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Human adipose glycerol flux is regulated by a pH gate in AQP10

Author

Listed:
  • Kamil Gotfryd

    (University of Copenhagen, Department of Biomedical Sciences)

  • Andreia Filipa Mósca

    (Universidade de Lisboa, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy)

  • Julie Winkel Missel

    (University of Copenhagen, Department of Biomedical Sciences)

  • Sigurd Friis Truelsen

    (Technical University of Denmark, Department of Environmental Engineering)

  • Kaituo Wang

    (University of Copenhagen, Department of Biomedical Sciences)

  • Mariana Spulber

    (Aquaporin A/S)

  • Simon Krabbe

    (University of Copenhagen, Department of Biology)

  • Claus Hélix-Nielsen

    (Technical University of Denmark, Department of Environmental Engineering
    Aquaporin A/S)

  • Umberto Laforenza

    (University of Pavia, Department of Molecular Medicine, Human Physiology Unit)

  • Graça Soveral

    (Universidade de Lisboa, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy)

  • Per Amstrup Pedersen

    (University of Copenhagen, Department of Biology)

  • Pontus Gourdon

    (University of Copenhagen, Department of Biomedical Sciences
    Lund University, Department of Experimental Medical Science)

Abstract

Obesity is a major threat to global health and metabolically associated with glycerol homeostasis. Here we demonstrate that in human adipocytes, the decreased pH observed during lipolysis (fat burning) correlates with increased glycerol release and stimulation of aquaglyceroporin AQP10. The crystal structure of human AQP10 determined at 2.3 Å resolution unveils the molecular basis for pH modulation—an exceptionally wide selectivity (ar/R) filter and a unique cytoplasmic gate. Structural and functional (in vitro and in vivo) analyses disclose a glycerol-specific pH-dependence and pinpoint pore-lining His80 as the pH-sensor. Molecular dynamics simulations indicate how gate opening is achieved. These findings unravel a unique type of aquaporin regulation important for controlling body fat mass. Thus, targeting the cytoplasmic gate to induce constitutive glycerol secretion may offer an attractive option for treating obesity and related complications.

Suggested Citation

  • Kamil Gotfryd & Andreia Filipa Mósca & Julie Winkel Missel & Sigurd Friis Truelsen & Kaituo Wang & Mariana Spulber & Simon Krabbe & Claus Hélix-Nielsen & Umberto Laforenza & Graça Soveral & Per Amstru, 2018. "Human adipose glycerol flux is regulated by a pH gate in AQP10," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07176-z
    DOI: 10.1038/s41467-018-07176-z
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    Cited by:

    1. Yasunori Saitoh & Namiki Mitani-Ueno & Keisuke Saito & Kengo Matsuki & Sheng Huang & Lingli Yang & Naoki Yamaji & Hiroshi Ishikita & Jian-Ren Shen & Jian Feng Ma & Michihiro Suga, 2021. "Structural basis for high selectivity of a rice silicon channel Lsi1," Nature Communications, Nature, vol. 12(1), pages 1-14, December.

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