Fuel-sensing mechanisms integrating lipid and carbohydrate utilization

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 appropria te and co-ordinate fuel utilization. Because its activity can either determ ine or reflect fuel preference (carbohydrate versus fat), the pyruvate dehy drogenase complex (PDC) occupies a pivotal position in fuel cross-talk. Act ive PDC permits glucose oxidation and allows the mitochondrially derived in ter-mediates (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 effecters. 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 sign alling through citrate formation. Substrate interactions at the level of ge ne transcription extend glucose-FA interactions to the longer term. We disc uss potential targets for substrate-mediated transcriptional regulation in relation to selective PDK isoform expression and the influence of altered P DK isoform expression in fuel sensing, selection and utilization.