Obesity has reached epidemic proportions, and complications related to obesity contribute substantially to health care costs and mortality. Since the accumulation of fat is the net result of a prolonged state of imbalance between energy intake and energy expenditure, one would think that an ideal fat mass in obese persons could be achieved relatively simply by either decreasing food intake or increasing energy expenditure, ultimately causing a sustained negative energy balance. Unfortunately, this is not so easy to achieve, because evolutionary pressure has rewarded those individuals and species able to store sufficient energy to survive famines; also, the unrestricted availability of food represents an unnatural condition. 1 Currently, most interventions, whether behavioral or pharmacologic, are aimed at the energyintake side of the equation and result in only moderate, often temporary improvements, with the notable exception of bariatric surgery.

Interventions designed to increase energy expenditure are relatively limited. An increase in physical activity, although effective, is not easy to sustain. The pharmacologic approach has also been disappointing. Supraphysiologic doses of thyroid hormones or adrenergic agonists result in an increase in energy expenditure, but their systemic adverse events preclude their use for the treatment of obesity.