Obesity – unravelling the interaction of genetics, biology and environment

During the past century, researchers and public health efforts have made tremendous advances in containing infectious diseases, but that progress is being partially offset by a sharp rise in the incidence of heart and lung disease, diabetes, lifestyle-related cancers, and other non-communicable diseases.¹ One of the major drivers of the increase in these diseases is the rising prevalence of obesity.

Biomedicine defines obesity as excessive fat accumulation that presents a risk to health. According to the World Health Organization (WHO), the fundamental cause of obesity and overweight is an energy imbalance between calories consumed and calories expended. Globally, there has been an increased intake of energy-dense foods that are high in fat and sugar, and a decrease in physical activity and energy expenditure (e.g. due to increased use of heating and air conditioning, the modern sedentary nature of many forms of work, changing modes of transportation, and increasing urbanization). Changes in dietary and physical activity patterns are often the result of environmental and social changes associated with development and a lack of supportive policies in sectors such as health, agriculture, transport, urban planning, environment, food processing, distribution, marketing, communi­cation, and education.²

Obesity should be considered as a chronic disease which derives from complex, systemic, multi-causal pathologies or problems rooted in the sedentary nature of modern post-industrial life. It can be linked to more widely available and more affordable food, changes in diet, potential alterations of the gut microbiome, psychological stimuli such as stress, epigenetic triggers, and disruption of the physiological internal milieu. As a condition that affects people of lower socio-economic status and women in particular, obesity is also an embodiment of social and health inequalities and, as a result, requires approaches that are empowering and accessible to everyone. To improve the treatment and prevention of obesity, a better understanding of obesity causes is urgently needed.

Researchers from biomedicine and the social sciences/humanities are digging deep into relevant dimensions of and potential solutions to the rapidly growing obesity epidemic. Although we are increasingly understanding how craving for food is disturbed in the brains of individuals with obesity, how gut and adipose tissue (AT) hormones regulate appetite and satiety in the hypothalamus, or how AT dysfunction causes secondary health problems, to date, we have been unable to translate such knowledge into prevention strategies at the societal level.

Although there is no doubt that the fundamental cause of obesity is a long term energy imbalance between too many calories consumed and too few calories expended, the factors contributing to overeating and physical inactivity are complex. The enormous complexity of the causal relations relevant to obesity has been compiled in the Obesity System Map.³

The key role of certain brain regions in the regulation of body weight became evident from observations that animals with lesions and humans with tumors affecting the hypothalamus develop abnormal food-seeking behavior and obesity.^4,5  With the finding that a mutation in the ob gene (which encodes the AT hormone leptin)⁶ causes severe obesity in ob/ob mice⁷, it became apparent that central neural circuits that control energy homeostasis integrate signals from peripheral tissues, such as AT⁸, highlighting the numerous biological influences at play.

Moreover, observations from twin and adoption studies^9,10 suggested that obesity might be an inherited disorder of energy homeostasis. The heritability of BMI has been estimated as 40–70%.^11,12 Indeed, discoveries that mutations in genes that play a central role in the regulation of energy homeostasis^13-17, can cause severe obesity in humans underlined the importance of biological factors in the pathogenesis of obesity. On the other hand, monogenetic causes of obesity are rare and cannot explain the extent of the obesity pandemic. In addition, genome wide association studies (GWAS) found that only ~2% of the BMI variability can be explained by common single genetic variations.¹⁸ Clearly, changes in population genetics cannot explain the rise of obesity prevalence in just 40 years.

Indeed, much of the BMI variability might be attributable to gene–environment or gene–behavior interactions, including in the pre-natal environment. Intriguingly, maternal diet during pregnancy can affect DNA methylation patterns that can persist over decades in offspring and might even be inherited by future generations.¹⁹

The social, environmental and biological factors that contribute to obesity are extremely complex and even more difficult to unravel. Whilst genetic factors and biological mechanisms involved in the regulation of body weight are undeniable, the sedentary nature of the modern age – combined with extreme environmental and social changes over the last century – continue to fuel the obesity pandemic, which, in turn, is accelerating the incidence of heart and lung disease, diabetes, lifestyle-related cancers, and other non-communicable diseases. To improve the treatment and prevention of obesity, we urgently need to work towards a better understanding of the causes of obesity, across all aspects of society and the obesogenic environment.