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An AMPK-dependent, non-canonical p53 pathway plays a key role in adipocyte metabolic reprogramming

  1. Hong Wang
  2. Xueping Wan
  3. Paul F Pilch
  4. Leif W Ellisen
  5. Susan K Fried
  6. Libin Liu  Is a corresponding author
  1. Boston University, United States
  2. Massachusetts General Hospital Cancer Center and Harvard Medical School, United States
  3. Icahn School of Medicine at Mount Sinai, United States
Research Article
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Cite this article as: eLife 2020;9:e63665 doi: 10.7554/eLife.63665

Abstract

It has been known adipocytes increase p53 expression and activity in obesity, however, only canonical p53 functions (i.e., senescence and apoptosis) are attributed to inflammation-associated metabolic phenotypes. Whether or not p53 is directly involved in mature adipocyte metabolic regulation remains unclear. Here we show p53 protein expression can be up-regulated in adipocytes by nutrient starvation without activating cell senescence, apoptosis, or a death-related p53 canonical pathway. Inducing the loss of p53 in mature adipocytes significantly reprograms energy metabolism and this effect is primarily mediated through a AMP-activated protein kinase (AMPK) pathway and a novel downstream transcriptional target, lysosomal acid lipase (LAL). The pathophysiological relevance is further demonstrated in a conditional and adipocyte-specific p53 knockout mouse model. Overall, these data support a non-canonical p53 function in the regulation of adipocyte energy homeostasis and indicate that the dysregulation of this pathway may be involved in developing metabolic dysfunction in obesity.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for figures.

Article and author information

Author details

  1. Hong Wang

    Department of Pharmacology & Experimental Therapeutics, Boston University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Xueping Wan

    Department of Pharmacology & Experimental Therapeutics, Boston University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Paul F Pilch

    Department of Biochemistry, Boston University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1997-0499
  4. Leif W Ellisen

    Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Susan K Fried

    Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Libin Liu

    Department of Pharmacology and Experimental Therapeutics, Boston University, Boston, United States
    For correspondence
    libin@bu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5056-1517

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (DK-112945)

  • Libin Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal studies were performed in accordance with the guidelines and under approval of the Institutional Review Committee for the Animal Care and Use of Boston University. (Protocol #201800404).

Reviewing Editor

  1. Michael Czech, University of Massachusetts Medical School, United States

Publication history

  1. Received: October 1, 2020
  2. Accepted: December 14, 2020
  3. Accepted Manuscript published: December 15, 2020 (version 1)
  4. Accepted Manuscript updated: December 18, 2020 (version 2)
  5. Version of Record published: December 23, 2020 (version 3)

Copyright

© 2020, Wang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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