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

The transcriptional coactivator PGC‐1α plays a central role in hepatic gluconeogenesis. We previously reported that alternative splicing of the PGC‐1α gene produces an additional transcript encoding the truncated protein NT‐PGC‐1α. NT‐PGC‐1α is co‐expressed with PGC‐1α and highly induced by fasting in the liver. NT‐PGC‐1α 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‐1α in the regulation of gluconeogenesis. Adenovirus‐mediated expression of NT‐PGC‐1α 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‐1α function in hepatic gluconeogenesis in vivo, we took advantage of a previously reported FL‐PGC‐1α (−/−) mouse line that lacks full‐length PGC‐1α (FL‐PGC‐1α) but retains a slightly shorter and functionally equivalent form of NT‐PGC‐1α (NT‐PGC‐1α (254)). In FL‐PGC‐1α (−/−) mice, NT‐PGC‐1α (254) was induced by fasting in the liver and recruited to the promoters of PEPCK and G6Pase genes. The enrichment of NT‐PGC‐1α (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‐1α (−/−) mice. Moreover, FL‐PGC‐1α (−/−) primary hepatocytes showed a significant increase in gluconeogenic gene expression and glucose production after treatment with dexamethasone and forskolin, suggesting that NT‐PGC‐1α (254) is sufficient to stimulate the gluconeogenic program in the absence of FL‐PGC‐1α. Collectively, our findings highlight the role of hepatic NT‐PGC‐1α in stimulating gluconeogenic gene expression and glucose production.