Regulation of metabolic transcriptional co‐activators and transcription factors with acute exercise

Abstract

SPECIFIC AIMS Transcription factors and their target genes, especially those involved with PPAR families, can be regulated directly via increases in free fatty acids (FA). As physical exercise stimulates lipolysis and increases circulatory FFA levels, the effect of exercise per se on the induction of metabolic transcription factors can be biased by elevated FFA levels. To better understand the pathways involved in eliciting the adaptive response to exercise, the aim of the present study was to investigate the effect of acute endurance exercise on the regulation of the mRNA of several key metabolic transcriptional coactivators, including PGC-1α and PRC, transcription factors PPARα, β/δ, and γ, RXR, SREBP-1c and FKHR, and to delineate the effect of exercise from the effect of elevated levels of circulating FFA. To this end, exercise was performed once in the fasted state and once in the glucose fed state. PRINCIPAL FINDINGS 1. The effect of FFA levels on the regulation of transcription factors Under resting pre-exercise conditions with similar blood glucose and FFA levels, there was no difference in expression of the transcription factors measured between trials. Plasma free fatty acid concentration increased during exercise in the fasted state, a response that was significantly blunted in the glucose ingestion trial at all time points (PP=0.002). By 4 h postexercise PGC-1α, was lower than at 1 h postexercise (P=0.01) and had almost returned to basal levels (P=0.065). PRC mRNA was increased significantly immediately postexercise and remained significantly elevated 4 h postexercise (P=0.01) (Fig. 1 ⤻ ). These results suggest that PGC-1α and PRC are regulated via signals inherent to the contracting skeletal muscle. Figure 1. Gene expression of metabolic transcription factors measured pre- and postexercise when performed in the fasted state (black bars) or with glucose ingestion (white bars). A) PGC-1α; **Pst and 1 h are significantly different from pre-exercise (PPB) PRC; **Pst, 1 and 4 h are significantly different from pre-exercise levels (PC) PPARβ/δ; **4 h is significantly different from pre-exercise levels (PD) FKHR; **4 h is significantly different from the other time points (PPE) MCIP1; *1 h is significantly different from all time points levels (PP=0.31), PPARγ mRNA(P=0.06) or RXR mRNA (P=0.7). In contrast, PPARβ/δ mRNA was increased by 2-fold 4 h postexercise (P=0.019), suggesting it is regulated via factors (other than circulating FFAs) associated with the contracting skeletal muscle (Fig. 1)⤻ . 4. SREBP-1c and FKHR SREBP-1c plays a crucial role in regulating genes involved in directing fatty acids toward storage and has been suggested to up-regulate fatty acid synthase (FAS), acetyl-CoA carboxylase-1 (ACC-1), and stearoyl-CoA desaturase-1 (SCD-1). FKHR has been suggested to influence glucose oxidation by regulating glucose –6-phosphatase, pyruvate dehydrogenase-4 (PDK4), and lipoprotein lipase gene expression. SREBP-1c mRNA did not change at any time point (P>0.05) whereas FKHR mRNA increased by 1.5- and 2-fold 1 and 4 h postexercise, respectively (P1) regulated by signals inherent to the contracting skeletal muscles; 2) regulated by factors, not inherent, but associated with muscle contraction; and 3) regulated independent of circulatory FFA levels, even if in the milimolar range. Our results suggest that induction of mRNA of the transcriptional...