1. Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
2. Touchstone Center for Diabetes Research, Departments of Biochemistry and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
3. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
4. Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA

Correspondence to: Bruce M. Spiegelman¹ Correspondence and requests for materials should be addressed to B.M.S. (e-mail: Email: bruce_spiegelman@dfci.harvard.edu).

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-4 (hepatic nuclear factor-4) 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.

1. Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
2. Touchstone Center for Diabetes Research, Departments of Biochemistry and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
3. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
4. Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA

Correspondence to: Bruce M. Spiegelman¹ Correspondence and requests for materials should be addressed to B.M.S. (e-mail: Email: bruce_spiegelman@dfci.harvard.edu).