SWELL1 is a regulator of adipocyte size, insulin signaling and glucose homeostasis
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Author
Zhang, Yanhui
Xie, Litao
Gunasekar, Susheel K.
Tong, Dan
Mishra, Anil
Wang, Chuansong
Fidler, Trevor
Marthaler, Brodie
Klingelhutz, Aloysius
Abel, E. Dale
Samuel, Isaac
Smith, Jessica K.
Cao, Lei
Sah, Rajan
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/ncb3514Metadata
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Zhang, Y., L. Xie, S. K. Gunasekar, D. Tong, A. Mishra, W. J. Gibson, C. Wang, et al. 2017. “SWELL1 is a regulator of adipocyte size, insulin signaling and glucose homeostasis.” Nature cell biology 19 (5): 504-517. doi:10.1038/ncb3514. http://dx.doi.org/10.1038/ncb3514.Abstract
SUMMARY 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 signaling. 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 signaling, 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 signaling. In vivo, shRNA-mediated SWELL1 knock-down and adipose-targeted SWELL1 knock-out 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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5415409/pdf/Terms of Use
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