SWELL1 is a regulator of adipocyte size, insulin signalling and glucose homeostasis

Yanhui Zhang; Litao Xie; Susheel K Gunasekar; Dan Tong; Anil Mishra; William J Gibson; Chuansong Wang; Trevor Fidler; Brodie Marthaler; Aloysius Klingelhutz; E Dale Abel; Isaac Samuel; Jessica K Smith; Lei Cao; Rajan Sah

doi:10.1038/ncb3514

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SWELL1 is a regulator of adipocyte size, insulin signalling and glucose homeostasis

Journal article

Peer reviewed

SWELL1 is a regulator of adipocyte size, insulin signalling and glucose homeostasis

Yanhui Zhang, Litao Xie, Susheel K Gunasekar, Dan Tong, Anil Mishra, William J Gibson, Chuansong Wang, Trevor Fidler, Brodie Marthaler, Aloysius Klingelhutz, …

Nature cell biology, Vol.19(5), pp.504-517

05/2017

DOI: 10.1038/ncb3514

PMCID: PMC5415409

PMID: 28436964

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Abstract

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.

Phosphorylation

Transfection

Signal Transduction

Energy Metabolism

Glucose Transporter Type 4 - metabolism

Humans

Glycogen Synthase Kinase 3 beta - genetics

Homeostasis

Male

Obesity - genetics

Adiposity

RNA Interference

Time Factors

GRB2 Adaptor Protein - genetics

Membrane Proteins - metabolism

Proto-Oncogene Proteins c-akt - metabolism

Phosphatidylinositol 3-Kinase - metabolism

Disease Models, Animal

Forkhead Box Protein O1 - metabolism

Glucose Transporter Type 4 - genetics

Membrane Proteins - genetics

Mice, Inbred C57BL

Cells, Cultured

Insulin Resistance

Cell Size

Adipocytes - pathology

Glycogen Synthase Kinase 3 beta - metabolism

Obesity - metabolism

Obesity - pathology

Chloride Channels - metabolism

Insulin - metabolism

Animals

Membrane Potentials

Adipocytes - metabolism

Glucose - metabolism

GRB2 Adaptor Protein - metabolism

Forkhead Box Protein O1 - genetics

Ion Channel Gating

Details

Title: Subtitle: SWELL1 is a regulator of adipocyte size, insulin signalling and glucose homeostasis
Creators: Yanhui Zhang - Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242, USA
Litao Xie - Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242, USA
Susheel K Gunasekar - Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242, USA
Dan Tong - Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242, USA
Anil Mishra - Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242, USA
William J Gibson - Harvard Medical School, Boston, Massachusetts 02115, USA
Chuansong Wang - Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio 43210, USA
Trevor Fidler - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa 52242, USA
Brodie Marthaler - Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242, USA
Aloysius Klingelhutz - Department of Microbiology, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242, USA
E Dale Abel - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa 52242, USA
Isaac Samuel - Department of Surgery, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242, USA
Jessica K Smith - Department of Surgery, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242, USA
Lei Cao - Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio 43210, USA
Rajan Sah - Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa 52242, USA
Resource Type: Journal article
Publication Details: Nature cell biology, Vol.19(5), pp.504-517
Publisher: England
DOI: 10.1038/ncb3514
PMID: 28436964
PMCID: PMC5415409
ISSN: 1476-4679
eISSN: 1476-4679
Grant note: R01 DK106009 / NIDDK NIH HHS R01 CA163640 / NCI NIH HHS R21 CA178227 / NCI NIH HHS R01 CA166590 / NCI NIH HHS T32 GM007753 / NIGMS NIH HHS P30 CA086862 / NCI NIH HHS R01 AG041250 / NIA NIH HHS
Language: English
Date published: 05/2017
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Microbiology and Immunology; Surgery; Radiation Oncology; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984002399902771

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