Quercetin and Quercetin-Rich Red Onion Extract Alter Pgc-1α Promoter Methylation and Splice Variant Expression

Pgc-1 alpha and its various isoforms may play a role in determining skeletal muscle mitochondrial adaptations in response to diet. 8wks of dietary supplementation with the flavonoid quercetin (Q) or red onion extract (ROE) in a high fat diet (HFD) ameliorates HFD-induced obesity and insulin resistance in C57BL/J mice while upregulating Pgc-1 alpha and increasing skeletal muscle mitochondrial number and function. Here, mice were fed a low fat (LF), high fat (HF), high fat plus quercetin (HF + RQ), or high fat plus red onion extract (HF + RO) diet for 9wks and skeletal muscle Pgc-1 alpha isoform expression and DNA methylation were determined. Quantification of various Pgc-1 alpha. isoforms, including isoforms Pgc-1 alpha-a, Pgc-1 alpha-b, Pgc-1 alpha-c, Pgc-1 alpha 4, total NT-Pgc-1 alpha, and FL-Pgc1 alpha, showed that only total NT-Pgc-1 alpha expression was increased in LF, HF + Q, and HF + RO compared to HF. Furthermore, Q supplementation decreased Pgc-1 alpha-a expression compared to LF and HF, and ROE decreased Pgc-1 alpha-a expression compared to LF. FL-Pgc-1 alpha was decreased in HF + Q and HF + RO compared to LF and HF. HF exhibited hypermethylation at the -260 nucleotide (nt) in the Pgc-1 alpha promoter. Q and ROE prevented HFD-induced hypermethylation. -260 ntmethylation levelswere associated with NT-Pgc-1 alpha expression only. Pgc-1 alpha isoform expression may be epigenetically regulated by Q and ROE through DNA methylation.