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Obesity is on its way to becoming the leading cause of preventable death in Western countries such as the United States. Similarly to hypertension and smoking, obesity represents one of the most important risk factors for cardiovascular diseases, which account for almost 30 per cent of all global deaths.
- Wolfgang Renner, Chief Executive Officer of Cytos Biotechnology.
Obesity is a body condition characterised by storage of excessive amounts of fat in adipose tissue beneath the skin, within other organs and in muscles.
All mammals store body fat for thermal insulation and as a way of storing energy for future need. Stored fat has twice the chemical potential energy of carbohydrate or protein. In normal women and normal men, 25% and 15% of body mass, respectively, is stored as fat.
However, storage of greatly increased amounts of fat is associated with impairment of health. Data from insurance company records show that people who weigh 30% or more than the correct weight run measurably increased risks of disease, notably diabetes, cardiovascular disease (CVD), gall-bladder disease and arthritis. Such people also often encounter complications during surgery, and recent research has shown that being overweight or obese is associated with accelerated ageing.
The problem is not just limited to Western countries. According to the World Health Organisation (WHO), obesity has reached epidemic proportions globally: more than a billion adults are overweight, of which at least 300 million of them are clinically obese.
According to the World Health Organisation, the number of people world-wide who were overweight in 2000 was rivalling the number who were underweight. The International Agency for Research on Cancer reported in 2001 that, in the UK, 46% of men and 36% of women were overweight. In Britain around 50% of the adult population is overweight while almost 1:5 (20%) of people are clinically obese; this being made up of 15% of men and 18% of women. Obesity is rising faster in Britain than in any other Western European nation and if the present trend continues, half the population of Britain will be obese by 2020. In the USA, the weight of 1:3 adults has reached danger levels. Indeed, the Centres for Disease Control and Prevention has found that one-third of adults, 12% of teenagers and 14% of children are overweight.
There is no country in the world where obesity is not rising.
- Dr Stephen Rössner Professor of Health Behaviour The Karolinska Institute, Stockholm, Sweden.
Definitions of Obesity
How does one define when a person is considered to be obese and not just somewhat overweight? Height-weight tables give an approximate guideline as to whether one is simply overweight or has passed into the obese stage.
The World Health Organisation recommends using a formula that takes into account a person's height and weight. The 'Body Mass Index' (BMI) is calculated by dividing the person's weight in kilograms by the square of their height in metres, and is thus given in units of kg/m2. A BMI of 18.5-24.9 is considered to be the healthiest. A BMI of between 25 and 29.9 is considered to be overweight, while a BMI of over 30 is considered to be obese.
However, it is recognised that this definition is limited as it does not take into account such variables as age, gender and ethnic origin, the latter being important as different ethnic groups have very different fat distributions. Another shortcoming is that it is not applicable to certain very muscular people such as athletes and bodybuilders, who can also have artificially high BMIs. Agencies such as the National Cholesterol Education Program (NCEP) in the USA and the International Diabetes Foundation (IDF) are starting to define obesity in adults simply in terms of waist circumference. For instance, the IDF uses >94cm for Caucasian men and >80cm for Caucasian women, while the NCEP cut-offs are a little larger.
What Causes Obesity?
For the first time in history, the world's total of overweight people equals the total of those who are underfed. Up to 1.2 billion people eat more than they need, and as many go hungry each day.
- The Guardian, March 2000.
More recently (2006) it has been reported that the world's total of overweight people has now exceeded those who are undernourished.
In simple terms, obesity is a result of taking in more energy in food than one expends by means of activity, and so lifestyle is a major factor in the development of obesity.
[Heart disease is] at least partly attributable to the misbalance of energy expenditure in a society where people were eating too much and exercising too little.
The causes of obesity are multifactorial. The greatest cause is overeating, which may be related to the wide availability of cheap and more varied foods of poor nutritional value. There is an association of obesity within families, and this may be due to a combination of genetics and lifestyle factors. One estimate is that a child with two fat parents has a 70% chance of growing up obese. Overeating due to anxiety (ie, an environmental factor) is also known to occur.
Less common 'secondary' causes of obesity are due to hypothalamic conditions that increase the appetite, and also endocrine disorders. The most common causes of secondary obesity are hypothyroidism2, which is due an under-active thyroid gland, and Cushing's syndrome, which specifically causes abdominal obesity.
Of particular concern is the epidemic of childhood obesity, which is becoming global. According to the International Obesity Task Force (London), more than 25% of ten-year olds in a number of countries across the world are also obese or overweight. Leading the list are Malta (33%), Italy (29%), and the USA (27%). In Britain, a quarter of the children under the age of ten are considered to be obese, together with one-quarter of children aged between four and ten years in Chile, Mexico and Peru. Although Asia lags behind the USA and Europe in obesity statistics, the situation in China is particularly alarming. Here, the 'one child per family' policy has resulted in a generation of spoilt, over-nourished children, with up to 10% of China's 290 million children considered to be overweight or obese - the so-called 'little emperor syndrome'. This figure is expected to double by the year 2013.
The causes of childhood obesity appear to be largely environmental. In particular, with the advent of television and computer games, children are much more sedentary these days. This is exacerbated by a tendency for schools in the UK to sell off playing fields. Furthermore, there have been significant changes in diet, with energy-rich, nutrient-deficient 'junk food' being more readily available. Such foods tend to contain more salt, sugar and saturated fats than is recommended, and insufficient fruit and vegetables. Furthermore, marketing campaigns by the 'big players' link the high-profit fast-food and soft drinks to toys, games, collectables, films and celebrities.
UK statistics show people are spending longer sitting in front of computer and TV screens - watching 26 hours of television a week in the mid-1990s compared with 13 hours in the 1960s.
The linking factor between calorie intake and exercise is insulin, which enables the body to store the extra calories as fat. Physical exercise helps to control insulin levels, while fatty food, in combination with starches and sugar, stimulates its massive release. A child who sits in front of his games console for hours on end, eating potato crisps, is bound to store the excess calories as fat.
About 9% of obese children and adolescents suffer from a premorbid condition known as 'metabolic syndrome'. This is a cluster of symptoms which includes changes in blood chemistry such as elevated levels of LDL lipoprotein which increases the risk of contracting atherosclerosis. LDL lipoprotein is one way of transporting cholesterol (which is essential for building of cell walls) in the plasma. Normally about 60% of the plasma cholesterol is carried as LDL lipoprotein, but elevated levels are associated with a high risk of ischaemic heart disease. Blood sugar levels are also increased, which presages Type 2 diabetes. The incidence of Type 2 diabetes in people under the age of 18 is soaring worldwide. Type 2 diabetes can lead to complications such as nerve and eye damage, which normally only appear in elderly people, but is now appearing in people in their 20s.
[Unless we do something about it] the steady increase in life expectancy that has marked the 20th Century may reverse itself in the 21st, and far too many of the next generation could end up dying before their parents.
- Prof. Philip James. Chairman, International Obesity Task Force.
Read about Jonathan Wallace, officially Britain's fattest teenager.
The obesity epidemic is not restricted to industrialised countries. According to the WHO, this increase is often faster in developing countries than in the developed world.
A person's genetics also have a strong influence on their chances of becoming obese. Part of the reason for this is that those people who are most susceptible to putting on weight as a result of eating high-fat, carbohydrate-rich diets do so because they produce high levels of circulating insulin. A good example of this are the inhabitants of the South Pacific island of Nauru, who as a result of having a ready supply of cheap energy-dense foods, along with a shift away from jobs requiring physical activity, are one of the most obese populations on Earth. There is also a high incidence of diabetes.
Genes are also directly involved in disorders such as Bardet-Biedl syndrome and Prader-Willi syndrome. Bardet-Biedl Syndrome (BBS) is a rare, recessively inherited disorder which affects approximately 1 in 100,000 babies born. Recessive genes are those which we carry but do not affect one's development. Both men and women can be carriers. In order for a child to be affected, both parents must carry the recessive gene. If both parents are carriers, then there is a one in four chance of the baby contracting the syndrome.
BBS is characterized mainly by obesity, but affected persons may also have pigmentary retinopathy, polydactyly, mental retardation and hypogonadism. Renal failure occurs in fatal cases. The polydactyly, which can occur on all four limbs, is associated with a defect on chromosome 3, while the other features are mapped to markers on chromosome 16.
Prader-Willi Syndrome (PWS) is a rare and complex genetic disorder which afflicts some 2000 people in the UK. PWS is caused by an abnormality, usually a deletion, on chromosome 15 which occurs around the time of conception. Its main characteristics are:
- Insatiable appetite
- Low muscle tone
- Emotional immaturity and instability, resulting in antisocial behaviour such as temper tantrums and confrontational attitude
- Immature physical development
- Learning disabilities, which may be very mild
There have only been three babies born to people with PWS in the UK, and none have been fathered by a person with PWS.
An Infectious Agent?
Another line of research has opened recently at the University of Wisconsin, Madison, USA, where a link has been discovered between human adenovirus-36 (Ad-36) and obesity. This virus is normally associated with the common cold, diarrhoea and conjunctivitis, but it has been found that between 20% to 30% of overweight people carry the virus.
This association came to light when a Dr Nikhil Dhurandhar, (working as a family physician in Bombay during the 1980s) noticed that chickens which had died due to a severe outbreak of the adenovirus, SMAM1, were unusually fat, with enlarged livers and kidneys, and had low cholesterol levels and atrophied thymus glands. Dhurandhar wondered whether this virus could affect people. On analysing the serum antibodies of his own patients, he found that 20% of his obese patients had been exposed to SMAM1, and that these people were also significantly heavier with lower cholesterol levels.
Researchers then found that inoculating chickens with Ad-36 resulted in fat chickens. Interestingly, animals cross-infected by receiving blood from the inoculated chickens also became seriously obese, although their serum triglyceride and cholesterol levels fell. The virus does not lead to increased food uptake, but in vitro studies revealed that it increases the number and size of fat cells (adipocytes), though the mechanism for this is not properly understood.
Since this time at least 10 different pathogenic agents have been found to cause obesity in animals. These include Canine Distemper Virus, the RAV7 avian retrovirus and MAM1 avian virus, the Borna virus in rats (which is also linked to depression in humans), types of scrapie agent (a prion), three adeno viruses including Ad-5, Ad-36 and Ad-37 which cause fat gain in several species, and Chlamydia pneumoniae bacteria. Scientists have also found that when mice are infected by general bacteria from the guts of other mice, the recipients' body fat increases.
It is thought that, should infectious obesity turn out to be a real disease, then it would be possible to design a vaccine to combat it. It might, however, emerge that obesity increases susceptibility to the virus rather than the virus causing obesity.
Health Effects of Obesity
Over 2000 years ago, the Greek physician Hippocrates wrote that 'persons who are naturally very fat are apt to die earlier than those who are slender.' This observation remains very true today. Obesity has a major impact on a person's physical, social and emotional well-being. It increases the risk of developing diabetes mellitus type 2 ('mature onset diabetes') and also makes Type 2 diabetes more difficult to control. Thus weight loss improves the levels of blood glucose and blood fats, and reduces blood pressure. The association between obesity and coronary heart disease is also well-known.
Furthermore, in 2001 medical researchers established a link between being overweight and certain forms of cancer3, and estimated that nearly 10,000 Britons per year develop cancer as a result of being overweight. This figure was made up of 5,893 women and 3,220 men, with the strongest associations being with breast and colon cancers. However, it is thought that being overweight may also increase the risk of cancer in the reproductive organs for women and in the prostate gland for men.
In late 2008, researchers from the National Cancer Institute (USA) reported that overweight women aged between 50 and 71 are 80% more susceptible to ovarian cancer than those of healthy weight. Ovarian cancer is the most fatal of the gynaecological cancers4, with fewer than 40% surviving five years after diagnosis. Scientists believe that the link with obesity is due to adipose tissue - which holds excess fat around the stomach - secreting the female sex hormone, oestrogen. This hormone may stimulate the growth of ovarian cells, and thus play a role in the development of cancer.
The link between breast cancer and nutritional status is thought to be due to the steroid hormones oestrogen and progesterone, which are produced by the ovaries, and govern a woman's menstrual cycle. Researchers have found that the more a woman eats, or the more sedentary her lifestyle, the higher are the concentrations of progesterone. This link could explain why women from less affluent countries have lower rates of breast cancer5. Women from less affluent nations tend to eat less food and to lead lifestyles which involve more daily movement. This lowers their progesterone level, resulting in lower predisposition to breast cancer.
The Times newspaper, in 2002 reported that obesity was the main avoidable cause of cancer among non-smokers in the Western world!
Research published by St Thomas' Hospital, London, UK in 2005 showed a correlation between body fat and aging, to the extent that being obese added 8.8 years to a woman's biological age. The effect was exacerbated by smoking, and a non-overweight woman who smokes 20 cigarettes a day for 20 years added 7.4 years to their biological age. The combination of being obese and a smoker added at least ten years to a woman's biological age, and although the study only involved women, the lead researcher Professor Tim Spector believes the finding would also apply to men.
The ageing effect was determined by measuring the length of telomeres, tiny 'caps' on the ends of chromosomes, which help protect the DNA from the ageing process. Indeed, telomeres have been dubbed the 'chromosomal clock' because, as an organism ages, they become progressively shorter, and can be used to determine the age of the organism. Beyond a certain point, the telomere becomes so short that it is no longer able to prevent the DNA of the chromosome from falling apart. It is believed that excess body fat, and the chemicals present in tobacco smoke release free radicals which trigger inflammation. Inflammation causes the production of white blood cells which increases the rate of erosion of telomeres.
Obesity is also linked with age-related hearing loss.
Recent research (2005) conducted in the USA shows that obesity in middle age is linked to an increased risk of dementia, with obese people in their 40s being 74% more likely to develop dementia compared to those of normal weight. For those who are merely overweight, the lifetime risk of dementia risk was 35% higher.
Scientists from the Ageing Research Centre at the Karolinska Institute in Sweden have been able to take information such as age, number of years in education, gender, body mass index, blood pressure level, physical activity and genetic factors, assigning each a risk score. They then used this information to devise a predictive test for dementia. This test will enable people at risk, for the first time, to be able to effect lifestyle changes which will reduce their risk of contracting dementia
The world-wide upsurge in obesity, particularly in children, is of major economic concern, liable to drain economies. Of further concern is that research conducted in Australia and published in 2006, shows that up to one third of breech pregnancies were undetected by the traditional 'palpation' examination, the danger being greatest for those women who are overweight or obese - a growing proportion of mothers. This means that such women are not getting the treatment required to turn the baby around in time for the birth, and in many cases require an emergency Caesarean section.
This is a true health-care crisis, far bigger than Severe Acute Respiratory Syndrome (SARS) and ultimately, even bigger than AIDS.
-Robert Lustig. Paediatric Endocrinologist, University of California.
Population surveys on both sides of the Atlantic have suggested a correlation between asthma and body mass index, asthma being more common in obese people. Thus, the number of youngsters considered fat or obese in the UK has almost doubled in the last decade, whereas childhood asthma rates have doubled in the last two decades. Indeed, it has been found that the fattest children were 77% more likely to have asthma symptoms. This has led scientists to speculate that the two conditions may be linked.
It had been thought that inactivity caused by asthma could lead to people putting on weight; however this has now been discounted since obesity often precedes the onset of asthmatic symptoms. Hence another suggested reason is purely physical/mechanical: that increased weight might lead to inflammation in the respiratory tract and lungs, which could cause asthmatic symptoms.
However, recent research at King's College, London has uncovered an immune-system protein, known as promelanin concentrating hormone, which causes inflammation in the lungs, and which is known to increase appetite.
To an extent, the measures needed to avoid becoming obese are obvious - to encourage children to eat a proper balanced diet and to take plenty of exercise - for people who are obese in childhood have a high risk of remaining obese as adults, with all the inherent health implications. More detail on these points can be found on the British Medical Association's 'Childhood Obesity' website.
Rather less obvious is the role of drinking water in weight control. Pure water, with no additives, is calorie-free. If the kidneys are not flushed through with sufficient water, they cease to function efficiently, requiring the liver to step in as a back-up. In doing this, the liver's ability to metabolise fat is compromised, and therefore fat remains stored in the body. Furthermore, if one drinks insufficient water, it is possible for the body to misinterpret thirst pangs for hunger pains, and thus one eats instead of drinking.
The real tragedy is that being overweight and obese, and their related chronic diseases, are largely preventable. Approximately 80% of heart disease, stroke, and type 2 diabetes, and 40% of cancer could be avoided through healthy diet, regular physical activity and avoidance of tobacco use.
- Dr Robert Beaglehole, WHO Director of Chronic Diseases and Health Promotion.
Strategies for Combating Obesity
Many approaches to weight loss have been tried in obese people. Up to now, low-fat diets, exercise programmes and drugs that suppress the appetite have been the main methods used to combat obesity.
Diets and Diet
Many complex diets have been promoted for weight loss, but no scientific evidence exists to show that they are effective for grossly obese people. One form of diet developed to provide nourishment for hospital patients, the 'liquid-protein diet' was marketed commercially until 1979, when it was discovered that several people had died whist using this mixture as the sole source of nutrition. The mixture upset the natural balance of sodium and potassium in the body, leading to impaired heart function.
Recent research (2005) has found that the daily consumption of foodstuffs containing omega-3 fatty acids6, such as oily fish, combined with moderate exercise can result in significant weight loss. However, taking the oils without exercise means that one's weight is likely to stay put.
It is believed that fish oils increase the elasticity of blood vessel walls, thus improving the flow of blood to muscles during exercise. Hence healthy snacks such as sardines on toast are a good option.
Finally, mention ought to be made of the concept of a new style of eating called 'intuitive eating'. Recent findings (2005/2006) from both the USA and UK indicate that, for women, eating only when they are hungry and stopping when they feel full, leads to a slightly lower BMI and higher levels of HDL7 or 'good' cholesterol, and is thus helpful to women wishing to lose weight.
During the 1950s, diet pills containing the Central Nervous System (CNS) stimulant drug dextro-amphetamine ('dexedrine') or one of its derivatives became popular, but it is believed that they did not work and could be habit-forming, and so their use soon declined. Nowadays this drug is used to treat Attention-Deficit Hyperactivity Disorder (ADHD) or Attention-Deficit Disorder Without Hyperactivity (ADD), and it is emphasised that it must not be used to help with weight loss.
Surgical procedures used to aid weight loss include intestinal bypass and gastric bypass. In the former operation, a length of intestine is removed to reduce absorption of nutrients. This operation has been largely abandoned because it produced severe side effects such as liver damage and chronic diarrhoea, and was responsible for several deaths. In the gastric bypass procedure, most of the stomach is closed off with surgical staples, leaving only a small pouch to receive food. This, therefore, greatly reduces a person's eating capacity. Stomach stapling works rather better than anti-fat drugs, which typically produce weight losses of 5-10%, but has a death rate of 1% and so shouldn't be undertaken lightly!
New treatments such as the slimming pill Xenical, which inhibits the breakdown and absorption of fat, and the appetite-controlling drug Reductil, are changing the way doctors treat the condition.
Xenical is the brand name for 'Orlistat', produced by Roche and which is approved by the National Institute for Health and Clinical Excellence, UK (NICE). Orlistat inhibits the absorption of fat in the small intestine, causing just under a third of the fat that would otherwise have been absorbed to pass straight through the gastro-intestinal tract, and be excreted in the faeces. A consequence of this is that a person using Orlistat may need to go to the toilet more frequently and urgently, with steatorrhea, the production of fatty stools, being a serious problem. These effects have the added effect of encouraging users to limit their fat intake!
Users of Orlistat may require vitamin supplements because fat-soluble vitamins may not be efficiently absorbed.
Reductil, also known as 'sibutramine' is also approved by NICE and is produced by Abbott Laboratories. In simple terms it works by producing the feeling of having eaten sufficient. Sibutramine has been known to cause an increase in blood pressure in some people and therefore is not recommended for those with hypertension problems.
The drug prevents re-absorption of two neurotransmitters8, noradrenaline and serotonin, by nerve cells in the brain once a message has been transmitted. Noradrenaline and serotonin are responsible for moderating mood and various other processes in the brain and, if these are free, they are thought to enhance the feeling of satisfaction from eating, thus causing one to feel satisfied from eating less food.
The Hoodia Gordonii cactus has been used for centuries by the Xhomani Sans bushmen of southern Africa's Kalahari desert to suppress the appetite during long hunting trips. It works by making the tribesman feel full after ingesting it. A drug from Hoodia Gordonii has been developed by Phytopharm (UK), that has been shown in a small study to lower food intake by 30-40%. The drug, called P57 is being further developed by the United States company, Pfizer, and was set to begin clinical trials in 2003.
The drug works by mimicking the processes which occur naturally after you've had a full meal. The hypothalamus in the brain possesses glucose sensors, which are sensitive to the blood sugar level. As your food is digested, the blood sugar level rises and the glucose sensors start firing to tell the brain that you are full. The Hoodia cactus seems to contain a molecule that is about 10,000 times as active as glucose. These are detected by the glucose sensors in the hypothalamus and make those nerve cells fire as if you were full. But you have not eaten, and neither do you wish to.
Rimonabant is an appetite suppressant which works by blocking endocannabinoid receptors in the brain and other tissues. Cannabinoids (present in cannabis) are known to cause cravings and to make you feel hungry, a symptom known colloquially as 'the munchies'. Hence a drug that blocks the cannabinoid receptors should stop one from feeling hungry. Rimonabant was licensed for use in Europe in 2006, but was withdrawn two years later as it had been linked with psychiatric disease and suicide in some patients.
Leptin (from the Greek leptos, meaning thin) is a protein hormone produced by white adipocytes that was discovered in the early 1990s in genetically obese mice. It was found to be encoded for by the Ob (obese) gene, which was subsequently mapped to chromosome 7 in humans. The protein has been shown to regulate energy expenditure, food intake and fat levels in mice, and its absence in rodents and humans has been shown to cause severe obesity. Leptin is thought to act as a lipostat - as the amount of fat stored in adipocytes rises, leptin is released into the bloodstream and signals to the brain that the body has had sufficient to eat.
It is thought that leptin targets taste receptors and that it is a 'sweet-sensing suppressor' and, indeed, that it is the 'missing link' between obesity and Type 2 diabetes. It is thought that if the leptin sensitivities of human taste cells could be increased, it would be possible to develop a treatment for obesity based on reducing the satisfaction that is derived from eating sweet foods.
The discovery of leptin initiated a flurry of research into the molecular basis of weight control. Initially, there was great enthusiasm that injections of the normal leptin hormone into obese patients might be effective in inducing significant weight loss. However, clinical trials have shown that even high doses of leptin produce only a modest loss of weight. This is thought to be due to the fact that, rather than having a low level of leptin production, some obese patients may have defective receptors for the protein.
Research into leptin has continued however, and, as the market for effective weight-reducing therapies is so enormous and potentially highly lucrative, pharmaceutical companies are working alongside basic research scientists to find possible drug targets among the plethora of molecules that contribute to weight homeostasis9.
A Vaccine for Non-Infectious Obesity?
Scientists have discovered a small peptide hormone called ghrelin which regulates appetite. It has been found that injecting extra ghrelin into people makes them hungrier and encourages them to eat more. Ghrelin has also been implicated in yo-yo dieting - obese people who lose weight develop higher levels of ghrelin, which encourages them to eat more and put the weight back. It is speculated that ghrelin evolved when mankind was subject to cycles of feast and famine. Those individuals whose genes promoted the gluttonous consumption of food during a time of plenty were more likely to survive subsequent periods of famine. Ghrelin was discovered as a result of stomach-stapling operations, which works in part because ghrelin levels are reduced in such patients. Scientists have found that eating protein-rich foods supress level of ghrelin, thus enabling an individual to feel sated. This may help to explain the effects of the high protein, low carbohydrate 'Atkins diet'.
The 'obesity vaccine', developed by Cytos Biotechnology, will work by inducing the recipient's immune system to create antibodies that bind to ghrelin and reduce the amount that reaches the brain. This should reduce the hunger signal and make it easier for obese people to stick to a weight-reducing diet.
It is considered that this vaccine will be a therapeutic one rather than a preventative one, and will require repeated injections. Animal experiments suggest that the vaccine may well be effective since injections of the vaccine into mice provoked high levels of antibodies against ghrelin. Vaccinated mice fed on a high-fat diet put on 15% less weight than their unvaccinated litter-mates.