Fuel-sensing mechanisms integrating lipid and carbohydrate utilization

Abstract

Fuel metabolism is highly regulated to ensure adequate energy for cellular function. The contribution of the major metabolic fuels - glucose, lactate and fatty acids (FAs) - often reflects their circulating levels. In addition, regulatory crosstalk and fuel-induced hormone secretion ensures appropriate and co-ordinate fuel utilization. Because its activity can either determine or reflect fuel preference (carbohydrate versus fat), the pyruvate dehydrogenase complex (PDC) occupies a pivotal position in fuel cross-talk. Active PDC permits glucose oxidation and allows the formation of mitochondrially derived intermediates (e.g. malonyl-CoA and citrate) that reflect fuel abundance. FA oxidation suppresses PDC activity. PDC inactivation by phosphorylation is catalysed by pyruvate dehydrogenase kinases (PDKs) 1–4, which are regulated differentially by metabolite effectors. Most tissues contain at least two and often three of the PDK isoforms. We develop the hypothesis that PDK4 is a ‘lipid status’-responsive PDK isoform facilitating FA oxidation and signalling through citrate formation. Substrate interactions at the level of gene transcription extend glucose-FA interactions to the longer term. We discuss potential targets for substrate-mediated transcriptional regulation in relation to selective PDK isoform expression and the influence of altered PDK isoform expression in fuel sensing, selection and utilization.