The aim of this area is to support research that will enhance understanding of the mechanisms of obesity and related diseases, and to develop interventions that will prevent or treat these conditions.
Obesity is associated with increased mortality and substantial morbidity, placing a significant burden on healthcare systems around the world.
MRC has identified eight priorities for obesity research and have divided them into two categories:
- scientific areas and experimental
- conceptual approaches.
Some research priorities are current areas of strength for UK research where significant progress is being made. Others are underdeveloped and in need of stimulation. A wide variety of approaches is required in combination to achieve our overall objectives of understanding the mechanisms of obesity and related disease, and developing interventions to prevent or treat these conditions.
Research priorities
We have developed a plan for obesity research and defined our priorities based on:
- disease burden
- unmet need
- timeliness
- value for money or added value
- impact on disease
- tractability or feasibility.
We recognise that many approaches are valuable in addressing obesity so our priorities are based on the areas most relevant to MRC and are not intended as priorities for other organisations with different remits.
Our obesity priorities focus on the factors most relevant to our remit but we acknowledge the importance of research into the wider socio-economic drivers that is performed by the national framework of funders.
Within MRC’s broad remit, we fund a significant amount of research relevant to obesity and obesity-related disease.
MRC invests around £22 million a year on research relevant to obesity through research grants and our units, centres and fellowships. This includes genetic, physiological research (studying underlying mechanisms of obesity and related diseases) and population-level research (including social, behavioural, environmental and dietary).
Obesity is a complex physiological and socio-economic issue, spanning many disciplines of research and requiring research investment from a variety of funders. Our objectives in obesity research are to produce an understanding of the mechanisms of obesity and of its links to disease, and to use these insights to develop effective interventions to prevent and treat these conditions.
Our activities in obesity research are centred on the causes of obesity and the processes by which it causes disease, and use a variety of approaches from molecular physiology to epidemiology.
Research into the prevention of obesity and related diseases is an area of growing interest, in which activity has increased as new translational opportunities have arisen. We have made substantial additional contributions to the National Prevention Research Initiative, a collaborative funding programme.
Underpinning research examining normal biological development and functioning is also important and well supported. Across these areas, a life course approach is taken, examining variation across different stages of life and the long term effects of early experiences. Thus we support a wide range of research activities related to obesity including mechanistic, epidemiological and proof of concept research.
In terms of our remit, obesity’s consequences for health are the dominant cause for concern. For example, obesity results in a substantial increase in risk of type 2 diabetes. This means that a balance between approaches – reducing or preventing obesity and breaking the link between obesity and related diseases – is required. An intermediate approach, targeting common points in the link (such as insulin resistance) is also possible.
Obesity is a complex problem that may seem intractable due to its complexity and the likely functional redundancy in systems controlling energy intake. It cannot be managed in the same way as single risk factor changes – such as smoking, where there is a clear and straightforward message.
It may therefore be useful to learn from examples of multifaceted research strategies that have been successful in improving health outcomes in other complex disease areas, such as cardiovascular disease.
Rather than focusing on a single causal pathway, multiple angles of attack are used in combination to address both socio-economic and physiological factors, for example:
- public health policies to reduce salt intake
- multiple drug therapies
- active screening.
For obesity, a similar combination of factors could be used including:
- population-level measures to reduce obesity through diet and activity
- therapies to produce and maintain negative energy balance: reducing energy intake – for example, targeting the brain directly or through peripheral signals, from neuroendocrine or adipose tissues – and increasing energy expenditure
- therapies designed to uncouple obesity from its adverse consequences.
The research priorities we have identified provide a scientific basis for these approaches to be designed and tested.
Given the substantial investment in obesity research worldwide, priority is given to those areas where MRC or the UK has particular strengths or where there are opportunities that can be exploited – for example, through our strength in cohort studies.
Scientific areas
MRC has identified priorities for obesity research in scientific areas approaches.
Mechanisms of obesity and of obesity-related diseases
An understanding of the mechanistic pathways of obesity and its relationship to disease is of central importance. Recent developments have provided new opportunities to increase understanding in this area.
Building on observational genetic and lifestyle research (such as genome-wide association studies or epidemiological associations), molecular (including genetic and epigenetic) and integrative physiological research is required to address both the causes and the consequences of obesity.
Likewise, population-level research is required to explore molecular and physiological findings. This is essential if basic research is to lead to new obesity therapies and prevention strategies. Across these areas, the importance of a life course approach is emphasised.
There are three specific areas which are particular priorities.
Extreme phenotypes
Identification of highly penetrant phenotypes (such as obesity or leanness, propensity or resistance to type 2 diabetes in those with obesity) and the mechanistic investigation of the determinants of these phenotypes (whether genetic or otherwise, and in animal models or humans).
This approach is powerful as it identifies control points in pathways for intervention, and exploits the UK’s strength in mammalian genetics and cohort studies. Intelligent and detailed phenotyping will be required to produce mechanistic insights.
Protective phenotypes
Why do most individuals remain lean in an obesogenic environment? Why do some obese individuals remain (metabolically) healthy while others do not? Current research focuses on the ill obese but an understanding of protective processes and natural resilience may also lead to the identification of therapeutic targets.
Identification of common pathways in obesity-related disease
These include, for example, insulin resistance and the components of metabolic syndrome, and discovery of control points in these pathways.
An iterative approach between human and animal models is essential and evidence of human relevance (for example, through genome-wide association studies) will help to define the most productive avenues of animal research. Synthesis of current understanding in a physiological context will provide maximum benefit from this research.
The UK’s strength in intensively phenotyped cohorts – large and small – provides opportunities to increase our mechanistic understanding of obesity and its consequences, through:
- embedding mechanistic research and experimental medicine in well-characterised population studies
- integrative physiology in well-defined subsets of existing cohorts, selected to address particular questions – for example, comparison of the extremely obese with and without fatty liver (steatohepatitis)
- identification of critical points in life for the development of obesity and obesity-related diseases – for example, early life, pregnancy, retirement – to allow intelligent targeting of interventions, and interactions between obesity and ageing.
Neuroscience, neuroendocrinology and psychology of obesity
The central role of the nervous system in the generation and maintenance of obesity is becoming increasingly clear, with obesity-related alleles frequently acting through neural substrates. The UK is particularly strong in the neurosciences, with wide coverage from biophysics and basic neurobiology through functional imaging to integrative systems neuroscience and experimental psychology.
Experimental methods and technologies are well developed and overall the field is well placed to be applied to the study of obesity. Despite this, except for a small number of excellent groups, the neuroscience of obesity is an under-studied area. Engaging the neuroscience community will be key to progress in this area – particularly encouraging expert neuroscientists from other fields to contribute to the study of obesity.
There are several methods and technologies include:
- the neurobiological (including neuroendocrine) control of appetite, particularly central nervous system satiety mechanisms and anorectic pathways (in both lean and obese individuals), explanatory genetic and pharmacological studies and the interaction between satiety and reward pathways (including links with addiction)
- the application of expertise in neurophysiology (for example, genetic tagging and manipulation, synaptic plasticity, neural networks) and functional imaging to the hypothalamus, an experimentally tractable but under-studied region central to appetite and energy regulation
- the physiology of peripheral signals (for example, leptin, adiponectin) particularly those emanating from the gut, and communication to and from the central nervous system as a tractable pharmacological target
- understanding behavioural change – if research on diet and lifestyle is to be translated into public health benefits, an understanding of the psychological mechanisms underpinning behavioural change, leading to effective intervention strategies, will be crucial. More broadly, understanding the determinants of food choice and eating behaviours will be central to preventive strategies
- understanding the link between the psychology of eating, mental health and obesity. While many mental illnesses may present with obesity as a side effect (due to medication or behavioural consequences), the fundamental relationship between obesity and mental health is not well defined. Research into both the effect of mental health on the risk of obesity and the effect of obesity and associated metabolic disturbances (and disease) on mental health is needed.
Prevention and intervention: explanatory trials and proof of concept studies for interventions
There is a great need for effective interventions to prevent or treat obesity.
To be of use in a public health context, however, these interventions must be feasible and cost-effective on a large scale as well as in a controlled (and resource-intensive) experimental setting.
It can also be challenging in general to conduct appropriate research for behavioural, psychological and environmental interventions.
Explanatory trials and proof of concept studies represent an important gap in research. Across all these areas, a balance between studies on prevention and on treatment will be required to produce a balanced approach to obesity and its related diseases.
The identification of critical points in the life course for intervention will be important, as will investigation of differences in effectiveness of interventions between different groups (for example, age or cultural groups).
These include:
- identification of (testable) opportunities for intervention from basic and small-scale detailed research (for example, psychological or behavioural manipulations) and translation into proof of concept trials in natural settings
- evaluation of natural experiments and opportunistic policy experiments – particularly when the primary focus is not obesity-related (for example, transport policy)
- explanatory and proof of concept trials of population-based interventions with a focus on how these can be used to influence policy development (and with an awareness of current policy, such as around incentives) and linked to biological mechanisms
- investigation of synergy and conflicts between different intervention strategies.
Experimental approaches
MRC has identified priorities for obesity research in experimental and conceptual approaches.
Physical activity
While it is apparent that physical activity has beneficial effects on health and reduces the negative consequences of excess weight, our understanding of its relationship to obesity – and of its mechanisms, effect size, optimal level and effective implementation for prevention or treatment – is limited. Developments in methodology and the use of cohorts are required to increase progress. Like bariatric surgery, physical activity may be a useful experimental tool with which to examine pathways linking obesity and disease.
Areas of research include:
- mechanistic research – physical activity appears to have a disproportionate effect on health outcomes (particularly insulin resistance and blood pressure) compared to its effect on weight, breaking the link between obesity and disease. As with bariatric surgery, increased understanding of the mechanistic basis of these effects will likely yield significant insights and novel therapeutic targets
- investigation of the determinants and effects of exercise and sedentary behaviour; physiology, genetics and social or environmental factors in regulation of exercise levels and sedentary behaviour
- incorporation of valid and relevant physical activity and sedentary behaviour measurements into large cohorts
- development of effective and efficient interventions to increase physical activity in contemporary populations.
Ethnicity and obesity
Different ethnic groups vary in susceptibility to obesogenic environments and to the adverse consequences of obesity, for both genetic or physiological and cultural or behavioural reasons.
Effective interventions may also depend on the social and cultural context in which they are applied. The study of ethnic differences, and of the impacts of migration on specific population groups, may provide important mechanistic insights into pathways to obesity risk and its adverse consequences. Also, information on the propensities of different ethnic groups to obesity and its adverse consequences will be valuable for clinical decision-making.
Areas of research include:
- ethnic differences and migration patterns provide useful experimental tools for gene-environment interaction studies and for research into cultural influences on obesity
- research should aim to understand the genetic and environmental factors that cause variations in the prevalence and incidence of metabolic disorders and their antecedents in specific populations.
Bariatric surgery as an experimental model
Bariatric surgery is an effective intervention for obesity and its metabolic consequences but its mechanism of action is poorly understood, particularly why positive metabolic effects are observed before (or independently of) weight loss.
This may be a result of the surgery itself or a consequence of the marked caloric restriction that follows. The clinical use of bariatric surgery provides an excellent opportunity to use it as a model to understand the mechanisms of the adverse physiological effects of obesity. The use of bariatric surgery as an experimental tool will provide important insights into gut to brain interactions, linking priorities in mechanistic and neuroendocrine research.
Suggested developments include:
- using bariatric surgery as an experimental tool to understand actions of and synergies between appetite regulation hormones, providing a basis for pharmacological simulation of surgery
- application of human and mouse genetics to bariatric surgery (including identification of responders and non-responders). Related studies, such as caloric restriction in the Ob/Ob mouse, have already generated insights
- establishment of an intensively phenotyped, UK-wide bariatric surgery cohort, integrating clinical and basic science.
Global health
Obesity is a global problem, including low income countries and sub-Saharan Africa but its causes (aside from at the most fundamental level) and consequences vary across countries and regions. There are special challenges driven by the burden of disease in low income countries and metabolic diseases represent one category of emerging non-communicable diseases.
Areas of research include the importance of global health view in obesity research – interventions suitable for developing-world settings need to be developed and tested locally, as context may be important. This provides opportunities for collaborative endeavours between researchers in developed and developing nations.
Method development (including dietary behaviour)
In many areas, obesity research is limited by a need for improved methodology. In particular, accurate, informative but scalable measurement techniques applicable to large studies are required. For example, the assessment of energy expenditure by doubly-labelled water is accurate but too expensive and time-consuming to be applied to large cohorts.
Developments in the following areas would be especially useful:
- measurement of dietary habits (including food intake and eating behaviour)
- measurement of physical activity and sedentary behaviour
- better (statistical) methods for evaluating natural experiments and for designing experiments in natural settings
- models for feeding behaviour.
Given that many of these areas are technically complicated, the best results are likely to come from collaborations between health researchers and researchers in other technical and mathematical sciences such as engineering and statistics.