(1) In a healthy environment, genes alone do not usually cause obesity and lifestyle-related diseases, and population variability in these characteristics is low (i.e., most people are lean and free of these diseases).

(2) In an unhealthy environment, genetically susceptible people become obese and/or develop disease, while others remain lean and healthy because they are not genetically susceptible.

(3) This results in an increase in population variability (e.g., more variability in body fatness between individuals).

(4) Diet and lifestyle environment have a major impact on obesity risk. For a genetically susceptible person, maintaining a leaner state is usually possible but it requires stepping out of the typical fattening environment. Genes are not destiny.

Our vision is to find the genetic determinants of body weight and by doing so, to find better ways to prevent and treat obesity and its complications.

Obesity results from interactions between environmental and genetic factors. Despite a relatively high heritability of common, non-syndromic obesity (40–70%), the search for genetic variants contributing to susceptibility has been a challenging task. Genome wide association (GWA) studies have dramatically changed the pace of detection of common genetic susceptibility variants. To date, more than 40 genetic variants have been associated with obesity and fat distribution. However, since these variants do not fully explain the heritability of obesity, other forms of variation, such as epigenetics marks, must be considered.

Epigenetic marks, or “imprinting”, affect gene expression without actually changing the DNA sequence. Failures in imprinting are known to cause extreme forms of obesity (e.g. Prader–Willi syndrome), but have also been convincingly associated with susceptibility to obesity. Furthermore, environmental exposures during critical developmental periods can affect the profile of epigenetic marks and result in obesity.

We review the most recent evidence for genetic and epigenetic mechanisms involved in the susceptibility and development of obesity. Only a comprehensive understanding of the underlying genetic and epigenetic mechanisms, and the metabolic processes they govern, will allow us to manage, and eventually prevent, obesity.

Obesity and its associated comorbidities represent one of the biggest public health challenges facing the world today. The heritability of body weight is high, and genetic variation plays a major role in determining the interindividual differences in susceptibility or resistance to the obesogenic environment. Here we discuss how genetic studies in humans have contributed to our understanding of the central pathways that govern energy homeostasis. We discuss how the arrival of technological advances such as next-generation sequencing will result in a major acceleration in the pace of gene discovery. The study of patients harboring these genetic variants has informed our understanding of the molecular and physiological pathways involved in energy homeostasis. We anticipate that future studies will provide the framework for the development of a more rational targeted approach to the prevention and treatment of genetically susceptible individuals.

Citerank: (19) 348770Tackling obesityMany policy interventions have been suggested to address the obesity crisis across multiple studies—and indeed many such measures have been implemented, and are being implemented, now. There's recognition too that these interventions need to be part of a coherent and comprehensive whole systems strategy [4]; with some grounds for optimism that such an approach has the potential to accomplish a significant reduction in the prevalence of obesity in the UK across the next decade. [2]565CA4D9, 351042Strategies of some companies are fuelling the obesity crisisSome companies and industries are fuelling the obesity crisis, through a variety of strategies that prioritise profitability and corporate brand value over public health, and, in the process, externalise significant costs.555CD992, 352528Subsidising the production of sugar and fatGovernments are subsidising production of fat and sugar compared with micronutrient-rich foods.555CD992, 352531Overseeing a decline in physical activitySuccessive governments have overseen a decline of physical activity (e.g. due to policies on transport, public spaces, and sports facilities).555CD992, 366559Encourage individuals and families to make healthier choices565CA4D9, 366896WHO's total budget is less than half the marketing budget of McDonaldsMcDonald’s and Coca-Cola’s marketing budgets are each twice the World Health Organization’s full-year budget.1198CE71, 366897Surgical and pharmaceutical solutions don't resolve societal problemsThere is a danger of searching for pharmaceutical or bariatric solutions; as technological solutions are unlikely to resolve societal problems – at best, they are a ‘sticking plaster’.13EF597B, 368179Production and marketing choices favour profit over diet optimisationDecisions made by many food and beverage companies tend to be shaped more by the immediate corporate financial interests of shareholders (and the associated interests of corporate officers) rather than the social goal of achieving optimal human diets; as reflected in, for example, the production and marketing a high volume of low-cost, highly processed foods that are rich in sugar, salt, and saturated fats.555CD992, 370363Unhealthy foods are cheaper and getting cheaper555CD992, 399546Tackling obesityMany policy interventions have been suggested to address the obesity crisis across multiple studies—and indeed many such measures have been implemented, and are being implemented, now. There's recognition too that these interventions need to be part of a coherent and comprehensive whole systems strategy [4]; with some grounds for optimism that such an approach has the potential to accomplish a significant reduction in the prevalence of obesity in the UK across the next decade. [2]565CA4D9, 399576Encourage individuals and families to make healthier choices565CA4D9, 399702Surgical and pharmaceutical solutions don't resolve societal problemsThere is a danger of searching for pharmaceutical or bariatric solutions; as technological solutions are unlikely to resolve societal problems – at best, they are a ‘sticking plaster’.13EF597B, 399888Strategies of some companies are fuelling the obesity crisisSome companies and industries are fuelling the obesity crisis, through a variety of strategies that prioritise profitability and corporate brand value over public health, and, in the process, externalise significant costs.555CD992, 399893Genetic susceptibility to an obesogenic environmentRoughly 70 percent of obesity risk is genetically inherited; however, this genetic inheritance is best understood as a susceptibility to a fattening environment––i.e. in a healthy environment, genes alone do not usually cause obesity: in an unhealthy environment, genetically susceptible people become obese, while others remain lean because they are not genetically susceptible. [1]555CD992, 399895Production and marketing choices favour profit over diet optimisationDecisions made by many food and beverage companies tend to be shaped more by the immediate corporate financial interests of shareholders (and the associated interests of corporate officers) rather than the social goal of achieving optimal human diets; as reflected in, for example, the production and marketing a high volume of low-cost, highly processed foods that are rich in sugar, salt, and saturated fats.555CD992, 399903Subsidising the production of sugar and fatGovernments are subsidising production of fat and sugar compared with micronutrient-rich foods.555CD992, 399904Overseeing a decline in physical activitySuccessive governments have overseen a decline of physical activity (e.g. due to policies on transport, public spaces, and sports facilities).555CD992, 399918Unhealthy foods are cheaper and getting cheaper555CD992, 399927WHO's total budget is less than half the marketing budget of McDonaldsMcDonald’s and Coca-Cola’s marketing budgets are each twice the World Health Organization’s full-year budget.1198CE71

The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65) is a positional candidate gene for obesity on Chromosome 10p11–12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of γ-aminobutyric acid (GABA), which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake... These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity.

Genes influence every aspect of human physiology, development, and adaptation. Obesity is no exception. Yet relatively little is known regarding the specific genes that contribute to obesity and the scale of so-called “genetic environment interactions” the complex interplay between our genetic makeup and our life experiences...

What’s increasingly clear from these early findings is that genetic factors identified so far make only a small contribution to obesity risk—and that our genes are not our destiny: Many people who carry these so-called “obesity genes” do not become overweight, and healthy lifestyles can counteract these genetic effects. This article briefly outlines the contributions of genes and gene–environment interactions to the development of obesity.

Understanding of the genetic influences on obesity has increased at a tremendous rate in recent years. By some estimates, 40 to 70 percent of the variation in obesity-related phenotypes in humans is heritable. Although several single-gene mutations have been shown to cause obesity in animal models, the situation in humans is considerably more complex. The most common forms of human obesity arise from the interactions of multiple genes, environmental factors, and behavior, and this complex etiology makes the search for obesity genes especially challenging. This article discusses the strategies currently being used to search for human obesity genes and recent promising results from these efforts.