Metabolic energy expenditure negatively regulates energy balance. Metabolic and catabolic pathways contribute to energy expenditure. Catabolic pathways split C-containing molecules into small molecules and generate reduced coenzymes and ATP. For a given amount of substrate, any increase in energy expenditure requires either increased ATP hydrolysis or decreased ATP synthesis. In skeletal muscles substrate utilisation is coupled to ATP production, whereas ATP hydrolysis is activated during physical exercise and increases energy expenditure. In brown adipose tissue activation of cells during exposure to cold increases substrate utilisation in such a way that glucose and fatty acid oxidation detach from the orthodox coupling to ATP synthesis and result in thermogenesis. The unique mechanism of uncoupling respiration that occurs in brown adipocyte mitochondria represents an attractive strategy for promoting energy expenditure and decreasing the fat content of the body. Moreover, ectopic expression of brown fat uncoupling protein (UCP) 1 in mouse skeletal muscle and induction of UCP1 in mouse or human white adipocytes promote fatty acid oxidation and resistance to obesity. In normal conditions UCP2 and UCP3 do not seem to contribute substantially to energy expenditure. Whether the induction of UCP1, the induction of other UCP or chemical mild uncoupling represent promising strategies for attenuating nutrient efficiency and counteracting obesity should be considered.