Loss of the
transcription factor E2F1 elicits a complex metabolic phenotype in mice underscored by reduced adiposity and protection from high fat diet-induced diabetes. Here, we demonstrate that E2F1 directly regulates the gene encoding PDK4 (
pyruvate dehydrogenase kinase 4), a key nutrient sensor and modulator of
glucose homeostasis that is chronically elevated in
obesity and diabetes and acutely induced under the metabolic stress of
starvation or fasting. We show that loss of E2F1 in vivo blunts PDK4 expression and improves myocardial
glucose oxidation. The absence of E2F1 also corresponds to lower
blood glucose levels, improved plasma
lipid profile, and increased sensitivity to
insulin stimulation. Consistently, enforced E2F1 expression up-regulates PDK4 levels and suppresses
glucose oxidation in C(2)C(12) myoblasts. Furthermore, inactivation of Rb, the repressor of E2F-dependent transcription, markedly induces PDK4 and triggers the enrichment of E2F1 occupancy onto the PDK4 promoter as detected by
chromatin immunoprecipitation analysis. Two overlapping E2F binding sites were identified on this promoter. Transactivation assays later verified E2F1 responsiveness of this promoter
element in C(2)C(12) myoblasts and IMR90 fibroblasts, an effect that was completely abrogated following mutation of the E2F sites. Taken together, our data illustrate how the E2F1
mitogen directly regulates PDK4 levels and influences cellular bioenergetics, namely mitochondrial
glucose oxidation. These results are relevant to the pathophysiology of
chronic diseases like
obesity and diabetes, where PDK4 is dysregulated and could have implications pertinent to the etiology of
tumor metabolism, especially in
cancers with Rb pathway defects.