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

• Published in: Nature cell biology Vol. 19; no. 5; pp. 504 - 517
• Main Authors: Zhang, Yanhui, Xie, Litao, Gunasekar, Susheel K., Tong, Dan, Mishra, Anil, Gibson, William J., Wang, Chuansong, Fidler, Trevor, Marthaler, Brodie, Klingelhutz, Aloysius, Abel, E. Dale, Samuel, Isaac, Smith, Jessica K., Cao, Lei, Sah, Rajan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2017; Nature Publishing Group
• Subjects: 13/95; 38/39; 38/91; 42/41; 631/443/319/2723; 631/80/86/2367; 631/80/86/2372; 64/60; 9/74; Adipocytes; Adipocytes - metabolism; Adipocytes - pathology; Adiposity; Animals; Cancer Research; Cell Biology; Cell Size; Cells, Cultured; Cellular signal transduction; Chloride; Chloride Channels - metabolism; Development and progression; Developmental Biology; Diabetes; Disease Models, Animal; DNA binding proteins; Energy Metabolism; Forkhead Box Protein O1 - genetics; Forkhead Box Protein O1 - metabolism; Glucose; Glucose - metabolism; Glucose Transporter Type 4 - genetics; Glucose Transporter Type 4 - metabolism; Glycogen Synthase Kinase 3 beta - genetics; Glycogen Synthase Kinase 3 beta - metabolism; GRB2 Adaptor Protein - genetics; GRB2 Adaptor Protein - metabolism; Growth; Homeostasis; Humans; Insulin; Insulin - metabolism; Insulin Resistance; Ion Channel Gating; Kinases; Life Sciences; Lipids; Male; Medicine; Membrane Potentials; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice, Inbred C57BL; Obesity; Obesity - genetics; Obesity - metabolism; Obesity - pathology; Phosphatidylinositol 3-Kinase - metabolism; Phosphorylation; Physiological aspects; Proto-Oncogene Proteins c-akt - metabolism; RNA Interference; Signal Transduction; Stem Cells; Time Factors; Transfection; United States; Iowa; Ohio; Iowa City Iowa; United States > US
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb3514

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. Sah and colleagues show that the volume-sensitive ion channel SWELL1 regulates adipocyte insulin-PI(3)K-AKT2 signalling, glucose uptake and lipid content through interactions with GRB2/Cav1.