Obesity

Our knowledge and understanding of obesity is really only in its infancy. Considered at the simplest level, obesity develops when individuals consume more energy than they expend over prolonged periods, but we don’t know why some individuals stay in balance without conscious effort and others do not. We believe there is a genetic susceptibility to obesity, but the exact genes and magnitude of the effect is unknown.

Although it is accepted that obesity is a risk to health, the exact magnitude and details of its effects are unknown and the mechanisms are only partially understood. We believe that weight reduction reduces risk factors for metabolic disease, but the data on most hard outcomes is lacking. Weight loss is difficult to achieve and adherence is poor, and we don’t understand the exact determinant of success.

First, consider just what we have learned, the myths that are out there and then what we need to know to progress.

What we do know about obesity

Genetics and development

Most obesity is not monogenic. Several monogenic forms of human obesity, such as mutations in leptin, the leptin receptor, POMC gene and MC4 receptor, have recently been discovered. Whilst providing important insights into appetite regulation in humans, and validating the use of rodent models of appetite regulation, they have also highlighted the fact that most cases of obesity do not have simple monogenic causes. (1)

Levels of general and central obesity vary with ethnicity in both men and women in England.Compared with the general population, levels of obesity are much lower in Pakistani, Indian,Chinese, and, most markedly, Bangladeshi men, who are three times less likely to be obese thanmen in the general population. Despite low levels of general obesity, Pakistani,Indian and Bangladeshi men have relatively high levels of raised waist to hip ratio, with 41% ofIndian men classified as centrally obese compared to 28% of men in the general population. BlackCaribbean and Chinese men are less likely to have a raised waist:hip ratio.

Among women, obesity prevalence is high for Black Caribbean and Pakistani women and lowfor Bangladeshi and Chinese women. However, all female minority ethnicgroups have levels of central obesity well above that of the general female population, with BlackCaribbean and Pakistani women two times, and Bangladeshi women over three times as likelyto have a raised waist to hip ratio as women in general.

Physiology & pharmacology

Appetite is regulated by the hypothalamus. After years of controversy it has now been established that the hypothalamus plays a major role in the regulation of food intake and energy expenditure in humans (2).

Peripheral signals of energy stores are important in regulating food intake. Fat had for many years been seen as a passive energy storage depot that accumulated any excess calories consumed. It has recently become clear that adipose tissue constitutes one of the largest endocrine organs in the body, secreting an array of adipokines, including leptin and resistin which have major effects in the regulation of energy homeostasis and insulin resistance (3).

Peripheral signals of food intake are important in regulating food intake. In addition to the peripheral signals of energy stores, it is now known that there are peripheral signals of food intake that control appetite. The major signals are gut hormones that inhibit food intake, including PYY, oxyntomodulin and PP. These have all recently been shown to inhibit food intake when infused into humans and provide a mechanism for meal termination. (4,5)

Appetite is susceptible to pharmacological intervention. Various receptors play key roles, e.g. y2. Many, including 5HT receptor subtypes, are under study. Certain receptor signalling intermediates play key roles in the transduction of hormone and nutrient signals into neural outputs. Multiple receptor and transduction targets for development of drugs to treat obesity are possible.

Targeting central catecholamine systems will reduce food intake, but with an increased likelihood of cardiovascular side-effects. Multiple transmitter, peptide and hormone systems are involved in specific CNS centres (e.g. hypothalamus and NTS) acting to control neural pathways involved in the control of food intake, energy expenditure and peripheral glucose homeostasis (via autonomic output).

The development of a number of therapies which limit appetite has quashed the notion that there is nothing that can be done to limit appetite and that one must rely on will power alone. However, there is a need for even more effective therapies to be developed. These may result from our increasing knowledge of the physiological mechanisms controlling appetite, for example, the gut hormones. (6)

Interventions at the level of the hypothalamus, designed to alter food intake, can also ameliorate peripheral insulin resistance and hyperglycaemia.

Activity and behaviour regards eating and exercise

Dietary advice can produce modest long-term weight loss in overweight adults, but there is no evidence for differences in the effectiveness of low fat, low carbohydrate or low calorie diets in promoting weight loss (7, 8) whilst the addition of drugs, exercise and behaviour therapy to dietary advice in adults is more likely to be effective than diet alone (9).

Modest weight loss is associated with modest but clinically significant improvement in risk factors for chronic disease (7, 10).

Diet and exercise interventions designed to prevent obesity in children often result in a change in behaviour, but have little short-term effect on BMI, particularly if carried out in combination (11).

Subsequent disease

There is evidence to support the belief that obesity results in an increased risk of most disease processes with deterioration of function in most organs.

Heart disease & obesity

Overweight and obesity increase the risk of coronary heart disease (12). As well as being an independent risk factor, obesity is also a major risk factor for high blood pressure, raised blood cholesterol, diabetes and impaired glucose tolerance. The adverse effect of excess weight is more pronounced when fat is concentrated mainly in theabdomen. This is known as central or abdominal obesity and can be identified by a high waistto hip ratio.

The INTERHEART case-control study (13) estimated that 63% of heart attacks inWestern Europe and 28% of heart attacks in Central and Eastern Europe are due to abdominalobesity (a high waist to hip ratio), and those with abdominal obesity are at over twice the riskof a heart attack compared to those without. This study also found that abdominal obesity wasa much more significant risk factor for heart attack than simple BMI.

Diabetes

The link between obesity prevalence and rates of diabetes in different populations was demonstrated by West with an increase in the prevalence of type 2 as the population becomes more obese (14). A woman with a BMI of 30 has roughly 30 times the risk of developing diabetes when compared with someone with a BMI of 22, while an individual with a BMI greater than 35 has a 90 fold higher risk (15). The AUSDIAB study showed increases in prevalence over recent years even at similar levels of BMI (16). BMI at the age of 21 was a significant independent risk factor (17) in that the amount of weight gain since early childhood significantly contributed to risk of acquiring diabetes in later life.

Data from the NHANES study shows that, for each kilogram of increase in weight of the population, the risk of diabetes increases by 4.5 % (18). More recent diabetes trends in the USA show an even steeper rise of diabetes with a 9% increased risk for each kilogram of weight gain (19).

Of newly presenting patients in a Minnesota diabetes clinic in the 1970s, 33% were obese, whereas this figure had increased to 49% by the 1980s (20). Amongst type 2 patients excess adiposity is almost the rule. In the diabetes clinic in Dundee about 80% of attending patients were either overweight or obese (21).

The greatest risk of diabetes is associated with central or truncal obesity, in which fat is deposited at intra-abdominal (visceral) sites. This is more typical in men and is referred to as android obesity as opposed to glutoeofemoral or gynoid obesity, more typical of women. In obesity fat accumulates at other sites such as muscle, liver and islet cells and may contribute to metabolic defects such as insulin resistance (22).

There has been a 10-fold increase in diabetes amongst children between 1982 and 1994 in the USA (23). Diabetes in this age group is clearly linked to obesity, although genetic and environmental factors also contribute, such as having a family history of the condition and belonging to an ethnic group (24). Type 2 diabetes may even replace type 1 as the more common form of childhood diabetes (25).

Other studies also show the association of obesity with the development of conditions such as type 2 diabetes (26) and the dyslipidaemia associated with accelerated cardiovascular disease – i.e. low HDL, high LDL and high TG (27).

The development of diabetes in susceptible individuals (impaired glucose tolerance, fasting hyperglycaemia) can be prevented or delayed with intensive lifestyle intervention and pharmacological intervention (28, 29, 30, 31). However, this level of intensive intervention is currently not deliverable within current NHS service commissioning.

One retrospective study has shown that weight loss increases diabetic life expectancy (32). Lifestyle modification and pharmacological treatment of obesity produce benefit in terms of symptom improvement, disease risk factor reductions (e.g. lipids and glycaemic control) and quality of life (33, 34) and may be useful in combination (35). Current weight loss agents are limited in terms of weight loss efficacy (average 10%, 5% placebo-subtracted, or 60-70%, 5% responders). Apart from prevention of diabetes, no hard clinical endpoint studies of pharmacological intervention exist. A new agent, Rimonabant, that may be licensed in 2006, produces similar weight loss to existing agents but may have other desirable effects of cardiovascular risk reduction (36,37).

For those with severe obesity (BMI >40), weight reduction surgery is the most cost-effective way to achieve and maintain weight loss, and has profound beneficial effects on diabetes. Laparoscopic surgical techniques have reduced the risks of is morbidity and mortality to an acceptable level (38, 39, 40).

The prevalence of childhood obesity is increasing (41, 42) and with it the likelihood of a concomitant increase in obesity related disorders, e.g. type 2 diabetes (43, 44, 45), but there is evidence that weight loss increases life expectancy (46).

Cancer and obesity

The WHO/FAO report of 2003 cites overweight and obesity (OO) as ‘the most important known avoidable cause of cancer’ after tobacco (47). However, other estimates suggest that it is of less importance than diet, alcohol and hormonal factors (48).

One study calculated that the total attributable risk of cancer from OO comes to about 5% of cases in women and 3% in men. Together, this accounts for up to about 12,000 new cases in the UK annually (49).

There is ‘convincing’ (47), ‘sufficient’ (50), and ‘clear’(51)evidence for a relationship between OO and an increase in cancer risk for the bowel, oesophagus, endometrium (lining of the uterus) and kidney, and breast in postmenopausal women. There is increasing evidence that it also increases the risk of gallbladder cancer, especially in women. There is ‘sufficient’ evidence that the avoidance of weight gain could reduce the risk of the above cancers (50).

There is also evidence that overweight and obesity increases the risk of mortality from several cancers. In a US cohort study, high BMI was associated with higher mortality rates from the above cancers, as well as liver, pancreatic, stomach, prostate, cervical and ovarian cancers, as well as non-Hodgkin’s lymphoma and multiple myeloma. This could reflect both the direct effects of obesity on survival, or indirect effects via differences in diagnosis or treatment (52).

A follow-up of the Boyd Orr study of Scottish and English children found that people who are obese as children have higher risks of some cancers later on in life (53). There is also some evidence that obesity during pregnancy could increase the lifetime cancer risk for the child (54).

What are the popular misconceptions about obesity?

Is technology to blame? Cars, lifts, labour-saving devices, television, computer games – there is an implication that these are somehow intrinsically bad and don’t encourage activity, but where is the evidence? Similarly as regards decreasing sport and exercise participation, with increased sedentary use of diminishing leisure time in adults and school children - but is it so?

Is it the fault of junk/fast food intake with people no longer sitting down to eat as a family - just how relevant is this? Considering the normal average slow weight gain over the years, what role does the increased average life expectancy play, now 80 in women, 75 for men? What about the cry of “I have a slow metabolism” or ‘It’s my hormones’. This is a controversial field, but the evidence suggests that the obese do not have a slower metabolism than the lean, and overall are likely have a higher rate of metabolism. To overcome these deeply ingrained misconceptions requires tackling of their root cause: the stigma attached to obesity. This stems from the belief that the obese are responsible for their condition and that all that is required is will power and less greed. This ignores the knowledge that there are powerful drives to eat which are extremely difficult to overcome without pharmacological intervention.

Perhaps more worrying is the recent rise in the belief that it is possible to be “fat and

fit” and that obesity therefore does not necessarily result in health problems. While it may be true that there are different levels of fitness amongst the overweight, there are no safe levels of obesity.

What we don’t know about Obesity

What we do know is insignificant compared to vast chasm of knowledge in every area of obesity, and endless questions generated by any gain in knowledge, in every area. It’s worth considering what gaps may help us proceed:

Genetics and development

We don’t know how much of obesity is genetic, whether there’s a major gene for obesity or the genetic and/or environmental basis for the development of obesity in most susceptible individuals. What is the relative contribution of genetic factors, early life exposures and contemporaneous exposures (and their interactions) to the growth in obesity; to the susceptibility of individuals; and to the different risk of obesity in different populations or population groups?

Obesity in childhood is growing, but does obesity in childhood really matter in individual children at various ages from birth to 18 years - what is an appropriate outcome-related definition of obesity in childhood? Obese children appear to be at risk of the same complications as are obese adults, but no data exists to correlate definitions of childhood obesity based on BMI cut-offs with the risk of adverse health outcomes in childhood. BMI criteria are used to highlight those who may be at greater risk and who would benefit from assessment and intervention with the greatest concern aimed at the development of Type 2 diabetes, but is BMI the best parameter in children? What about central obesity and girth?

Physiology

We are only starting to understand the basic physiological regulation of energy balance and the effect of exercise. We know little about which receptor subtypes mediate activity of certain adipokines, the influence of different physiological or pathological states on receptor regulation on adipocytes or of obesity itself, as it develops, on receptor number/regulation. What are the specific functions of the manifold appetite regulatory systems and can they be manipulated in a sustained manner by pharmacological and non-pharmacological means? Does manipulating any one or combination of these pathways lead to sustained change in weight control?

The last decade’s tremendous progress in our knowledge of the hypothalamic circuits regulating appetite only highlights the limits to our knowledge. The hypothalamic regulation of appetite and energy expenditure is now known to be incredibly complex (55). We know that the hypothalamus integrates a number of peripheral and central nervous system signals to co-ordinate appetite and energy expenditure, and therefore body weight. These signals include important factors such as adipokines, gut hormones, and neural inputs from the gut and the higher brain, but their relative positions in the energy homeostasis signalling hierarchy are unknown (56, 57). The control of energy homeostasis is intimately linked to pleasure circuits in the brain (58), but the specific role of hedonic reward signalling in the hypothalamic regulation of appetite and body weight is unknown. The hypothalamus is thought to have a ‘set-point’ to which it tries to return body weight following a period of starvation. It is unknown if or how changes in lifestyle can override this set-point and whether it can be pharmacologically adjusted. Interestingly, the current obesogenic environment may help our search for the pertinent hypothalamic circuits, as thin and fat people may show differential expression of the genes important in the regulation of this set-point. (59)