The obesity epidemic is not simply the result of changes in the lived environment but a complex interplay between genes and surroundings that has driven people who would have been genetically susceptible — but remained thin in previous eras — to become obese, says one expert. This was the argument put forward as part of a debate on whether an individual's body weight is determined by "nature or nurture" at the recent Society for Endocrinology BES Conference 2019 in Brighton, UK. Before the debate began, Rob Semple, MD, University of Edinburgh, UK, introduced the speakers and polled the audience on their "baseline" views on the statement: "This house believes that nature not nurture determines our body weight." The response was 36% "for" the statement (ie, nature) and 64% "against," which Semple noted suggested that the first speaker, Sadaf Farooqi, MBChB, PhD, "will have her work cut out" to convince the audience that nature is the main driver of obesity. Farooqui is professor of metabolism and medicine at the University of Cambridge, UK, and was the winner of the 2019 American Diabetes Association Outstanding Scientific Achievement Award. Farooqi's adversary in the debate was John Wilding, DM, of the University of Liverpool, UK, who Semple described as "similarly formidable." Plenty of Evidence That Genes Play a Role in Weight Regulation Farooqi began by saying that the question before the audience is "fundamentally important," and noted that there is plenty of evidence to suggest there is a biological system for regulating body weight. Experiments have shown that animals and humans maintain a set point for weight that they return to after periods of limited food intake, regardless of how much weight they lose. Initially, the hypothalamus was found to play a key role in weight regulation, but it was the discovery of leptin that allowed the whole system, with its links to adipose tissue, the pancreas, and the intestines, to be elucidated, she explained. Work with children then revealed the influence of genetic factors on the body weight "set point." Identical twins reared apart were found to have a very similar body weight, and adoptive children were shown to have a similar weight to their biologic, rather than adoptive, parents. Tying these observations to individual or small numbers of genetic variants has, however, proven difficult, beyond the known variants associated with thinness and the rare variants in 15 genes linked to severe obesity. That is, Farooqi said, until the publication of US research earlier this year testing a polygenic risk predictor involving 2.1 million common variants in more than 300,000 individuals. The research showed that, across polygenic score deciles, there was a 13-kg gradient in weight and a 25-fold gradient in the risk of severe obesity. Moreover, another 2019 study, this time by Farooqi's team, revealed some loss of function variants in the melanocortin 4 receptor gene are linked to an increased risk of obesity, type 2 diabetes, and coronary artery disease, and some gain in function variants are linked to a lower risk of obesity and cardiometabolic disorders. Abundance of Food Farooqi believes the reason there is an obesity epidemic is that the physiological system for regulating weight "evolved to stop us starving" but is now faced with "an abundance of food." The impact of this is all the greater because we live in a "complex food environment," with high sugar and high fat foods that are seen as "very rewarding," as demonstrated on brain scans of people shown pictures of such foods. Individuals also engage in stress-related eating, which is played out via neural circuits linking the hypothalamus to the limbic system. She characterized such eating as a "biologically appropriate thing to do because it gives you a rewarding, pleasurable feeling." She said that, together, this underlines that the "biology of appetite" is a mixture of both innate and learned behaviors. Farooqi concluded: "I hope I've made the case for you that there is clear, strong, compelling evidence" that weight is regulated by a homeostatic system centered on the hypothalamus, and genetic disorders, tumors, surgery, radiotherapy, and medications can all "perturb" weight regulation. "In some people, that promotes obesity, in some people it protects them against obesity," she said. Rapid Change in Obesity Prevalence Must Be Down to Surroundings Taking to the podium, Wilding proceeded to present the case for the notion that body weight is determined "by nurture." He pointed to data from the World Obesity Federation on adult obesity showing that, between the 1960s and 1990s, the prevalence of obesity topped more than 15% in only a few developed countries and no developing nations. But from 2000 onwards, the situation has completely reversed. At least 15% of the population is obese in most developed countries, rising to over 25% in the United States, Canada, Australia, and the UK, among others. The prevalence of obesity is also rising rapidly in many middle-income countries. Yet, Wilding pointed out, humanity cannot have evolved genetically to a sufficient extent over that period to account for the change. He turned to the UK Government's obesity system map, which is a visual representation of the different factors that influence obesity levels. Although it places physiological energy balance at the heart of the map, and a large part of that is devoted to biologic processes, Wilding highlighted that the visual also places a great degree of emphasis on food production and consumption, societal influences, individual psychology and movement, and the "activity environment." He also showed data suggesting it is not so much energy and fat intake that is associated with obesity trends as the increase in the number of cars per household and hours spent watching television. For example, it is estimated that, compared with the 1950s, the average adult now walks, on average, a marathon (approximately 26 miles) less per week, he said. Nurture Not Nature: Environment Remains the Major Contributor The Cuban economic crisis of the 1990s also provides an illuminating example, Wilding added. The sudden end of Soviet subsidies to Cuba led to food shortages, the loss of public and private transport, and the import of 1.5 million bicycles from China. The subsequent drop in the prevalence of obesity was associated with a reduction in the incidence of diabetes and diabetes-related mortality, with all three increasing substantially once food and transport levels were restored. Taking a more recent example, Wilding showed longitudinal findings from the HUNT study, which involved almost 119,000 individuals with repeated body mass index (BMI) measurements from 1963, and over 67,000 who were tested for 96 known obesity genes. The HUNT authors concluded that, although "genetically predisposed people are at greater risk for higher BMI and that genetic predisposition interacts with the obesogenic environment resulting in higher BMI...BMI has increased for both genetically predisposed and nonpredisposed people, implying that the environment remains the main contributor." Wilding said that, taken together, obesity is "common and increasing almost everywhere," and that the epidemic "is driven by societal change," despite the underlying biology determining an individual's susceptibility. He ended his pitch to much laughter with a quote by Farooqi from a 2014 review that supports his argument: "Evidence clearly shows that both increases in energy intake and reductions in energy expenditure during physical activity have driven increases in the mean BMI seen in many countries over the past 30 years." Environment Change Has Unmasked Genetic Susceptibility of Some Both speakers were then invited back to the podium, allowing Farooqi to respond that, although she did indeed pen that statement in a 2014 review, if one were to look "carefully," the article discussed the last 30 years, and indeed, "our genes haven't changed in that time, but the environment has." "We agree on that point, and hence my quote," she said, "but what our environment has done is it has unmasked the genetic susceptibility of some individuals, so what we see when we look at the pattern of BMI in the population is that the mean BMI has increased...but also the proportion of people with severe obesity has increased." She clarified that what this suggests is that, within any population, there are some people who are genetically more susceptible to obesity, so some of those who may not have been obese 30 years ago now are because of the environment. "It is the environment acting on genetic susceptibility that is contributing to the distribution of BMI," she emphasized. Wilding again pointed to the HUNT study, which showed that, even in individuals with "thin genes," there has been a rise in mean BMI. Farooqi said this, in fact, underlines a limitation of that study, which is they only used 96 well-known genetic variants associated with obesity, but the polygenic risk study she highlighted earlier used 2.1 million genetic variants. Consequently, data from the HUNT study "captures some of the variation but not all," she stressed. No Matter Which Side You're On, It's Not the Individual's Fault... The debate continued, with questions from the floor covering many aspects of obesity. The final question was directed at Farooqi: "What proportion of somebody's weight is considered to be genetic...as opposed to the nurtured weight?" She replied this is a "hugely important" question, because "if we don't recognize that there’s a biological role for the regulation of weight, how on earth can politicians, with their somewhat different capacity for taking on new information, do that?" The "evidence suggests around 40% of a person's weight is influenced by genetic factors," she said. "In some people it's higher, where there are penetrant genes having an effect, in other people it's about 40% with a combination of genes which, added together, influence their risk of either gaining weight or staying thin." In response, Wilding was keen to stress: "No matter which side of the argument you're on, the point is that this is not the individual's fault." "It's either a response to their environment...or it's something that they've inherited and don't have individual control over," he noted. "Sadaf [Farooqi] said it herself, 40% of our body weight is genetic, that means that 60% is environmental, and I rest my case," Wilding said. However, that did not hold sway with the audience, who, when they voted again at the end of the debate, indicated they had changed their minds: 53% agreed with the statement that nature, not nurture, determines body weight, and 47% disagreed. A win for the lady, it would seem. Source
