Control of hepatic gluconeogenesis through the transcriptional coaotivator PGC-1

John Yoon, Pere Puigserver, Guoxun Chen, Jerry Donovan, Zhidan Wu, James Rhee, Guillaume Adelmant, John Stafford, C. Ronald Kahn, Daryl K. Granner, Christopher B. Newgard, Bruce M. Spiegelman

Research output: Contribution to journalArticle

1352 Scopus citations

Abstract

Blood glucose levels are maintained by the balance between glucose uptake by peripheral tissues and glucose secretion by the liver. Gluconeogenesis is strongly stimulated during fasting and is aberrantly activated in diabetes mellitus. Here we show that the transcriptional coactivator PGC-1 is strongly induced in liver in fasting mice and in three mouse models of insulin action deficiency: streptozotocin-induced diabetes, ob/ob genotype and liver insulin-receptor knockout. PGC-1 is induced synergistically in primary liver cultures by cyclic AMP and glucocorticoids. Adenoviral-mediated expression of PGC-1 in hepatocytes in culture or in vivo strongly activates an entire programme of key gluconeogenic enzymes, including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, leading to increased glucose output. Full transcriptional activation of the PEPCK promoter requires coactivation of the glucocorticoid receptor and the liver-enriched transcription factor HNF-4α (hepatic nuclear factor-4α) by PGC-1. These results implicate PGC-1 as a key modulator of hepatic gluconeogenesis and as a central target of the insulin-cAMP axis in liver.

Original languageEnglish (US)
Pages (from-to)131-138
Number of pages8
JournalNature
Volume413
Issue number6852
DOIs
StatePublished - Sep 13 2001
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)
  • General

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    Yoon, J., Puigserver, P., Chen, G., Donovan, J., Wu, Z., Rhee, J., Adelmant, G., Stafford, J., Kahn, C. R., Granner, D. K., Newgard, C. B., & Spiegelman, B. M. (2001). Control of hepatic gluconeogenesis through the transcriptional coaotivator PGC-1. Nature, 413(6852), 131-138. https://doi.org/10.1038/35093050