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*, Pontus Gourdon

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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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.

Original languageEnglish
Article number4749
JournalNature Communications
Volume9
Issue number1
Number of pages11
ISSN2041-1723
DOIs
Publication statusPublished - 2018

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