The peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) enhances oxidative metabolism in skeletal muscle. Excessive lipid oxidation and electron transport chain activity can, however, lead to the accumulation of harmful metabolites and impair glucose homeostasis. Here, we investigated the effect of over-expression of PGC-1 alpha on metabolic control and generation of insulin desensitizing agents in extensor digitorum longus (EDL), a muscle that exhibits low levels of PGC-1 alpha in the untrained state and minimally relies on oxidative metabolism. We demonstrate that PGC-1 alpha induces a strictly balanced substrate oxidation in EDL by concomitantly promoting the transcription of activators and inhibitors of lipid oxidation. Moreover, we show that PGC-1 alpha enhances the potential to uncouple oxidative phosphorylation. Thereby, PGC-1 alpha boosts elevated, yet tightly regulated oxidative metabolism devoid of side products that are detrimental for glucose homeostasis. Accordingly, PI3K activity, an early phase marker for insulin resistance, is preserved in EDL muscle. Our findings suggest that PGC-1 alpha coordinately coactivates the simultaneous transcription of gene clusters implicated in the positive and negative regulation of oxidative metabolism and thereby increases metabolic flexibility. Thus, in mice fed a normal chow diet, overexpression of PGC-1 alpha does not alter insulin sensitivity and the metabolic adaptations elicited by PGC-1 alpha mimic the beneficial effects of endurance training on muscle metabolism in this context. (C) 2011 Elsevier Inc. All rights reserved.