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 (eg genome-wide association studies; 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.
The following specific areas are particular priorities:
- Extreme phenotypes – identification of highly penetrant phenotypes (eg 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 (eg 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 (eg 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.
- 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 (eg 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 (eg leptin, adiponectin), particularly those emanating from the gut, and communication to and from the central nervous system as a tractable pharmacological target (see also bariatric surgery). This area could link well to clinical studies.
- 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 (eg age or cultural groups).
- Identification of (testable) opportunities for intervention from basic and small scale detailed research (eg psychological/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 (eg transport policy) - see discussion of methodology.
- 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.