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

TY - JOUR

T1 - Human adipose glycerol flux is regulated by a pH gate in AQP10

AU - Gotfryd, Kamil

AU - Mósca, Andreia Filipa

AU - Missel, Julie Winkel

AU - Truelsen, Sigurd Friis

AU - Wang, Kaituo

AU - Spulber, Mariana

AU - Krabbe, Simon

AU - Hélix-nielsen, Claus

AU - Laforenza, Umberto

AU - Soveral, Graca

AU - Pedersen, Per Amstrup

AU - Gourdon, Pontus Emanuel

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-018-07176-z

DO - 10.1038/s41467-018-07176-z

M3 - Journal article

C2 - 30420639

SN - 2041-1723

VL - 9

SP - 1

EP - 11

JO - Nature Communications

JF - Nature Communications

M1 - 4749

ER -