Animal life depends on the capacity to match metabolic fuel supply to changing rates of energy use. The fluxes of multiple substrates must be modulated to achieve real-time selection of mixtures able to support adequate metabolic rates for variable physiological circumstances: from years of torpor to seconds of sprinting. The regulation of energy metabolism is a complex challenge because the fuels available vary widely in stored quantity, energy density, speed of conversion to ATP and water solubility. Therefore, fuel selection strategies aim to exploit the advantages of individual substrates while minimizing the impact of their disadvantages. The rate of energy expenditure necessary for a particular task determines for how long that task can be maintained. Fig.1A illustrates the relationship between metabolic intensity and duration by plotting record times of human athletes running over different distances vs average speed. This example is used to characterize the shape of the more general relationship between metabolic rate and duration. Fig.1B-E compares lipids and carbohydrates for the main parameters determining whether these fuels tend to support prolonged low-intensity tasks or intense activities of short duration.Lipids show unique characteristics that make them ideally suited for long-lasting physiological work because they contain the most energy per unit mass (Fig.1B) and, therefore, are stored in large amounts (Fig.1C). Lipids pack more joules per gram because they can be stored dehydrated and, to a lesser extent, because they are more chemically reduced than other fuels. Their highly reduced state also allows them to yield more metabolic water than proteins or carbohydrates when they are oxidized. Therefore, organismal dehydration can be avoided by producing metabolic water through the oxidation of lipid stores: a strategy commonly used by birds lacking access to drinking water during long migrations (Carmi et al., 1992;Klaassen, 1996). The low maximal rate of ATP production from lipids ( Fig.1E) is not a limiting factor for prolonged, low-to moderate-intensity tasks. Similarly, the low solubility of lipids in water (Fig.1D) would severely restrict the capacity to transport them from storage sites, but this serious handicap is greatly reduced by the solubilizing action of albumin in the plasma (van der Vusse, 2009) and fatty acid binding proteins (FABPs) in the cytosol (Haunerland and Spener, 2004). These specialized transport proteins ensure that lipids can be shuttled between tissues, at least rapidly enough to support low-to moderate-intensity tasks. This requirement for transport proteins may be partly responsible for limiting maximal rates of lipid oxidation.In contrast to lipids, carbohydrates show high maximal rates of ATP production, especially under anaerobic conditions (Fig.1E), and high solubility in water (Fig.1D). These fundamental characteristics make them essential for intense physiological work. For most animals, carbohydrates also provide the benefit of being the only usable...