Magic bullet for obesity

Who would not rejoice to find a magic bullet that we could fire into obese people to make them permanently slim and healthy? In the United States about a third of adults are obese—that is, have a body mass index (weight(kg)/height(m)²)) above 27.¹ The diagnosis can be made with reasonable accuracy by anyone. Obese people appear “chunky” and usually have some abdominal protuberance with or without unsightly thighs. Tens of billions of dollars are spent on diets, pills, spas, or special foods and advice on behavioural change. Any scientific discovery that deals with food intake or obesity quickly becomes a “hot item” for the media. The best seller list usually contains a book giving recommendations for a new diet or mixture of diet and behaviour that assures successful weight control. Medical authorities, particularly public health officials, warn the public of the rising prevalence and hazards of obesity.

A recent editorial in the New England Journal of Medicine documented the failures of current treatment and questioned the benefits of weight loss while reminding us of the strong correlation of obesity with disorders such as hypertension and diabetes.² Since current treatment so often fails, only a magic bullet would allow us to perform an experiment to determine the full benefit of weight loss. Are we on the brink of finding a drug which will solve the problem?

Summary points

• More and more people in developed countries are becoming obese, and millions of pounds are spent on overcoming it

• Drug treatments have so far had limited efficacy and some have had serious side effects

• Maintenance of energy balance is complex and affected by hormonal, genetic, psychosocial, and environmental factors

• Genetic studies seem unlikely to reveal a universal magic bullet in the near future, although treatments for people with rare mutations may be identified

• The search for a magic bullet remains worth while as it increases our understanding of the control of energy metabolism

Methods

This article is based on my observations and a review of recent literature on drug treatment of obesity.

Drugs for obesity

For many years sympathetic agonists such as amphetamines, which have a transient anorexigenic effect, were used to treat obesity. Although over the counter preparations such as phenylpropanolamine with or without caffeine were still being purchased, by 1992 drug treatment for obesity was losing its appeal. The main approaches to reducing obesity were low fat diets and increased physical activity with or without behavioural modification.

A new wave of enthusiasm for pharmacological treatment developed after the publication of a study showing that a combination of phentermine, an amphetamine-like drug, and fenfluramine, a serotonin reuptake inhibitor, led to weight reduction that persisted for long periods.³ This raised enormous excitement, even though careful review of the published results revealed that only about a fifth of those who began the study completed the full three to four year treatment and that those who stayed the course lost only about 9% of initial body weight. Furthermore, the effect seemed to be waning in some who continued the treatment.⁴

The fusillade of not so magic bullets reached its peak in 1996, when 18 million prescriptions for phentermine and fenfluramine were written and more than 2 million for the newest addition, dexfenfluramine.⁵ Dexfenfluramine is one of two isomers of fenfluramine and has the full anorexigenic action but fewer side effects than the mixture of isomers. The long term effects of the new drugs were not fully evaluated, but a good guess is that patients could achieve a 10 to 12% reduction in body weight in one year, although this would not be fully maintained with continued treatment—hardly a magic bullet. It turned out, however, that the so called “phen-fen” combination might be more bullet than magic. Many people who received the drugs developed unexpected cardiac valvular disturbances, and dexfenfluramine was removed from the UK and American markets last year.

Present candidates for the magic bullet include sibutramine, a drug which inhibits reuptake of both serotonin and noradrenaline to induce anorexia; olestra, a fat substitute which has the qualities of fat but cannot be absorbed; and orlistat, which blocks the action of pancreatic lipase thereby inhibiting fat absorption. To assess the likelihood of success of these new agents it is useful to step back and review our understanding of the regulation of energy metabolism in humans and its most prevalent disturbance, obesity.

Maintaining energy balance

In a recent review my colleagues and I emphasised the incredible intricacy and complexity of the system that maintains a fixed level of energy storage.⁶ The balance of food intake and energy expenditure that maintains constant energy storage either at normal or obese levels is determined by the metabolism of muscle, liver, pancreas, and intestine. The balance is regulated by the adrenal and sex steroids as well as adipose tissue itself, which together create a complex set of signals that are centrally transduced into autonomic nervous and humoral controls affecting energy dissipation and food intake. Hovering over this complex system are potent psychosocial and behavioural factors. The total system assures relatively constant fat storage in adipose tissue and responsiveness to external environmental events such as the scarcity of food or cultural aspects of food intake and physical activity.

There are so many redundant pathways and accessory means of controlling energy metabolism that any single alteration is unlikely to change the level of fat storage in the long run. For a drug to be even partially helpful it must traverse and impair the function of several important loops in the system, which makes it likely that unwanted adverse effects will occur. Treatment will have to be aimed at a large proportion of the population, daily and for life. With pervasive slimness-seeking in our culture, the potential for abuse or misuse of such drugs is of great concern. Without full knowledge of how the system works more harm may be caused than help. Bullets shot into control mechanisms will produce weight loss for a while, but no magic bullet yet exists that can strike the central control mechanism and make permanent changes in fat storage with either no adverse effects or so few side effects that the biological price would be acceptable.

Genetic factors

Filling in all the gaps of the organisational plan for the control of energy metabolism is the next step in the search for a magic bullet. If we can localise the central control mechanisms or particularly powerful elements that set the level of fat storage then perhaps we could devise magic bullets to reset these mechanisms and thereby eradicate obesity. Genetic studies are now adding new information to the organisational map. Knowledge based on physiological and biochemical observations along with the effects of specific brain ablation and brain stimulation is being enriched by study of the genome in rodent mutants that become obese. Five mutant mouse obesities and one rat obesity have been known for years, but the exact location of the genetic defects in these animals has been ascertained only recently.⁷ All mutant genes responsible for animal obesities have now been identified, and strong homology exists between the rodent genes and human genes. Furthermore, the evidence for genetic factors in human obesity has become increasingly strong with studies of twins and families with and without obesity.

An example of the relation of these genes to human obesity is given by the ob mouse. The mouse carries a recessive autosomal disorder resulting in the inability of adipose tissue to secrete the protein leptin. Leptin functions as a signal to the central nervous system for both food intake and energy expenditure, and in the homozygous ob mouse leptin deficiency resets the control mechanisms to the obese state. For such animals, leptin is indeed a magic bullet. Although humans produce leptin, deficiency is extraordinarily rare.⁸ But the ob and other mouse mutants do give new information about the organisation of energy control.

Other mutations such as those that produce the rodent obesities have been sought in humans but must be very rare. They are rare in rodents as well. Nevertheless, the pharmaceutical and biotechnology industries are investigating the rodent mutant genes and the peptides with which they interact, such as neuropeptide Y, to determine their potential for treatment of obesity. The products of these genes seem likely to become magic bullets only in those instances in which there is a homologous human gene mutation. Since this is rarely the case, it is hard to be optimistic that the right bullet is on the horizon.

Will there ever be a magic bullet?

The astonishing increase in obesity when food is plentiful and we are enticed into greater consumption of food and reduced energy expenditure suggest that the genetic factors which control energy metabolism are responsive to environmental influences during growth and development. The relatively long infancy and childhood of humans compared with other animals suggests that early environmental effects may exist. If human obesity is a multigenic event and growth and development can be altered by differential environmental effects on many genes, the system is much more intricate than that found in rodents. But the search for bullets, even before the mechanism that controls energy metabolism is fully understood, remains valuable. Each step forward gives better definition of the control systems, and ultimately this information can be used along with careful observation and experimental analysis of the genetic events that are active and modifiable at each stage of growth and development. It may be that only in the rarest instances can the final structural “set” be reversed by any bullet, but means may be found to reverse the interaction between obesity and the most important associated illness—type II diabetes. Even better, would be safe interventions at early stages of development to prevent the occurrence of obesity in the first place.

Thus, the possibility of finding a magic bullet for obesity may be remote, but the search is important because it uncovers new information about how we develop and how we manage the mysterious energy balance over so much of our lives. There may never be a magic bullet, but the search is a new and important target for the drug industry and could lead to some pharmacological help in curbing the current epidemic of obesity.

Figure.

Living in hope of a magic bullet?