Human adipose glycerol flux is regulated by a pH gate in AQP10
(2018) In Nature Communications 9(1).- 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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2018-11-12
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nature Communications
- volume
- 9
- issue
- 1
- pages
- 1 pages
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85056305828
- pmid:30420639
- ISSN
- 2041-1723
- DOI
- 10.1038/s41467-018-07176-z
- language
- English
- LU publication?
- yes
- id
- 32ec6cf2-318c-4fd7-981c-528c5d7f73d1
- date added to LUP
- 2018-11-21 14:49:11
- date last changed
- 2024-06-12 01:41:07
@article{32ec6cf2-318c-4fd7-981c-528c5d7f73d1,
abstract = {{<p>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.</p>}},
author = {{Gotfryd, Kamil and Mósca, Andreia Filipa and Missel, Julie Winkel and Truelsen, Sigurd Friis and Wang, Kaituo and Spulber, Mariana and Krabbe, Simon and Hélix-Nielsen, Claus and Laforenza, Umberto and Soveral, Graça and Pedersen, Per Amstrup and Gourdon, Pontus}},
issn = {{2041-1723}},
language = {{eng}},
month = {{11}},
number = {{1}},
publisher = {{Nature Publishing Group}},
series = {{Nature Communications}},
title = {{Human adipose glycerol flux is regulated by a pH gate in AQP10}},
url = {{http://dx.doi.org/10.1038/s41467-018-07176-z}},
doi = {{10.1038/s41467-018-07176-z}},
volume = {{9}},
year = {{2018}},
}