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

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 Amstrup Pedersen () and Pontus Gourdon ()
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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
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

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07176-z

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