The presence of substrate cycles in tissues has been demonstrated by direct isotope methods in recent years. This demonstration has provided the impetus for a reappraisal of the roles of substrate cycling in metabolic regulation and in heat production. These aspects of substrate cycling are discussed in this paper. The relationship between near-equilibrium reactions and substrate cycles is emphasized, since this provides a basis for the derivation of a function describing in precise quantitative terms the factors governing the amplification provided by substrate cycles in metabolic regulation. Some examples of the roles of substrate cycles in providing sensitivity in metabolic regulation are described. The importance of substrate cycling in heat generation in the flight muscle of the bumble-bee and in brown adipose tissue is discussed in detail. 2. We point out that the two possible roles of cycling, heat production and amplification, are intimately linked so that they must be discussed together. It is proposed that variable rates of substrate cycling may be possible so that, for short periods of time. sensitivity can be maximal without excessive heat generation. Variable rates over the long term may be involved in weight control, and the control of such variability in cycling rates may be impaired in obese subjects. Finally, the possibilities that substrate cycles provide explanations for the specific dynamic action of food and for alcoholic and accidental hypothermia are raised.
