besity: hoA ._ iscomplex condition. In hum

$J on the physiological me L.. Edatails of these mechanis

ii : i . . . 1

us is a ‘feeding con- , liver cells or cells of

ce chemical signals that ring about sensations of hunger and sati- the nature of these signals, particularly

continues to be an important goal for

pursuing the more of obesity to prevent us ture deaths in the sho

f tfke UK, 16.5% of women e (Box 1). In the USA, appr leti a& 59% of the adult po

.ha..e an increased risk of art disease and other c tones, and some cancers (Box 13, In

Bere an estimated 300 000 ‘premature j&ion to these direct effects on health, Defining obesity

human and rodent chromosomes One, the ob gene, is expressed in

ant role in regulating body weight yf ob RHA has shown that it ch has the structural feature f;ion of ob RNA increases dr

In 1990, the World Health Organization and most experts worldwide accepted Garrow’s definition of obesity as a body mass index (BMI) of 30 kg mm2 or moret5. BMI is the weight of the person (in kg) divided by the square of the person’s height (in m).

Longevity When measured by relative weight (actual weight as a percentage of av- erage or desirable weight for a given height/age/sex group), obesity has an adverse effect on longevity16*17.

Dismea with increased incidence in obese people Hypertension, hypercholesterolaemia and diabetes are all more prevalent in obese subjects of all ages, when compared with their peers of normal weight.

Coronary heart dii Obesity is consistently linked to coronary artery heart disease (CAHD) risk factors, but there is less hard evidence that obesity is linked to an in- creased incidence of CAHD. This discrepancy appears to have arisen be- cause of the problems of designing studies that separate the effects of obesity from the effects of other factors such as socioeconomic back- ground. Studies in which obesity predicted CAHD usually found that obesity was not a risk factor independent of the standard risk factors. However, the Framingham Study, a large general population-based study that is strengthened by having long-duration follow-up data, recently di* closed an increasing risk of CAHD with increasing levels of obesity, in- dependent of the other standard risk factors.

Cancer In an epidemiological study of 1 million people in the USA, obese males, regardless of smoking habits, had a higher mortality from cancer of the colon, rectum and prostate. Obese females had a higher mortality from cancer of the gall bladder, biliary passages, breast (postmenopausal), uterus (including both cervix and endometrium) and ovarie@.

Perspectives

study showed that serum leptin concentrations and the levels of ob mRNA in adipocytes in obese humans are elevated, not decreased, and there is a strong positive correlation between serum leptin con- centrations and degree of obesity. In obese human subjects, therefore, there seems to be a decreased sensitivity to leptin, rather than leptin underproduction. An insensitivity to the action of leptin, presumably in the hypothalamus, might be one of the fundamental mechanisms of obesity. This could be due to mutations of the gene for leptin re- ceptors in the brain, post-receptor abnormalities in leptin signal transduction. or other abnormalities in hypothalamic function.

Why is the incidence of obesity increasing? While the molecular details of the origins of obesity are an exciting prospect for researchers and might provide new treatments in the long term, the medical consequences of obesity are approaching critical proportions. The prevalence rates for obesity have risen steeply during this century, particularly in the past 20 years in Europe, the USA, Canada and Australia - and even in less-affluent nations such as those in Africa and Asia. The reasons for this are unclear, but one funda- mental consideration is life expectancy. Before the industrialization, sanitary improvements and medical advances that are the hallmark of the twentieth century. most people died before they had the chance to become obese. While the genotype of an individual has some effect on how susceptible that person is to gaining weight. the speed with which the weight of populations has ballooned obviates an expla- nation that relies very much on genetics. It is much more likely that environmental and behavioural factors are the major influences.

Energy balance The issue of balance between energy intake and energy output is cru- cial, points out Jane Bruce (Rowett Research Institute, Aberdeen, UK). There is a huge amount of evidence to suggest that energy out- put has gone down during the last century, she says; the nature of the diet has changed throughout the world across a period of 50-100 years and the consumption of fats and refined foods has increased with a concurrent reduction in complex carbohydrate intake. If mam- mals are fed on a high-fat, palatable and varied diet, and their physi- cal activity is restricted, every species tested becomes fat. The desert rat, for example, is a superb survivor in the desert but, when provided with ample food and little exercise it becomes floridly obese and then diabetic. One of the few experimental studies in humans shows that our response to over-feeding is remarkably similar. The Vermont over-feeding study5 showed that healthy male adults with no family or personal histories of either obesity or diabetes developed insulin insensitivity when over-fed to such an extent that they started to put on weight. Encouragingly, when the subjects lost the weight that they had gained, their insulin sensitivity returned to its original level.

Bruce is convinced that obesity is a result of humans battling with the overwhelming change in environmental factors that is the result of industrialization. She comments that in the affluent west, we now need to do so little physical activity and have the opportunity to eat so much. She implicates: town planning systems that restrict pedes- trian and cycling activity; buildings with escalators and lifts; and a food industry that makes most of its profits from selling refined prod- ucts with high fat and sugar content. ‘In the last 20 years, the spread of mechanization and the “fast-food” invasion of developing coun- tries has begun to mirror the conditions found in the west.’ Bruce be- lieves that this is why many more cases of obesity in Africa and Asia are being reported.

E&lcation Obese individuals are less likely than their non-obese counterparts to be accepted into elite colleges and universities in the USAi8.

Employment Employers judge obese people as less competent, less productive, more disorganized, less successful, and less self-disciplined than their under- weight or average-weight peers19.

socioeconomic status In the UK, those born into a lower socioeconomic group become more overweight as adults than those born into an upper socioeconomic group20,21.

Prejudice in healthcare Mental health professionals more often described case histories that were accompanied by photographs of obese women as ‘agitated, ego- centric, obsessive and compulsive people’ compared with identical his- tories with ‘normal’ weight photos. They were assessed to have a higher rate of various other personality traits including hypochondria, poor hy- giene, a propensity for self-injury and total psychological dysfunctionzz.

The stigma of obesity Obesity is stigmatized m many cultures. The physical appearance and the character of the obese person are both regarded as inferior, attitudes that are formed early in life: children as young as six years old described obese children as ‘ugly, lazy, dirty and stupid’h. When US college students were asked whom they would marry, an obese person was rated fifth lowest of 14 options: they preferred embez- zlers, cocaine or marijuana users or shoplifters’. As a result, discrimi- nation against the obese has become one of the last ‘acceptable’ forms of prejudice.

Obesity also has economic and social effects, although the re- lationship between obesity and socioeconomic status is not simple. There is a strong positive relationship between low socioeconomic status and obesity 8,9, For example, obese men and women attain far fewer educational qualifications than their thinner peers; they have a lower success-rate in finding a well-paid job: and they are more likely to remain unmarried by the age of 30. While people of lower socioeconomic status are more likely to be obese than their wealthier counterparts, being born into a family with lower socioeconomic sta- tus also makes it more likely that individuals will become obese in adulthood. A vicious circle therefore results as obesity results from - and also leads to - social deprivation and poverty. This view has been supported by several studies (Box 2). Health professionals are not immune to negative views of obesity. Many health professionals con- tinue to believe that obesity is a self-inflicted condition that results from a lack of will-power combined with sloth and gluttony’(‘.

What should be done about obesity? Given the enormous health, financial and social costs of obesity, it is clear that something must be done, but by whom and how? The health benefits that result from weight loss are significant” and there seems to be little evidence that weight-cycling (continually losing

205

Questions arising for molecular medicine

l Should lifelong drug therapy to control obesity ever be considered? l Do education/information programmes designed to promote a healthier lifestyle have any impact? Why do so many people ignore them? l Some researchers think that the only way to control obesity is by societal intervention to change our environment, for example, by introducing taxes on high-fat, high-calorie foods. Would this be acceptable? l Should food industries take responsibility for the potential effects of their products? Should high-fat foods carry health warnings?

and regaining weight) carries inherent risks’?. George Bray, a leading exponent of multi-faceted obesity management, argues that preven- tion and treatment are equally important”. For example. high-risk in- dividuals could be identified using genetic. metabolic and demo- graphic predictors, and intervention strategies could selectively target them for education or treatment. Bray cites convincing evidence that pre-pubertal children in high-risk groups respond well to education to encourage behavioural modification; action taken at this stage of life offsets further development of obesity in adulthood.

For those who are already obese, various treatments are available and can be used to effect substantial weight loss. Diets that are very low in calories have been widely publicized as having dramatic suc- cess in the treatment of clinically severe obesity. Extreme diets do in- duce weight loss but, unless patients also change their eating habits and increase their physical activity, they tend to regain most of the weight within a couple of years of ceasing their diet. This. however, creates a paradox: if severe obesity results in the first place from a physiological inability to regulate food intake appropriately, it is dif- ficult to see how patients who receive drastic short-term treatments can suddenly start to control their appetite after losing some of their excess weight. Bray Ii advocates long-term drug therapy to control obesity, in the same way that drugs are used to control high blood pressure. In some patients, lifelong drug therapy might be the only way to ensure that substantial weight loss is achieved and that this is followed by better weight regulation. Susan Yanovski. Executive Director of the US National Task Force on the Prevention and Treatment of Obesity, stresses ‘Although there are important poten- tial benefits of long-term pharmacotherapy for the management of obesity. studies are needed to demonstrate reductions in morbidity and mortality with drug treatment.’ 14. The four-year Wientraub trialZ3 is the longest one carried out so far, but the effects of taking drugs in the very long term are still not known.

Concluding remarks A cohesive strategy involving various forms of treatment and inter- vention to educate and inform high-risk groups at a fairly young age seems to be the way forward in the control of obesity. Some re- searchers remain pessimistic about reducing the prevalence of obesity in affluent industrialized societies. Stevle Heymstield (Obesity Research Center, St Luke’s+Roosevelt Hospital Center, New York. NY, USA) thinks that obesity is a tremendous ‘economic engine’ be- cause so many people ‘profit’ from it; for example, $33 billion was spent in the USA alone in 1990 on diets, weight-loss services and

206

products. He even points the finger at healthcare professionals be- cause of their need to treat obese patients. ‘Obesity is built into the very fabric of our economic system in the USA’ he comments, ‘I sus- pect that it is an essentially irreversible state.’

References

1 Bouchard. C (1996) Genetics of obesity in humans: current issues, lo The O~I#LY

and Consequencer 0.f Ohesi+ (Ciba Found&on Symposium 201), (Chadwick, D.J.

and Cardew. G., eds). pp. 108-I 14, John Wiley & Sons

2 Zhang, Y. ef al. ( 1994) The obesity (ob) gene. Positional cloning of the mouse

obese gene and its human homologue. N~ur-e 372,42532X

3 Rohner-Jeanrenaud. F. (1995) A neuroendocriue reappraisal of the dual-centre hy-

pothesis: its implications for obesity and insulin resistance. M. J. Ohesi~ 19,

530-532

4 Stephens, T.W. er ~1. (1995) The role of neuropeptide Y in the antiobesity action of

the obese gene product, N&o-e 377. SW543

5 Sims. E.A.H. er a/. ( 1973) Endocrine and metabolic effects of experimental

obesity in man, Recent Pru,y. Horn. Rrs. 29.4.57-496

6 Cracker, J., Cornwell. B. and Major, B. I 1993) The stigma of the overweight: afkc-

tive consequences and attributional ambiguity, J krv. Sot. Psycho/. 64.6&70

7 Venes, A.M., Krupka, L.R. and Gerard, R.J. (1982) Overweight/obese patients: an

overview, ne Pmctirioner 226. 1102-l 109

8 Gortmaker, S.L., Must, A. and Perrin, J.M. (1993) Social and economic conse-

quences of overweight in adolescence and young adulthood, New EqI. J. Med.

329. 1008-1019

!J Sargent, I.D. and Blanchflower. D.G. (1994) Obesity and stature in adolescence

and earnings in young adulthood: analysis of a British birth cohort, Arch. Pcdiarr:

Ad&xc. Med. 14X.681-687

10 Yanovski, S.Z. (1993) Are anorectic agents the ‘magic bullet’ for obesity? Arch.

Fmily Med. 2. 1025~1027

11 Williamson, D.F. er u/. (1995) Prospective study of intentional weight loss and

mortality in never-smoking overweight US white women aged 40-64 years, 4m.

J. Epidemioi. 141, 1128-I I41

12 Atkinson, R.L. er ui. (1994) Weight cycling. J. Am. Med. A.ssoc. 272, I 196-l 202

13 Bray, G.A. (1996) Coherent, preventative and management strategies for obesity,

m Tile Origins rind Consequencr~ of Obesig (Cuba Foundation Symposium 201).

(Chadwick, D.J. and &dew, G., eds), pp. 228-254, John Wiley 81 Sons

14 The National Task Force on the PreventIon and Treatment of Obesity (1996) Long

term pharmacotherapy in the management of obesity, J. Am. Med. Aswc. 276,

1907-1915

15 Carrow. J.S. (1982) Twut Obrsi@ Serwu.\/\ (1 C/inicu/ Munuu/, Churchill

Livingstone

16 Lew. E.A. and Garfinkel. L. (1979) Variations in mortality by weight among

750 000 men and women, L Cl~rorzic Dis. 32.5633576

17 Llssner, L. er a/. (199 1) Yariability of body weight and health outcomes in the

Framingham population. NM EqyI. .I. Mrd. 324,1839-l 844

18 Canning, H. and Mayer, J. (1966) Obesity - its possible effect on college accep-

tance, New EngI. J. Med. 275, I 172-l I74

19 Lxkin, J.C. and Pines, HA (1979) No fat persons need apply: experimental stud-

ies of the overweight stereotype and hiring preferences, Sot. Work Occupa~ionv 6,

3 12-327

20 Braddon, F.W.M. et rrl. ( 1986) Onset of obesity in a 36 year birth cohort study,

B,: Med. J. 293,299-303

21 Power. C. and Moynihan, C. (1988) Social class changes and weight-for-height

between childhood and early adulthood, Ior. J. Ohn. 12.445453

22 Young, L.M. and Powell, B. (1985) The effects of obesity on clinical judgements of

mental health professionals, J. Health SK. Brhau 26, 233-246

23 Wxntraub, M. (1992) Long-term weight control study, C/in. Phcinm~o/. Ther: 51.

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