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

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