The global obesity epidemic has stimulated in-tense interest in the study of homeostatic mech-anisms governing the balance between energy intake and energy expenditure over time, and recent progress in gene targeting and related technologies has pushed mouse models to the forefront of this effort. Although current methods for the measurement of energy expenditure (EE) in mice are sensitive, reproducible, and widely available, their potential to inform the study of obesity remains limited by controversy regarding how best to control for the powerful, independent impact on EE of variation in body size per se (1, 2). In this article, we briefly review the recent work that has fueled this controversy and propose an approach to its resolution. We also highlight aspects of EE measurement relevant to obesity pathogenesis that merit additional study. Although we focus on studies in mice, the principles presented can be applied to most other animal models. Dramatic increases in the prevalence of obesity and its burden of health and economic consequences heighten the need for new insights into mechanisms that govern energy balance. At a superficial level, the problem of obesity resolves to simple math: energy balance, defined as the difference between rates of EE and energy intake (EI), sums over time to determine body energy content stored as fat mass (FM). Hence, obesity can be seen as the consequence of a sustained increase of energy intake relative to energy expenditure. This simplistic thermodynamic explanation, however, belies a far more complex pathophysiology that is crucial for understanding why weight loss is so difficult to achieve and sustain in obese individuals. At the core of this complexity is a biological process termed energy homeostasis, through which energy intake and expenditure are matched over long time intervals to promote the stability of FM. This process is influenced by interactions between genes and environment that affect innumerable physiological and biochemical processes that dictate energy flow and partitioning, and recent progress in understanding these processes is beginning to shed light on the pathogenesis of both common (3, 4) and rare forms of obesity (5). Although research has for many years focused on EI as the predominant determinant of obesity risk, emphasis is increasingly being placed on the EE side of the energy balance equation.

To judge the impact of a change of EE on obesity phenotypes, a usual starting point is to compare EE between lean and obese groups. Unlike food intake studies, however, EE measures are typically made over only relatively short time intervals (ranging from a few hours to 2 or 3 days) and hence offer only a snapshot of any differences in EE that might be present. Making matters worse, body size itself is a crucial but complex determinant of EE. Larger animals typically have higher absolute rates of EE owing to an increase in the total amount of metabolically active mass, whereas smaller animals typically have higher per-kg rates of EE (6), in part because their larger body surface area (BSA) relative to volume increases heat loss and thus requires greater heat production to maintain body temperature homeostasis. Consequently, EE data must be adjusted for the influence of body size variation per se to assess whether a change of EE contributed to weight changes in a given experimental model. A traditional (and recurring) remedy for this problem is to divide individual measures of EE by either total body mass (TBM) or lean body mass (LBM)(or fat free mass [FFM]) to yield measures of EE that can be compared between groups. Although these strategies might intuitively be …