TY - JOUR
T1 - SWELL1 is a regulator of adipocyte size, insulin signalling and glucose homeostasis
AU - Zhang, Yanhui
AU - Xie, Litao
AU - Gunasekar, Susheel K.
AU - Tong, Dan
AU - Mishra, Anil
AU - Gibson, William J.
AU - Wang, Chuansong
AU - Fidler, Trevor
AU - Marthaler, Brodie
AU - Klingelhutz, Aloysius
AU - Dale Abel, E.
AU - Samuel, Isaac
AU - Smith, Jessica K.
AU - Cao, Lei
AU - Sah, Rajan
N1 - Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - Adipocytes undergo considerable volumetric expansion in the setting of obesity. It has been proposed that such marked increases in adipocyte size may be sensed via adipocyte-autonomous mechanisms to mediate size-dependent intracellular signalling. Here, we show that SWELL1 (LRRC8a), a member of the Leucine-Rich Repeat Containing protein family, is an essential component of a volume-sensitive ion channel (VRAC) in adipocytes. We find that SWELL1-mediated VRAC is augmented in hypertrophic murine and human adipocytes in the setting of obesity. SWELL1 regulates adipocyte insulin-PI3K-AKT2-GLUT4 signalling, glucose uptake and lipid content via SWELL1 C-terminal leucine-rich repeat domain interactions with GRB2/Cav1. Silencing GRB2 in SWELL1 KO adipocytes rescues insulin-pAKT2 signalling. In vivo, shRNA-mediated SWELL1 knockdown and adipose-targeted SWELL1 knockout reduce adiposity and adipocyte size in obese mice while impairing systemic glycaemia and insulin sensitivity. These studies identify SWELL1 as a cell-autonomous sensor of adipocyte size that regulates adipocyte growth, insulin sensitivity and glucose tolerance.
AB - Adipocytes undergo considerable volumetric expansion in the setting of obesity. It has been proposed that such marked increases in adipocyte size may be sensed via adipocyte-autonomous mechanisms to mediate size-dependent intracellular signalling. Here, we show that SWELL1 (LRRC8a), a member of the Leucine-Rich Repeat Containing protein family, is an essential component of a volume-sensitive ion channel (VRAC) in adipocytes. We find that SWELL1-mediated VRAC is augmented in hypertrophic murine and human adipocytes in the setting of obesity. SWELL1 regulates adipocyte insulin-PI3K-AKT2-GLUT4 signalling, glucose uptake and lipid content via SWELL1 C-terminal leucine-rich repeat domain interactions with GRB2/Cav1. Silencing GRB2 in SWELL1 KO adipocytes rescues insulin-pAKT2 signalling. In vivo, shRNA-mediated SWELL1 knockdown and adipose-targeted SWELL1 knockout reduce adiposity and adipocyte size in obese mice while impairing systemic glycaemia and insulin sensitivity. These studies identify SWELL1 as a cell-autonomous sensor of adipocyte size that regulates adipocyte growth, insulin sensitivity and glucose tolerance.
UR - http://www.scopus.com/inward/record.url?scp=85018671850&partnerID=8YFLogxK
U2 - 10.1038/ncb3514
DO - 10.1038/ncb3514
M3 - Article
C2 - 28436964
AN - SCOPUS:85018671850
SN - 1465-7392
VL - 19
SP - 504
EP - 517
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 5
ER -