The fat of the land

This essay was written by Chris Hentschel and was first published in the 1995 Mill Hill Essays.

There are few medical research topics that so many people feel that they can relate to personally as those dealing with obesity. Obesity is a medical term which basically means that someone is too fat for their well-being. As a subject for medical research, the obese person presents one of the most perplexing challenges and one that is only now beginning to be understood. There has been much media excitement recently about breakthroughs in understanding the scientific basis of obesity, coupled with often feverish speculation that science would soon provide a ‘quick fix’ for the condition. Alas, the truth has often been lost in the enthusiasm and, not surprisingly, many people seem more confused than ever as to what is really happening.

My aim here is to give a personal interpretation of what really lies behind the headlines. Firstly, it is important to get some feel as to the size of the problem. Obesity is arguably the most common chronic disease in Europe and the USA. Some would consider the term ‘disease’ inappropriate since there may be little or nothing basically wrong with a fat person. Yet in its broad sense of an affliction or ailment, it has been estimated that as much as a quarter of the population of Europe and up to a third of the population of the USA is unhealthily fat. Moreover, the numbers have been rising steadily for several decades. I use the word unhealthily quite deliberately since the chance of getting several common diseases is much increased in the obese and there is a clear consequent reduction in life expectancy. Excess body fat, particularly when distributed on the upper body, has been shown to increase greatly the risk of diseases of the blood vessels, heart disease, non-insulin-dependent diabetes, gallbladder disease, breathing disorders, gout, and certain types of cancer. Being overweight also puts an increased strain on joints and, not surprisingly, these wear out much faster in the obese. To put all of this into some context, it has been calculated that about eight percent of all health care costs in the USA are due to obesity and that obesity constitutes the second largest preventable cause of early death after smoking.

Why then are there so many fat people in Western societies and, for that matter, increasingly in the newly affluent countries? The simple answer is that over a period of time fatness results from an imbalance between energy intake and energy expenditure. Fat people have over a period of time eaten too much relative to their needs. Even a slight sustained excess in daily energy intake, such as the calorie content of a single chocolate biscuit, will result in one kilogram weight gain in a year.

This ‘dietary imbalance’ explanation however hides a much more interesting and complex set of interactions that contribute to the end result. While not fully understood, these include an interplay between genetic, environmental, cultural, and behavioural factors. The environmental, cultural, and behavioural factors are easiest to understand since they comprise such obvious things as unhealthy eating habits, poor appetite control, and not least, lack of exercise. The economic means to over-indulge in calorie-laden foods might also be considered an environmental factor.

The genetic factors influencing obesity are those which are inherited at birth and it is in this category that scientific breakthroughs have been occurring. The idea that inheritance plays some role in fat accumulation and deposition is not new in itself. For example, there are several, albeit rare genetic diseases associated with fatness. These, however, account for less than one percent of the obese population. Women are also on average fatter than men and there are clear gender differences in the way fat is distributed quite irrespective of environment or behaviour. Moreover, examples of well-studied genetically distinct groups, such as the American Pima Indians who have a very high proportion of obesity-linked diabetes in their population, testify to the importance genetics can play in human obesity.

o the research scientist, however, humans are for many reasons not a promising starting point for research aimed at understanding the details of the genetic factors influencing obesity. Apart from the fact that, except for identical twins, we are all genetically very different, there is the fact that we tend to make poor experimental subjects. Inbred strains of mice on the other hand are, as near as makes no odds, genetically identical and at least in the laboratory one can control their feeding patterns precisely. Even more important is the fact that very small genetic differences have been known for many years to be able to affect the degree of obesity of otherwise identical rodents. Inbred strains of obese mice exist which, for example, differ from their normal relatives by single mutations in basic genetic units, or genes. These obesity regulating genes have been given names such as tubby, fat or ob.

Since the ob gene in particular has recently been the subject of much publicity, it deserves some more explanation. Ob, like any other gene, is now known to be a single unit of genetic instruction written in the universal DNA instruction code. The instruction manifests itself as the production of a specific protein, often by a specialised type of cell. For example, the red blood cells are instructed by a specific set of globin genes to make the red protein (haemoglobin) which characterises this cell type; specific pancreas cells make the hormone insulin under the instruction of a corresponding insulin gene. Given this underlying mechanism, the questions scientists in the obesity field asked were: what exactly was the protein coded for by the ob gene, and why, when it was inactivated by mutation, did the mice become fat?

The first question was essentially a technical problem and, as such, relatively easy to solve; the gene was isolated by a group of molecular biologists at the Rockefeller University in December 1994 and its sequence patented. The protein coded for by the ob gene was given the name leptin from the Greek word for thin, leptos. Within months the rights to the patent describing leptin were auctioned to the highest bidder, the US biotechnology company Amgen, for 19 million dollars making the “inventor” a millionaire in the process and adding almost a billion dollars to Amgen’s capital value. To add to the excitement, by the summer of 1995 several groups showed that leptin injections were capable not only of inducing dramatic weight reductions in very fat ob mice but were also able to reduce overfed normal mice. Eureka!

The answer to the second question, how does it work?, has proved a little more elusive. One idea is that leptin acts on some sort of brain-located regulatory device acting on appetite. Like a thermostat, but for weight rather than temperature control, the “weightstat” setting is thought to be adjusted downwards by increasing leptin concentrations. If this idea is correct the obesity of the ob mice is simply a problem of an inappropriately high setting in the brain’s weightstat due to an absence of leptin.

The weightstat concept also has resonance with ideas about obesity in humans, most of whom appear to regulate their weight reasonably. In humans, whether fat or thin, the degree of weight stability that is generally observed is impressive and implies a rather precise match between energy intake and expenditure over a prolonged period. This precision in balancing energy intake and energy expenditure would be difficult to achieve without some form of feedback regulation. While far from proof, it is more reasonable to suppose that this reflects the operation of a weightstat rather than an individual’s will power, or lack of it. Moreover, the underlying mechanism of the weightstat is likely to be similar in mice and men.

Unfortunately, the superb science that the mouse leptin work undoubtedly represents has been swept aside by a torrent of often ill informed media embellishment, and the simple analogy suggesting that a “cure” for human obesity was round the corner seems at best rather naive. This is not because humans don’t have the equivalent of the ob gene, they do. Human fat cells also make the human version of leptin. The naivete lies in the fact that correcting a genetic defect by “replacement therapy”, for example, by injecting the non-existent or defective protein, is much simpler experimentally than trying to affect the actual condition, which involves an interplay between genetic, environmental and behavioural factors. Most obese humans are, in fact, very unlikely to be deficient in the human leptin. Available data suggest that the reverse is true, they have more of it than the average person. This observation is not particularly surprising since leptin is made by fat cells and fat people have, compared to the average person, bigger fat cells and possibly more of them.

Can we then conclude that the human leptin will be useless for human therapy except for the rarest of cases where individuals are genetically deficient in it? No, this also would be a premature conclusion. Advocates of the possible benefits of leptin therapy have been quick to point out that the level of the protein may not be what is defective, but the sensitivity of the brain weightstat to it. They point to the case of one of the commonest forms of diabetes where patients make plenty of insulin but are simply not very sensitive to it. Such patients, with elevated insulin levels, can nevertheless benefit from more! Only time will tell if the same proves true for the human leptin.

Are there any other drug approaches that are currently being researched? Yes, given the commercial incentive it is not surprising that there are several. Some trial drugs affect the absorption of food or affect appetite. Others affect how food is transformed when in the body. All these drugs are designed to be combined with a calorie controlled diet. Why not a diet alone? one might reasonably ask. The obvious answer is that for most people they don’t work over the long term. Going back to the weightstat/thermostat analogy, a diet pure and simple might be likened to trying to cool an overheated house by restricting the gas supply to the burner rather than by adjusting the thermostat. It may work in the short term, but it’s not really a good idea. In fact, obsessive dieting is not only generally ineffectual, it carries some risks. Severely energy-restricted or unbalanced diets are linked to deficiency syndromes, gallstones, heart arrhythmias, and even sudden cardiac death. Even relatively balanced diets can lead to chronic fatigue, impaired concentration, cold intolerance, mood changes, and malaise as weight drops below the weightstat set point. Cycles of dietary deprivation followed by refeeding, “yo-yo” dieting, may even over time enhance metabolic efficiency, thus promoting weight gain! Under these circumstances it is not surprising that “yo-yo” dieting is linked to low self-esteem as the dieter fails to either lose weight or maintain a weight loss and that eventually a more radical, often pharmaceutical, or even surgical solution is sought.

Surgical or mechanical procedures that have been used to aid weight loss include jaw wiring, painful waist cords, and many variants of intestinal bypass and stomach bypass operations. 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 caused several deaths. In the gastric bypass procedure, most of the stomach is closed off with surgical staples. Only a small pouch remains to receive food, thereby greatly reducing the person’s eating capacity.

Surgical intervention, however, has not only been aimed at the stomach. The fat cells themselves (the adipocytes) have more recently been the direct target of surgery using the technique of liposuction. This simply means that the surgeon uses a powerful vacuum suction mechanism to suck out the cells from deposits under the skin after they have been softened and dispersed either by the injection of enzymes or with powerful ultrasound probes. One reason why this direct approach works is that, in adults at least, the fat cells don’t seem to grow back. Several attempts to count the numbers of fat cells in fat and thin adults have concluded that the main difference between them is not the number of fat cells but their size. To the extent that this is true, it does provide an explanation both for the long term effects observed with liposuction and for the permanent loss of fat tissue in some rare diseases.

Fat cells then basically act as reservoirs for fat storage. Like reservoirs they can be empty or full of fat and to a surprising extent they appear to be removable without harmful side effects. I say surprising because any cells that we have are only there because they gave some advantage, at least at some point in human evolution. This advantage basically seems to be that humans have the capacity to survive through conditions of feast and famine by using the fat reservoirs. In affluent countries this capacity now seems, to an increasing proportion of the population, to work to our disadvantage – there just aren’t enough famines!

Liposuction is to date the only approach that directly reduces fat cell numbers in humans. A form of biological liposuction is, however, also theoretically possible and the development of this technique (pioneered at the Hannah Research Institute in Scotland) is the goal of a newly formed biotechnology company, ObeSys. Essentially biological liposuction works because it is possible to trick the immune defences into thinking that the fat cells are appropriate targets for elimination. The deception is achieved using antibodies, highly specialised protein molecules that stick to, and so mark only the fat cells. Many animals, ranging from rats to pigs and sheep, have been treated in this way and reductions in the number of fat cells and in the percentage of body fat have occurred. It thus seems possible that at some point in the not too distant future biological liposuction will provide another, and arguably complementary, approach to the treatment of human and animal obesity.

As we move towards a new millennium many scientists, at least the more optimistic amongst them, are beginning to believe that science, and specifically molecular biology, will ultimately provide the “cure” for obesity. In the meantime, managing obesity involves recognising that the health hazards of moderate obesity can be overstated and probably do not justify drastic calorie-restricted diets that are ineffective and even counter-productive. Sensible food choices and regular exercise will, for most people, almost always be preferable to calorie restriction or to any pharmaceutical or surgical intervention.

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