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

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44 Scopus citations

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.

Original languageEnglish
Pages (from-to)504-517
Number of pages14
JournalNature Cell Biology
Volume19
Issue number5
DOIs
StatePublished - May 1 2017
Externally publishedYes

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    Zhang, Y., Xie, L., Gunasekar, S. K., Tong, D., Mishra, A., Gibson, W. J., Wang, C., Fidler, T., Marthaler, B., Klingelhutz, A., Dale Abel, E., Samuel, I., Smith, J. K., Cao, L., & Sah, R. (2017). SWELL1 is a regulator of adipocyte size, insulin signalling and glucose homeostasis. Nature Cell Biology, 19(5), 504-517. https://doi.org/10.1038/ncb3514