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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 were identified as 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.

Priorities for MRC obesity research Mechanisms of obesity and associated disease Neuroscience of obesity Prevention and intervention: obesity and links to disease Physical activity Ethnicity and obesity Bariatric surgery as a research tool Global health Method development (including dietary behaviour)