Obesity.

Obesity is almost invariable in developing countries and almost all people accumulate some fat as they get older. The World Health Organization now also acknowledges that obesity is a world-wide problem which also affects many developing countries. Obesity implies an excess storage of fat, and this can most easily be detected by looking at the undressed patient. Most patients suffer from simple obesity, but in certain conditions obesity is an associated feature (Table 5.12). Even in the latter situation, the intake of calories must have exceeded energy expenditure over a prolonged period of time. Hormonal imbalance is often incriminated in women (e.g. postmenopause or when taking contraceptive pills), but most weight gain in such cases is usually small and due to water retention.

'Simple' obesity. Not all obese people eat more than the average person, but all obviously eat more than they need. Suggested mechanisms Genetic and environmental factors These have always been difficult to separate when studying obesity. However, refeeding experiments in both monozygotic and dizygotic twins, reared together or apart, suggest that genetic influences account for 70% of the difference in body mass index (BMI) later in life, and that the childhood environment has little or no influence. The refeeding experiments also showed that weight gain did not occur in all pairs of twins, suggesting that in some a facultative increase in thermogenesis occurred so that part of their extra dietary energy was expended inefficiently. Genetic factors have led to the discovery of a putative gene, firstly in the obese (ob ob) mouse and now in humans.

The ob gene was shown to be expressed solely in both white and brown adipose tissue. The ob gene is found on chromosome 7 and produces a 16 kDa protein called leptin. In the ob ob mouse a mutation in the ob gene leads to production of a non-functioning protein. Administration of normal leptin to these obese mice reduces food intake and corrects the obesity. A similar situation has been described in a very rare genetic condition in humans, in which leptin is not expressed. In massively obese subjects, leptin mRNA in subcutaneous adipose tissue is 80% higher than in controls. Plasma levels of leptin are also very high, correlating with the BMI. Weight loss due to food restriction decreases plasma levels of leptin. However, in contrast to the ob ob mouse, the leptin structure is normal and abnormalities in leptin are not the prime cause of humanobesity. Leptin secreted from fat cells could act as a feedback mechanism between the adipose tissue and the brain, acting as a 'lipostat' (adipostat), controlling fat stores by regulating hunger and satiety (see below). However, many other signals are involved and a unified theory of appetite regulation and its links to obesity is lacking. From an evolutionary perspective it seems that humans evolved to defend against energy deficit better than excess energy, which has been a relatively recent phenomenon in human history. Therefore, it is not surprising that obesity is largely restricted to humans, and animals that are domesticated or in zoos. Food intake Many factors related to the home environment, such as finance and the availability of sweets and snacks, will affect food intake. Some patients eat more during periods of heavy exercise or during pregnancy and are unable to get back to their former eating habits. The increase in obesity in social class 5 can usually be related to the type of food consumed (i.e. food containing sugar and fat). Psychological factors and how food is presented may override complex biochemical interactions. It has been shown that obese patients eat more than they admit to eating, and over the years a very small daily excess can lead to a large accumulation of fat. For example, a 44 kJ (10.5 kcal) excess would lead to a 10 kg weight gain over 20 years. Control of appetite This is complex and depends partly on external stimuli, such as the company, the type of food, the surroundings and the person's habitual behaviour.

Appetite is the desire to eat and this usually initiates food intake. Following a meal, satiation occurs. This depends on gastric and duodenal distension and the release of many substances peripherally and centrally.

Figure 5.8 The proposed feedback loop between peripheral adipose tissue and central feeding pathways. Peripheral and central factors (listed under 'other stimuli') influence food intake; some may interact with leptin. Following a meal, cholecystokinin (CCK), bombesin, glucagon-like peptide 1 (GLP1), enterostatin, and somatostatin are released from the small intestine, and glucagon and insulin from the pancreas. All of these hormones have been implicated in the control of satiety. Centrally, the hypothalamus particularly ventromedial, dorsomedial, paraventricular and arcuate nuclei - plays an important role in integrating signals involved in appetite and bodyweight regulation (Fig. 5.8). Leptin receptors have been found in the above hypothalamic nuclei and their activation produces complex responses, which can be viewed functionally as: (a) inhibition of signals that have a positive effect on appetite (orexigenic signals), such as melanin-concentrating hormone in the lateral hypothalamus and neuropeptide Y (NPY) in the arcuate nucleus; (b) stimulation of signals that have a negative effect on appetite (anorexigenic signals), such as alpha melanin-stimulating hormone (alpha MSH), which has effects on the melanocortin-4 (MC4) receptors in the paraventricular nucleus, preopiomelanocortin (POMC) precursor polypeptide and cocaine- and amphetamine-regulated transcript (CART) in the arcuate nucleus, and corticotrophin-releasing factor (CRF) in the paraventricular nucleus. This system potentially provides sensitive feedback regulation, whereby a reduction in leptin release, resulting from a reduction in adipose tissue mass,

stimulates appetite and restores the energy deficit. In contrast, excess adipose tissue results in more leptin release, which is expected to reduce appetite. The system is more complex than might first appear for at least three reasons. First, although obese individuals have excess adipose tissue and increased circulating leptin concentrations, appetite is not reduced. This has led to the notion of leptin resistance, which may be due to changes in leptin receptors or other downstream effects. Secondly, in some circumstances, leptin release from adipose tissue may occur independently of adipose tissue mass, e.g. during starvation, when the circulating concentration rapidly decreases far below that expected from loss of adipose tissue mass. Thirdly, new signals are being discovered in mammals and their role in appetite regulation still remains to be defined. Amongst these are central hypothalamic signals such as orexins, and peripheral signals, such as Ghrelin, an endogenous growth hormone secretagogue which is surprisingly produced by the stomach (and kidney) and not the hypothalamus. Animal studies suggest that acute illness may increase circulating leptin concentrations, at least partly through cytokine action, but the effects disease has on leptin in humans are not so clear cut. Lastly, the effects of some appetite signals are not mediated by leptin. It is known that cytokines, such as TNF and IL-2, which are elevated in a wide range of inflammatory and traumatic conditions, also suppress appetite, although the exact pathways involved are not entirely clear. Energy expenditure Basal metabolic rate (BMR). BMR in obese subjects is higher than in lean subjects, which is not surprising since obesity is associated with an increase in lean body mass. Physical activity. Obese patients tend to expend more energy during physical activity as they have a larger mass to move. On the other hand, many obese patients decrease their amount of physical activity. The energy expended on walking at 3 miles per hour is only 15.5 kJ/min (3.7 kcal/min) and therefore increasing exercise plays only a small part in losing weight. Nevertheless, because increased body fat develops insidiously over many years, any change in energy balance is helpful. Thermogenesis About 10% of ingested energy is dissipated as heat and is unconnected with physical activity. This dietary induced thermogenesis has been reported to be lower in obese and post-obese subjects than lean subjects. This would tend to favour energy deposition in obesity and those predisposed to obesity. However, other workers have found no difference in dietary induced thermogenesis between lean and obese subjects.

Brown adipose tissue in animals, when stimulated by cold or food, dissipates in the form of heat the energy derived from ingested food. This can be a major component of overall energy balance in small mammals. However, the importance of brown adipose tissue thermogenesis in adult humans is likely to be very small, and of doubtful clinical significance. 3-Adrenergic receptors are the principal receptors mediating catecholamine-stimulated lipolysis in brown adipose tissue and to a lesser extent at other sites. Drugs with 3-adrenergic activities have been developed, but side-effects have limited their use. Morbidity and mortality Obese patients are at risk of early death, mainly from diabetes, coronary heart disease and cerebrovascular disease. The greater the obesity the higher the morbidity and mortality rates. For example, men who are 10% overweight have a 13% increased risk of death, while the increase in mortality for those 20% overweight is 25%. The rise is less in women, and in men over 65 obesity is not an independent risk factor. Weight reduction reduces this mortality and therefore should be strongly encouraged. The benefits are probably greater in more obese subjects (Table 5.13). Clinical features Most patients recognize their own problems, although often they are unaware of the main foods that cause obesity. Many symptoms are related to psychological problems

or social pressures, such as the woman who cannot find fashionable clothes to wear.

The degree of obesity can be assessed by comparison with tables of ideal weight for height, from the BMI (Box 5.4), and by measuring skinfold thickness. The latter should be measured over the middle of the triceps muscle; normal values are 20 mm in a man and 30 mm in a woman. A central distribution of body fat (a waist/hip circumference ratio of > 1.0 in men and > 0.9 in women) is associated with a higher risk of morbidity and mortality than is a more peripheral distribution of body fat (waist/hip ratio < 0.85 in men and < 0.75 in women). This is because fat located centrally, especially inside the abdomen, is more sensitive to lipolytic stimuli, with the result that the abnormalities in circulating lipids are more severe. Box associated risk of co-morbidities 5.4 Ranges of body mass index (BMI) used to classify degrees of overweight and

Table 5.14 Table 5.14 shows the conditions and complications that are associated with obesity. The relationship between cardiovascular disease (hypertension or ischaemic heart disease), hyperlipidaemia, smoking, physical exercise and obesity is complex. Difficulties arise in interpreting mortality figures because of the number of factors involved. Many studies of obesity do not, for instance, differentiate between smokers and non-smokers or between the types of physical exercise taken. Many do not take into account the cuff-size artefact in the measurement of blood pressure (an artefact will occur if a large cuff is not used in patients with a large arm). Nevertheless, obesity almost certainly plays a part in all of these diseases and should be treated. The only exception is that stopping smoking, even if accompanied by weight gain, is more important than any of the other factors. Treatment Dietary control This largely depends on a reduction in calorie intake.

The most common diets allow a daily intake of approximately 4200 kJ (1000 kcal), although this may need to be nearer 6300 kJ (1500 kcal) for someone engaged in physical work. Very low calorie diets are also advocated by some, usually over shorter periods of time, but unless they are accompanied by changes in lifestyle, weight regain is likely. Patients must realize that prolonged dieting is necessary for large amounts of fat to be lost. Furthermore, a permanent change in eating habits is required to maintain the new low weight. It is relatively easy for most people to lose the first few kilograms, but long-term success in moderate obesity is poor, with an overall success rate of no more than 10%. Many dietary regimens aim to produce a weight loss of approximately 1 kg per week. Weight loss will be greater initially owing to accompanying protein and glycogen breakdown and consequent water loss. After 3-4 weeks, incremental weight loss may be very small because only adipose tissue is broken down and there is less accompanying water loss. Patients must understand the principles of energy intake and expenditure, and the best results are obtained in educated, well-motivated patients. Constant supervision by a doctor, by close relatives or through membership of a slimming club helps to encourage compliance. It is essential to establish realistic aims. A 10% weight loss, which is regarded by some as a 'success' (see Table 5.13) is a realistic initial aim. An increase in exercise will increase energy expenditure and should be encouraged provided there is no contraindication - since weight control is usually not achieved without exercise. The effects of exercise are complex and not entirely understood. However, exercise alone will usually produce little long-term benefit. On the other hand there is evidence to suggest that in combination with dietary therapy, it can prevent weight being regained. In addition, regular exercise will improve general health. The diet should contain adequate amounts of protein, vitamins and trace elements. A diet of 4200 kJ (1000kcal) per day should be made up of more than 50 g protein, approximately 100 g of carbohydrate, and 40 g of fat. The carbohydrate should be in the form of complex carbohydrates such as vegetables and fruit rather than simple sugars. Alcohol contains 29 kJ/g (7 kcal/g) and should be discouraged. It can be substituted for other foods in the diet, but it often reduces the willpower. With a varied diet, vitamins and minerals will be adequate and supplements are not necessary. A balanced diet, attractively presented, is of much greater value and safer than any of the slimming regimens often advertised in magazines.

Most obese people oscillate in weight; they often regain the lost weight, but many manage to lose weight again. This 'cycling' in bodyweight may play a role in the development of coronary artery disease. Behavioural modification The aim of behavioural modification is to encourage the patient to take personal responsibility for changing lifestyle, which will determine dietary habits and physical activity. Family therapy may also be useful, especially when it involves obese children. It can be time-consuming and expensive. Cognitive behavioural therapy is even more time-consuming and expensive. Drug therapy Drugs can be used in the short term (up to 3 months) as an adjunct to the dietary regimen, but they do not substitute for strict dieting. Centrally acting drugs.

Drugs acting on the noradrenergic pathways do suppress appetite but all have been withdrawn in the UK due to cardiovascular side-effects. Drugs acting on both serotoninergic and noradrenergic pathways, e.g. sibutramine. Peripherally acting drugs. Orlistat is an inhibitor of pancreatic and gastric lipases. It reduces dietary fat absorption and aids weight loss. Weight regain occurs after the drug is stopped. It has been used continuously in a large-scale trial for up to 2 years. The patients may complain of diarrhoea during treatment and to avoid this take a low fat diet resulting in weight loss.

Surgical treatment Operations that involve bypassing parts of the small intestine have fallen out of favour because of their side-effects and cannot be recommended. Jejunoileal bypass was the most common operation and involved the anastomosis of approximately 18 cm of jejunum to the terminal 18 cm of the ileum. Complications are chiefly those of intestinal resection (p. 294). A fatty liver often occurs and in a few patients cirrhosis is seen. Surgical procedures are still performed in cases of severe morbid obesity (BMI >40 kg/m2) or BMI >35 with obesity-related medical co-morbidities:

Wiring the jaws to prevent eating. This permits liquid feeds only. It can be used as a temporary measure but good dental hygiene is essential. Weight gain usually occurs after the wires have been removed, but in some individuals this

can be controlled by the use of a tight waist cord. This procedure can be used to reduce postoperative complications after a major elective operation.

Gastroplasty. A small gastric pouch is created by vertically stapling across the wall of the stomach. Good results have been claimed but slow weight regain occurs owing to change in eating patterns, e.g. ingestion of small frequent meals that do not cause discomfort.

Gastric banding. An adjustable band is encircled around the proximal stomach to compartmentalize it into a small pouch and a large remnant. This can be performed laparoscopically. The results are variable.

Gastric bypass. A Roux-en-Y gastrojejunostomy is performed. Loss of excess weight of 50-60% has been reported at 10 years but there are many long-term complications which need careful surveillance.

Liposuction. The removal of large amounts of fat by suction does not deal with the underlying problem and weight regain frequently occurs. Prevention Preventing obesity must always be the goal because most obese people find it difficult to maintain any weight loss they have managed to achieve. All health professionals must be aware of the dangers of obesity and encourage children, young as well as older adults, from gaining too much weight. A small gain each year over a long period produces an obese individual for whom treatment is difficult.