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SAPS3 subunit of protein phosphatase 6 is an AMPK inhibitor and controls metabolic homeostasis upon dietary challenge in male mice

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  • Ying Yang

    (University of California, Irvine)

  • Michael A. Reid

    (Beckman Research Institute of City of Hope National Medical Center)

  • Eric A. Hanse

    (University of California, Irvine)

  • Haiqing Li

    (City of Hope National Medical Center)

  • Yuanding Li

    (University of California, Irvine)

  • Bryan I. Ruiz

    (University of California, Irvine)

  • Qi Fan

    (University of California, Irvine)

  • Mei Kong

    (University of California, Irvine)

Abstract

Inhibition of AMPK is tightly associated with metabolic perturbations upon over nutrition, yet the molecular mechanisms underlying are not clear. Here, we demonstrate the serine/threonine-protein phosphatase 6 regulatory subunit 3, SAPS3, is a negative regulator of AMPK. SAPS3 is induced under high fat diet (HFD) and recruits the PP6 catalytic subunit to deactivate phosphorylated-AMPK, thereby inhibiting AMPK-controlled metabolic pathways. Either whole-body or liver-specific deletion of SAPS3 protects male mice against HFD-induced detrimental consequences and reverses HFD-induced metabolic and transcriptional alterations while loss of SAPS3 has no effects on mice under balanced diets. Furthermore, genetic inhibition of AMPK is sufficient to block the protective phenotype in SAPS3 knockout mice under HFD. Together, our results reveal that SAPS3 is a negative regulator of AMPK and suppression of SAPS3 functions as a guardian when metabolism is perturbed and represents a potential therapeutic strategy to treat metabolic syndromes.

Suggested Citation

  • Ying Yang & Michael A. Reid & Eric A. Hanse & Haiqing Li & Yuanding Li & Bryan I. Ruiz & Qi Fan & Mei Kong, 2023. "SAPS3 subunit of protein phosphatase 6 is an AMPK inhibitor and controls metabolic homeostasis upon dietary challenge in male mice," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36809-1
    DOI: 10.1038/s41467-023-36809-1
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    1. Eryun Zhang & Lihua Jin & Yangmeng Wang & Jui Tu & Ruirong Zheng & Lili Ding & Zhipeng Fang & Mingjie Fan & Ismail Al-Abdullah & Rama Natarajan & Ke Ma & Zhengtao Wang & Arthur D. Riggs & Sarah C. Shu, 2022. "Intestinal AMPK modulation of microbiota mediates crosstalk with brown fat to control thermogenesis," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Li Jiang & Vitali Stanevich & Kenneth A Satyshur & Mei Kong & Guy R. Watkins & Brian E. Wadzinski & Rituparna Sengupta & Yongna Xing, 2013. "Structural basis of protein phosphatase 2A stable latency," Nature Communications, Nature, vol. 4(1), pages 1-11, June.
    3. Ying Yang & Mari B. Ishak Gabra & Eric A. Hanse & Xazmin H. Lowman & Thai Q. Tran & Haiqing Li & Neta Milman & Juan Liu & Michael A. Reid & Jason W. Locasale & Ziv Gil & Mei Kong, 2019. "MiR-135 suppresses glycolysis and promotes pancreatic cancer cell adaptation to metabolic stress by targeting phosphofructokinase-1," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
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