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Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & Bruce M. Spie, 2001. "Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1," Nature, Nature, vol. 413(6852), pages 131-138, September.
    • Handle: RePEc:nat:nature:v:413:y:2001:i:6852:d:10.1038_35093050
    DOI: 10.1038/35093050
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    Cited by:

    1. Qian Ye & Yi Liu & Guiji Zhang & Haijun Deng & Xiaojun Wang & Lin Tuo & Chang Chen & Xuanming Pan & Kang Wu & Jiangao Fan & Qin Pan & Kai Wang & Ailong Huang & Ni Tang, 2023. "Deficiency of gluconeogenic enzyme PCK1 promotes metabolic-associated fatty liver disease through PI3K/AKT/PDGF axis activation in male mice," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Michelle L. Headland & Peter M. Clifton & Jennifer B. Keogh, 2019. "Effects of Weight Loss on FGF-21 in Human Subjects: An Exploratory Study," IJERPH, MDPI, vol. 16(23), pages 1-5, December.
    3. Simeon R. Mihaylov & Lydia M. Castelli & Ya-Hui Lin & Aytac Gül & Nikita Soni & Christopher Hastings & Helen R. Flynn & Oana Păun & Mark J. Dickman & Ambrosius P. Snijders & Robert Goldstone & Oliver, 2023. "The master energy homeostasis regulator PGC-1α exhibits an mRNA nuclear export function," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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