We are facing a revival of the strategy to counteract obesity and associated metabolic disorders by inducing thermogenesis mediated by mitochondrial uncoupling protein-1 (UCP1). Thus, the main focus is on the adaptive non-shivering thermogenesis occurring both in adipocytes contained in the typical depots of brown adipose tissue (BAT) and in UCP1-containing cells that could be induced in white adipose tissue (WAT) and could represent a separate cell lineage. A possibility to reduce adiposity based on the induction of energy expenditure in classical white adipocytes is largely neglected. Nevertheless, the contribution of WAT to resting metabolic rate in lean human subjects is close to 5% and it doubles in obesity (1), while in adult mice reared at 20oC, the total oxidative capacity of WAT represents ~30-50% of BAT oxidative capacity (2). Data will be presented, which support a notion that induction of energy expenditure in WAT may influence total energy balance and reduce obesity: (i) studies in both humans and rodents document negative associations between oxidative capacity of mitochondria in WAT and obesity; (ii) pharmacological activation of AMPK in rats (3) as well as cold-acclimation of the UCP1-ablated mice (4) confers obesity resistance, which is associated with the increased oxidative capacity in WAT; and (iii) combined intervention using long-chain n-3 polyunsaturated FA (omega 3) and mild calorie restriction exerted synergism in the prevention of obesity in mice fed HF diet (5), which was associated with a strong prevention of low-grade obesity-associated inflammation of WAT, hypolipidemic and insulin-sensitizing effects, and synergistic induction of mitochondrial oxidative phosphorylation (OXPHOS) in epididymal WAT, an effect that could not be detected either in other fat depots including interscapular BAT or in non-adipose tissues. These changes in WAT metabolism occurred in the absence of UCP1 induction and resulted in a significant stimulation of palmitate oxidation measured ex vivo in both tissue fragments and adipocytes liberated from epididymal WAT of mice subjected to the combined intervention. Whole-body effects could not be explained by changes either in food intake or physical activity (5). Results document the involvement of a futile substrate cycle (6) in white adipocytes, which is based on lipolysis and re-esterification of free fatty acids and it is associated with the induction of mitochondrial OXPHOS capacity, β-oxidation, and energy expenditure in WAT. Quantitatively, the degree of induction of lipid catabolism in WAT in response to the combined intervention is similar to that observed in the transgenic mice rendered resistant to obesity by ectopic expression of UCP1 in WAT (7). Thus, the induction of UCP1-independent energy expenditure in WAT in response to a combination of the two physiological stimuli could be involved in the induction of obesity resistant phenotype. New combination treatments for obesity may be designed using naturally occurring micronutrients like omega 3 or plant polyphenols, reduced calorie intake, and pharmacological compounds, which are based on the induction of UCP1-independent energy expenditure in adipocytes.