Over the last 5 decades there has been an explosion in the rates of obesity throughout the world. In the USA for example the obese population (defined as those with a body mass index of > 30) expanded from <5% in 1960 to over 25% in 2004. The centre for disease control in the USA in 2010 announced that 33.8% of American adults were obese based on the national health and examination survey (NHANES) and that no state in the US had an obesity rate lower than 20%. Although obesity rates are lower in China it was estimated that already by 2007, 9% of the adult population was obese. Obesity is a major health problem because it increases the risk for a number of chronic illnesses. Perhaps the most significant of these is type 2 diabetes. The healthcare costs of diabetes already amount to between 2 and 6% of total healthcare spending in most westernised societies. Matched with the increased risk of type 2 diabetes is an elevation of insulin resistance and increased risk for cardiovascular disease, fatty liver disease, and cancer.
Obesity is caused by an imbalance between the number of calories consumed and the number that are expended. The global obesity epidemic has placed a large premium on increasing our understanding of the regulation of energy balance and how this may be dysregulated in obesity. The mouse has been a key tool in this research field. For example during the 1990s the key hormone leptin was discovered by characterisation of the genetic mutation that causes the ob/ob mouse, and the leptin receptor was similarly discovered from characterisation of the mutation that causes the db/db mouse. Subsequent expansion of our understanding of energy balance regulation has hinged on the mouse as a primary research model, principally because the widespread availability of genetic tools to manipulate the mouse genome to generate mice with transgenic over-expression or knock-out of specific genes.
In recent years, however, the field has become confused because of different approaches adopted by different groups for how to analyse the level of energy expenditure in different mouse models. The principal research tool for making such measurements is indirect calorimetry. This works by measuring the gas exchange of mice when housed in a sealed chamber through which a controlled gas stream is passed. The consumption of oxygen and the production of carbon dioxide by the mouse can then be used to characterise the metabolic substrates it is using and the total amount of energy it is burning. One might imagine then that comparing between two groups of mice – one with a specific genetic manipulation, and the other without, would be a relatively straightforward affair. The problem, however, is that the genetic manipulations that cause differences in energy expenditure generally also cause differences in body size. So the problem becomes to what extent is the difference in energy expenditure due to the genetic manipulation, and to what extent is it a secondary consequence of the genetic manipulation on body weight. Resolving this problem is not quite as straight-forward and there have been several different approaches tried out by different groups that have varying levels of success.
Perhaps the easiest approach is to express the energy expenditure per gram of body weight. While this is the simplest approach it is also the one most likely to generate an artefactual result because the approach assumes that the relationship between energy expenditure and body weight passes through the origin – when generally it does not. Various other approaches have been tried and they each have their advantages and disadvantages, but most confusingly they produce different answers to the key question. Now a team of scientists from 19 different research labs across the world have come together to agree a consolidated view of not only how to perform these complex analyses but also to consider exactly how experimental work in the entire field of mouse energetics in relation to obesity work should best be conducted.
This consensus perspective with John Speakman as co-first author has been published this month in Nature methods (Tschoep et al (2012) A guide to analysis of mouse energy metabolism. Nature methods 9: 57-63).
AUTHOR CONTACT:
John R. Speakman, Ph.D.
Email: J.speakman@genetics.ac.cn
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
