Although much research has been conducted regarding UCP2 and UCP3, their physiologic roles are yet to be determined. The emerging picture is that accurate physiologic information can most confidently be obtained when mitochondrial uncoupling is assessed in vivo within the physiologic range of UCP regulation. Furthermore, it will be important to study humans to define the metabolic role of UCP in humans. This particularly applies in the area of energy expenditure, because adult humans do not have brown fat, and heat production per kilogram of body weight is much lower than in rodents. This lesson was learned in the case of leptin, which exerts major effects on energy expenditure in rodents but no apparent affect on resting energy expenditure in humans. Thus, scientific efforts to define the physiologic role of UCPs remain challenging and exciting.