A recurring problem with the analysis of energy expenditure in genetic models expressing lean and obese phenotypes

AA Butler, LP Kozak - Diabetes, 2010 - Am Diabetes Assoc
AA Butler, LP Kozak
Diabetes, 2010Am Diabetes Assoc
Defining the molecular mechanisms linking obe-sity 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 …
Defining the molecular mechanisms linking obe-sity 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 goal is to discover mechanisms to avoid a positive energy balance, a pathway to weight gain, increased susceptibility to insulin resistance, and diseases of the metabolic syndrome (6, 7).
There has been significant progress in understanding how organisms regulate caloric intake and adiposity. Identification of factors secreted from peripheral organs, including leptin and adiponectin from adipocytes, insulin from the pancreas, ghrelin from the stomach, and fibroblast-growth factor-21 from the liver and examining how they regulate adiposity and insulin sensitivity has been essential for the evolving concepts of energy homeostasis (8–10). These factors have been found to interact with networks of specific neurons in the hypothalamus and brain stem, modulating behaviors relevant to energy homeostasis including satiety, reward, and motivation (11–13). Through regulating autonomic and neuroendocrine output, and by acting directly on peripheral tissues, these factors can regulate glucose and lipid homeostasis. Importantly, aberrant regulation and action of these molecules has been linked to the development of insulin resistance and diabetes in the obese state. These findings have given hope that therapies designed to restore or replace the normal function of these peptides will provide effective treatment for obesity and the associated metabolic disorders.
Am Diabetes Assoc