2. Academic Validation
  3. Human adipose glycerol flux is regulated by a pH gate in AQP10

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

  • Nat Commun. 2018 Nov 12;9(1):4749. doi: 10.1038/s41467-018-07176-z.
Kamil Gotfryd 1,  Andreia Filipa Mósca 2,  Julie Winkel Missel 1,  Sigurd Friis Truelsen 3,  Kaituo Wang 1,  Mariana Spulber 4,  Simon Krabbe 5,  Claus Hélix-Nielsen 3 4,  Umberto Laforenza 6,  Graça Soveral 2,  Per Amstrup Pedersen 7,  Pontus Gourdon 8 9
Affiliations

Affiliations

  • 1 University of Copenhagen, Department of Biomedical Sciences, Nørre Allé 14, DK-2200, Copenhagen N, Denmark.
  • 2 Universidade de Lisboa, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal.
  • 3 Technical University of Denmark, Department of Environmental Engineering, Bygningstorvet Building 115, DK-2800 Kgs, Lyngby, Denmark.
  • 4 Aquaporin A/S, Nymøllevej 78, DK-2800, Lyngby, Denmark.
  • 5 University of Copenhagen, Department of Biology, Universitetsparken 13, DK-2100, Copenhagen OE, Denmark.
  • 6 University of Pavia, Department of Molecular Medicine, Human Physiology Unit, Via Forlanini 6, I-27100, Pavia, Italy.
  • 7 University of Copenhagen, Department of Biology, Universitetsparken 13, DK-2100, Copenhagen OE, Denmark. papedersen@bio.ku.dk.
  • 8 University of Copenhagen, Department of Biomedical Sciences, Nørre Allé 14, DK-2200, Copenhagen N, Denmark. pontus@sund.ku.dk.
  • 9 Lund University, Department of Experimental Medical Science, Sölvegatan 19, SE-221 84, Lund, Sweden. pontus@sund.ku.dk.
PMID: 30420639 DOI: 10.1038/s41467-018-07176-z
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.

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