Coordinated balancing of muscle oxidative metabolism through PGC-1α increases metabolic flexibility and preserves insulin sensitivity

Abstract

Coordinated balancing of muscle oxidative metabolism through PGC-1α increases metabolic flexibility and preserves insulin sensitivity. Biochemical and biophysical research communications, Vol. 408, H. 1. S. 180-185.-1 - AbstractThe peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) 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-1α on metabolic control and generation of insulin desensitizing agents in extensor digitorum longus (EDL), a muscle that exhibits low levels of PGC-1α in the untrained state and minimally relies on oxidative metabolism. We demonstrate that PGC-1α 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-1α enhances the potential to uncouple oxidative phosphorylation. Thereby, PGC-1α 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-1α 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, over-expression of PGC-1α does not alter insulin sensitivity and the metabolic adaptations elicited by PGC-1α mimic the beneficial effects of endurance training on muscle metabolism in this context.

PGC-1α and exercise in the control of body weight

“…It coordinately increases the expression of key regulators of lipid oxidation (MCAD; Medium Chain Acyl CoA Dehydrogenase, CPT1b; Carnitine palmitoyltransferase), Krebs cycle (citrate synthase) and oxidative phosphorylation (subunits of complexes I to IV). 40 However, a careful regulation of this process is important as excessive or dysbalanced oxidative metabolism impairs insulin sensitivity. Acylcarnitines are generated when the amount of lipids fluxed into b-oxidation exceeds the capacity of the Krebs cycle and/or oxidative phosphorylation.…”

“…The levels of inhibitors of lipid oxidation (ACC2), antagonists of ROS generation (UCP3; Uncoupling Protein and ANT; Adenine Nucleotide Translocator), and ROS-detoxifying enzymes are all elevated by PGC-1a. 40,45 Whereas the overall gene expression pattern is ambiguous, the net rates are nonetheless clearly showing an increased oxidation of fatty acids and an elevated mitochondrial membrane potential. 40 Therefore, the increased b-oxidation and the subsequent Krebs cycle and oxidative phosphorylation are tightly regulated and balanced by PGC-1a.…”

“…40,45 Whereas the overall gene expression pattern is ambiguous, the net rates are nonetheless clearly showing an increased oxidation of fatty acids and an elevated mitochondrial membrane potential. 40 Therefore, the increased b-oxidation and the subsequent Krebs cycle and oxidative phosphorylation are tightly regulated and balanced by PGC-1a. The concomitant induction of both positive and negative regulators of fatty acid oxidation and oxidative phosphorylation through PGC-1a boosts metabolic flexibility and restrains excessive oxidation.…”

“…The concomitant induction of both positive and negative regulators of fatty acid oxidation and oxidative phosphorylation through PGC-1a boosts metabolic flexibility and restrains excessive oxidation. 40 In addition, PGC-1a drives glucose uptake and determines fuel selection. 46 Glucose is diverted away from glycolysis and oxidation by inhibiting the activity of the pyruvate dehydrogenase complex through PDK4 (pyruvate dehydrogenase kinase 4).…”

“…36,37 Inversely, transgenic mice with elevated muscle PGC-1a levels do not display improved whole body glucose homeostasis in the sedentary state, and even develop peripheral insulin resistance on a high-fat-containing diet, possibly due to increased lipid accumulation in skeletal muscle. 40,49,57 Exercise is the real thing: PGC-1a-a partial exercise mimetic, not a substitute Exercise induces a complex pleiotropic response in skeletal muscle. Even one single bout of endurance exercise comprises changes in the expression of more than 900 genes.…”