Giles Yeo
The MRC Metabolic Diseases Unit, Addenbrooke’s Hospital, UK

https://doi.org/10.36866/pn.96.12

Just recently a major supermarket chain opened an ‘express’ store at the hospital where I am based, one of these places that sells primarily convenience food and drink. I was there one day getting a sandwich for lunch, with what appeared to be everyone else in the hospital, and was standing in line behind a nurse who had, clutched in her hand, a salad and a yogurt. This nurse had clearly started her foraging expedition with all the best will in the world, and if the cash till had been right there, she would have made it out of the shop with an undeniably healthy lunch. However, as the line snaked in Disneyland-like fashion inexorably towards the checkout, so began the obstacle course of chocolates, candies, crisps and other temptations that are located, as is typical, close to the tills. The nurse looked longingly at every treat but managed to shuffle past each time. This must have happened 10 or more times. In my head, I was cheering her on: ‘Come on! You can do it!’ Finally she made it to the till, and as her guard dropped, the cashier pounced with a deadly offer: ‘Would you like some freshly baked cookies? Two for one today?’ And the battle was lost. The nurse walked out the shop with almost 800 extra calories in cookies.

Since time immemorial, the control of food intake and body weight has been thought to be simply an issue of self-control and willpower. Gluttony is, after all, one of the ‘seven deadly sins’. So as obesity has become an increasing public health problem, reaching epidemic proportions in most developed and emerging economies, society in turn blames those overweight and obese for a lack of moral fortitude. ‘The obese only have themselves to blame, all they have to do is to eat less…’ so the argument goes.

From a thermodynamic standpoint, this view is of course quite accurate. Body-weight is clearly a balance between energy intake and energy expenditure. Thus, the only way to gain weight is to eat more than you burn, and the only way to lose weight is to eat less than you burn. There, in one succinct statement, is the cause and cure of the obesity epidemic. However, this sage piece of advice that your grandmother could have given you is clearly not working. The story above of the foraging nurse is by no means unique. A far more complex and interesting question to ask is why some people eat more than others. Few would dispute that the obesity epidemic has been driven by lifestyle and environmental changes. However, individuals respond differently to these ‘obesigenic’ environmental changes and this variation in response has a strong genetic element underlying physiological variations. Indeed studies of BMI (body mass index; weight in kg/height in m2; a correlate of body fat mass) correlations of monozygotic, dizygotic, biological and adopted siblings reveal heritability of fat mass to be between 40 and 70%. Consequently, genetic approaches offer an effective tool for characterising the molecular and physiological mechanisms of food intake and body weight control, and allow us to understand how these may become defective in the obese state.

The control of energy balance involves a homeostatic feedback control circuitry, whereby peripheral signals communicate energy availability to the central nervous system (CNS), and hypothalamic circuits drive appropriate feeding and fuel partitioning responses. It was first proposed in the 1950s that circulating signals generated in proportion to body fat stores influenced food intake and energy expenditure in a coordinated manner to regulate body weight. However, it was not until the cloning of leptin in 1994 that the molecular basis for this homeostatic control was identified. The study of extreme phenotypes in both mice and humans has subsequently identified a number of genes that when mutated cause severe obesity. Although relatively rare, these monogenic disorders indicate a fundamental failure of the mechanisms of energy homeostasis, and together with genetically modified mouse models, have illuminated the critical role that these molecules play in the physiological control of food intake and bodyweight. We now know that peripheral homeostatic regulators of energy balance can be broadly divided into (a) fat derived hormones such as leptin responsible for signalling long-term energy stores, and (b) gut-derived hormones, which regulate short-term control of food intake. These long- and short-term peripheral nutritional signals are sensed by the brain, in particular by the hypothalamus and the nucleus of the solitary tract in the brainstem, where they are integrated and acted upon to appropriately regulate food intake and energy expenditure

However, the major burden of disease is carried by ‘common obesity,’ which to date has resisted yielding meaningful biological insights. In contrast to the Mendelian obesity syndromes, common obesity is likely to have a ‘polygenic’ aetiology, with multiple variations each having a subtle effect. Only recently has the spate of genomewide association studies (GWAS) begun to reveal some of the genetic architecture underlying common obesity. Powerful though it has been, it is however important to consider the limitations of what GWAS can offer. GWAS is after all a gene agnostic approach. SNPs reaching the appropriate statistical threshold for a given phenotype or disease can appear anywhere in the genome, within, near or far away from any coding sequence. The current assumption that the closest coding region, which is sometimes hundreds of kilobases away, is the likely candidate is perhaps a reasonable first guess, but not necessarily true! Additionally, because of its ‘hypothesis free’ nature, the power of GWAS lies in uncovering potentially new biology that would not have been possible using a candidate gene approach. The problem with new biology, of course, is that, by definition, little or nothing at all might be known about the gene. Many ‘scientist hours’ are now being dedicated to turning these statistical hits into biological insight.

There is still the strongly held belief in many quarters that we are in full ‘executive control’ of our own eating behaviour; that the environment is responsible for our shape and size, and that our genes, our ‘nature’, has minimal, if any, effect. However, it is crucial to remember that the drive to consume food is one of the most primitive of instincts to promote survival. It has been shaped by many millions of years of evolution and has provided living creatures with powerful and redundant mechanisms to adapt and respond to times of nutrient scarcity. Thus, I would argue that to be overweight in our current environment is indeed the natural, highly evolved even, response. The main issue is that the current environment, such as the lunch obstacle course faced by the nurse on a daily basis, in which energy dense foods and stimulatory food cues are ubiquitous, coupled with concurrent changes in lifestyle, is in dissonance with the millennia of austere surroundings to which we have adapted. This has consequently pushed obesity to become the serious problem it is today. I am fully aware that without this ‘obesogenic’ environment, most of us would not be overweight or obese; but to deny the central role that our genes have played in our response to this environment is unhelpful as we strive to tackle one of the greatest public health challenges of the twenty-first century.