Transcriptional coactivator NT-PGC-1 promotes gluconeogenic gene expression and enhances hepatic gluconeogenesis

The transcriptional coactivator PGC-1 plays a central role in hepatic gluconeogenesis. We previously reported that alternative splicing of the PGC-1 gene produces an additional transcript encoding the truncated protein NT-PGC-1. NT-PGC-1 is co-expressed with PGC-1 and highly induced by fasting in the liver. NT-PGC-1 regulates tissue-specific metabolism, but its role in the liver has not been investigated. Thus, the objective of this study was to determine the role of hepatic NT-PGC-1 in the regulation of gluconeogenesis. Adenovirus-mediated expression of NT-PGC-1 in primary hepatocytes strongly stimulated the expression of key gluconeogenic enzyme genes (PEPCK and G6Pase), leading to increased glucose production. To further understand NT-PGC-1 function in hepatic gluconeogenesis invivo, we took advantage of a previously reported FL-PGC-1(-/-) mouse line that lacks full-length PGC-1 (FL-PGC-1) but retains a slightly shorter and functionally equivalent form of NT-PGC-1 (NT-PGC-1(254)). In FL-PGC-1(-/-) mice, NT-PGC-1(254) was induced by fasting in the liver and recruited to the promoters of PEPCK and G6Pase genes. The enrichment of NT-PGC-1(254) at the promoters was closely associated with fasting-induced increase in PEPCK and G6Pase gene expression and efficient production of glucose from pyruvate during a pyruvate tolerance test in FL-PGC-1(-/-) mice. Moreover, FL-PGC-1(-/-) primary hepatocytes showed a significant increase in gluconeogenic gene expression and glucose production after treatment with dexamethasone and forskolin, suggesting that NT-PGC-1(254) is sufficient to stimulate the gluconeogenic program in the absence of FL-PGC-1. Collectively, our findings highlight the role of hepatic NT-PGC-1 in stimulating gluconeogenic gene expression and glucose production.