A Recurring Problem With the Analysis of Energy Expenditure in Genetic Models Expressing Lean and Obese Phenotypes

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Defining the molecular mechanisms linking obesity with insulin resistance is important for developing new therapies against the rising incidence of type 2 diabetes in industrialized nations. Maintaining a balance between calorie intake and energy expenditure is critical for preventing insulin resistance, the precursor for type 2 diabetes (1). Mouse genetics has made enormous contributions to theoretical models explaining how organisms balance energy intake and energy expenditure. A seminal event was the positional cloning of the obese gene (now called the Leptin gene) by Friedman and colleagues in the early 1990s (2). Leptin deficiency causes severe obesity in mice and humans (3), and leptin was proposed to regulate energy homeostasis by suppressing appetite and increasing energy expenditure (4). However, it has clearly been forgotten that the interpretation of energy expenditure data from mice homozygous for the Lepob mutation was challenged shortly after the initial publication (5). Increasingly sophisticated technologies for manipulating the mouse genome are now used routinely to analyze new genes linked to energy homeostasis, resulting in many new mouse models with obese or lean phenotypes. Altered energy expenditure is frequently cited as the primary mechanism underlying the obese or lean phenotype. However, in many cases the same issues with interpretation of energy expenditure data are evident. Here, we discuss what has developed into a recurring problem in the literature with the analysis of energy balance. Specifically, we shall discuss the practice of using body weight as a denominator in analyzing energy balance to overestimate the role of energy expenditure. The growing number of individuals with chronic metabolic diseases like type 2 diabetes provides a powerful incentive for investigating mechanisms linking obesity with insulin resistance. That a balance between food intake and energy expenditure (thermogenesis) is maintained through homeostatic mechanisms is a central tenet of obesity research. A major …