Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1

J. Cliff Yoon, Pere Puigserver, Guoxun Chen, Jerry Donovan, Zhidan Wu, James Rhee, Guillaume Adelmant, John Stafford, C. Ronald Kahn, Daryl K. Granner, Christopher B. Newgard and Bruce M. Spiegelman ()
Additional contact information
J. Cliff Yoon: Harvard Medical School
Pere Puigserver: Harvard Medical School
Guoxun Chen: Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center
Jerry Donovan: Harvard Medical School
Zhidan Wu: Harvard Medical School
James Rhee: Harvard Medical School
Guillaume Adelmant: Harvard Medical School
John Stafford: Vanderbilt University School of Medicine
C. Ronald Kahn: Harvard Medical School
Daryl K. Granner: Vanderbilt University School of Medicine
Christopher B. Newgard: Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center
Bruce M. Spiegelman: Harvard Medical School

Nature, 2001, vol. 413, issue 6852, 131-138

Abstract: 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.

Date: 2001
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DOI: 10.1038/35093050

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