin, which is known to increase hunger.
The pleasurable feeling – known as ‘reward’ – in response to eating food can vary between individuals. People may continue eating even when they are full because their sensation of reward is greater than hormonal signals indicating they should stop. A team at the MRC Centre for Obesity and Related Metabolic Diseases in Cambridge, set up in 2006 and led by Professor Steven O’Rahilly, has been investigating a hormone that plays a key role in regulating energy intake and energy expenditure called leptin. Leptin affects brain responses to visual food stimuli – it diminishes the perception of food reward and enhances the response to satiety signals generated during food consumption.
The team used MRI scans of relevant brain areas to show that leptin affects the brain responses to food stimuli by decreasing reward associated with food and by increasing the sense of being full during eating12. A key strategy to treat obesity will be to identify agents that affect the pleasurable aspects of food intake, as well as the physiological mechanisms driving hunger.
Drs Andy Calder and Andrew Lawrence at the MRC Cognition and Brain Sciences Unit in Cambridge showed that some people’s brains are more vulnerable to food advertising than others13. The team found that answers to questions about food correlated with activation of the brain’s reward network in response to appetising food images.
A genetic component
Researchers have shown that genes are likely to be responsible for a significant proportion of the variation in obesity between individuals. The genetic defects found so far all affect hunger, involving the function of appetite control centres in the brain, rather than speed of metabolism.
A gene called FTO has been associated with early onset and severe obesity, revealed after a search for type 2 diabetes–susceptibility genes among nearly 40,000 people showed one that predisposes to diabetes through an effect on body mass index14. The 16 per cent of adults who had two copies of this gene weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those without. The FTO gene’s association with obesity has been confirmed by MRC researcher Philippe Froguel at Imperial College London15.
Professor Steven O’Rahilly’s group has examined a number of genes linked to childhood obesity and ‘insulin resistance’, which is one of the most important early warning signs of diabetes. They found several conditions, all with a different genetic basis. In one very rare condition – ‘congenital leptin deficiency’, people get no sense of being full so will continue eating if food is available. Professor O’Rahilly’s research showed that daily injections of leptin altered this behaviour and eliminated obesity. There are very few people with this particular genetic condition (perhaps ten in the world!), but the study confirms the importance of leptin in obesity, and scientists suspect that there could be similar defects in more common conditions.
There also appears to be a parental link to obesity. Women who begin their menstrual periods before they are 11 are increasingly likely to have children who also start puberty early and are more overweight. This was reported by Dr Ken Ong at the MRC Epidemiology Unit who studied 6,000 children as part of the Avon Longitudinal Study of Parents and Children (ALSPAC) at the University of Bristol16.
Beyond the obese
The main concern with obesity is that it leads on to other illnesses. Around three-fifths of type 2 diabetes and one-fifth of heart disease cases are attributable to excess body fat. Six cancers are also linked to obesity17. Obese people are more likely to suffer from social and psychological problems, such as depression, prejudice, discrimination, stigmatisation and low self-esteem. Being overweight also increases the risk of dementia – Alzheimer’s disease for example – and could lead to infertility.
Diabetes is a huge and growing problem. In 2000, it accounted for more than eight per cent of deaths in the US, Canada, and the Middle East. The total number of people with diabetes worldwide is projected to rise from 171 million in 2000 to 366 million in 2030. Scientists are investigating the molecular mechanisms of why obesity leads to diabetes. Dr Antonio Vidal-Puig, an MRC researcher at the University of Cambridge, is genetically manipulating mice and has found a mechanism in fat cells that delays the onset of obesity-associated diabetes18.
Recently, researchers showed that women who are obese are twice as likely to be diagnosed with asthma as women who aren’t. An team at the MRC and Asthma UK Centre for Allergic Mechanisms of Asthma at King’s College London extracted a type of immune cell from the blood of obese asthmatics and found that, as well as causing asthma, the cells secreted high levels of a hormone, promelanin. This is usually found in the brain and affects appetite. If obese people lose weight, their asthma usually improves20.
The future is fat
The worrying projections about the obesity epidemic, and its impact on the UK economy, have led the Government to consider its approach to the issue. MRC scientists have played a major role in advising policy makers on the research, and its potential to influence public policy.
Already there are advanced plans for a social marketing campaign to tackle obesity, based on a review of the evidence by MRC Human Nutrition Research in Cambridge in March 2007. No country has a well developed strategy or effective action plan to deal with obesity, but the UK Government is to use its scientists’ expertise is to tackle the problem in a new way.
It will base its plans on a report from the UK Government’s Foresight’s programme, launched in October 2007, which uses scientific evidence to develop a vision for a sustainable response over the next 40 years21. Foresight sets out a broad, ambitious strategy which includes the promotion of healthy diets, redesigning the built environment to promote walking, and wider cultural changes to shift societal values around food and activity.
Foresight likens the obesity crisis to climate change – both issues need individual and societal action. The report, which includes major contributions from MRC scientists, acknowledges that individuals do have a personal responsibility for their diet and lifestyle. However, it concludes that in our ‘obesogenic’ environment, with its abundance of energy-dense food, motorised transport and sedentary lifestyles, obesity is the default condition.
The Foresight team recommends action by the Government, both central and local, industry, communities, families and individuals. It emphasises the importance of scientific research to inform interventions and to evaluate their impact in a way which can shape future policy. Government ministers are to publish proposals for action based on the report.
References
1. Prentice et al. (1986). High levels of energy expenditure in obese women. BMJ, 292, 983.
2. Prentice & Jebb (1995). Gluttony or sloth? BMJ, 311, 437
3. Van Sluijs et al. (2007). Effectiveness of interventions to promote physical activity in children and adolescents: systematic review of controlled trials. BMJ, 335,703.
4. Ekelund et al. (2006). TV viewing and physical activity are independently associated with metabolic risk in children: the European youth heart study. PLOS Medicine, 3, e488.
5. Prentice & Jebb (2007). Fast foods, energy density and obesity: a possible mechanistic link. Obesity Reviews 4, 187.
6. Johnson et al. (2007). A prospective analysis of dietary energy density at age 5 and 7 years and fatness at 9 years among UK children. Int J of Obesity, [epub ahead of print].
7. Neel (1962). Diabetes mellitus: a ‘thrifty’ genotype rendered detrimental by ‘progress’? Am J Hum Genet, 14, 353.
8. Wynne et al. (2006). Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: a randomised controlled trial. Int J Obes (Lond).
9. Batterham et al (2006). Critical role for peptide YY in protein-mediated satiation and body-weight regulation. Cell Metab, 3, 223.
10. Batterham et al. (2007). PYY modulation of cortical and hypothalamic brain areas predicts human feeding behaviour. Nature, 14 Oct [Epub ahead of print].
11. Kuo et al. (2007). The temporal sequence of gut peptide-central nervous system interactions tracked in vivo by magnetic resonance imaging. Journal of Neuroscience, 7 November 2007, Manuscript ID: JN-RM-2391-07.R1
12. Farooqi et al. (2007). Leptin regulates striatal regions and human eating behaviour. Science, 317, 1355.
13. Beaver et al. (2006). Individual differences in reward drive predict neural responses to images of food. J. Neurosci. 26, 7775.
14. Frayling et al. (2007). A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889.
15. Dina et al. (2007). Variation in FTO contributes to childhood obesity and severe adult obesity. Nat. Genet. 39, 724.
16. Metcalf et al. (2004). The regulation of physical activity in young children, Education and Health, 22, 61.
17. Food, nutrition, physical activity, and the prevention of cancer: a global perspective (2007). World Cancer Research Fund.
18. Sethi & Vidal-Puig (2007). Targeting fat to prevent diabetes. Cell metab. 5, 323.
19. Williams et al. (2004). The ProActive trial protocol – a randomised controlled trial of the efficacy of a family-based, domiciliary intervention programme to increase physical activity among individuals at high risk of diabetes. BMC Public Health, 4, 48.
20. Sandig et al. (2007). Human Th2 cells selectively express the orexigenic peptide, pro-melanin-concentrating hormone. PNAS, 104, 12440.
21. Jebb et al. (2007). Executive Summary: FORESIGHT ‘Tackling Obesities: Future Choices’ project. Obesity reviews, suppl 1, vi-ix 17316292.
MRC, November 2007