The cloning of murine and human obese genes in 1994, and the subsequent identification that the product of the obese gene, leptin, is secreted from adipose tissue, stimulated a tremendous amount of interdisciplinary interest in adipose tissue endocrinology and the potential role of this tissue in the regulation of energy balance. Exercise, with concomitant changes in fuel flux, systemic hormone levels and energy expenditure, may contribute to the regulation of plasma leptin levels and presumably, leptin action. The initial work characterising the leptin-exercise relationship was equivocal. Cross-sectional studies provided some mixed evidence regarding the relationship between aerobic capacity or habitual physical activity and plasma leptin. In contrast, studies on acute bouts of exercise and exercise training interventions have, with few exceptions, suggested that exercise does not alter systemic leptin independent of changes in fat mass. In general, these studies did not carefully control for energy balance, and sampled only a single fasting plasma leptin level. Two recent studies utilising experimental designs in which energy balance was controlled and 24-hour profiles of plasma leptin were determined have provided the most compelling evidence to date of the interaction between exercise, energy balance and systemic leptin in humans. These studies provide a clear explanation for the apparent lack of an acute effect of exercise on systemic leptin and underscore the importance of clearly defining the balance between energy intake and energy expenditure when studying the physiology of leptin. The aim of this brief review is to provide an overview of the interaction between energy expenditure during physical activity and systemic leptin level. Special emphasis will be placed on those studies in which energy intake/balance was carefully controlled.

The increasing prevalence of overweight and obesity worldwide is daunting and requires prompt attention by the affected, health care profession, government and the pharmaceutical industry. Because overweight/obesity are defined as an excess of adipose tissue mass, all approaches in prevention and treatment must consider redirecting lipid storage in adipose tissue to oxidative metabolism. Lipid partitioning is a complex process that involves interaction between fat and other macronutrients, particularly carbohydrate. In an isocaloric environment, when fat is stored carbohydrate is oxidized and vice versa. Processes that influence fat partitioning in a manner in which weight is maintained must be modified by changes in organ-specific fat transport and metabolism. When therapy is considered, however, changes in lipid partitioning alone will be ineffective unless a negative energy balance is also achieved, i.e. energy expenditure exceeds energy intake. The intent of this review is to focus on molecules including hormones, enzymes, cytokines, membrane transport proteins, and transcription factors directly involved in fat trafficking and partitioning that could be potential drug targets. Some examples of favorably altering body composition by systemic and/or tissue specific modification of these molecules have already been provided with gene knockout and/or transgenic approaches in mice. The translation of this science to humans remains a challenging task.

This cross-sectional investigation sought to determine the relationship between selected metabolic, endocrine, and anthropometric factors and skeletal muscle UCP3 mRNA in healthy adult humans. Twenty-four healthy adults (13 male and 11 female) across a range of aerobic capacity, age, and body composition were studied. Muscle biopsies were obtained from the vastus lateralis, from which UCP3 mRNA was quantified by Northern blot, and fiber type was determined by use of the myosin ATPase staining procedure. In addition, resting energy expenditure and maximum rate of oxygen consumption were determined by indirect calorimetry, body composition was determined by dual-energy X-ray absorptiometry, and fasting plasma leptin and insulin were determined by ELISA. UCP3 mRNA was correlated positively with the percent type I fibers (r ϭ 0.842, P Ͻ 0.001), plasma leptin (r ϭ 0.454, P ϭ 0.026), and plasma insulin (r ϭ 0.615, P Ͻ 0.001) and inversely to age (r ϭ Ϫ0.411, P ϭ 0.046). Stepwise multiple regression analysis determined that percent type I muscle fibers was the best predictor of vastus lateralis UCP3 mRNA, and no other variable entered the equation (model r 2 ϭ 0.66). This study suggests that of the variables measured, UCP3 mRNA is primarily related to skeletal muscle fiber type in healthy adults. The factors that contribute to fiber-specific differences in UCP3 mRNA expression will need to be examined in future studies. uncoupling proteins; leptin; metabolic rate THE FACTOR(S) THAT CONTRIBUTE to the interindividual variability in resting metabolic rate have been the subject of intense research interest (38,44,54). The recent cloning of novel uncoupling protein isoforms (UCP2 and UCP3) has stimulated interest in potential molecular mediators of the variability in metabolic rate and susceptibility to obesity (8,13,15). The canonical UCP isoform (UCP1) is well accepted to act as an uncoupler of electron transport and oxidative phosphorylation in brown adipose tissue (BAT), resulting in the regulated production of heat (11,25). In contrast, there is considerable debate about whether the novel UCPs are truly uncouplers in vivo, and the specific physiological role of UCP2 and UCP3 in skeletal muscle remains to be elucidated (33). There is evidence indicating that UCP2 and UCP3 function similarly to UCP1 in dissipating the proton gradient of the inner mitochondrial membrane during oxidative respiration (8,13,15,17). It is intuitive then to investigate the relationship between the expression of these novel proteins and other variables known to be associated with metabolism.Studies aimed at understanding the regulation of UCP3 gene expression have demonstrated tissue-specific responses to perturbations designed or "hypothesized" to alter UCP3 gene regulation. The expression and regulation of UCP3 in skeletal muscle are of considerable interest because of the large mass of this organ and its well-documented contribution to both basal metabolism (40) and basal proton leak (39). UCP2 is speculated to function similarly to UCP3; ho...

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