SWELL1 is a regulator of adipocyte size, insulin signaling and glucose homeostasis
Gunasekar, Susheel K.
Abel, E. Dale
Smith, Jessica K.
Sah, RajanNote: Order does not necessarily reflect citation order of authors.
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CitationZhang, 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.
AbstractSUMMARY 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.
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