TY - JOUR
T1 - SWELL signalling in adipocytes
T2 - can fat 'feel' fat?
AU - Gunasekar, Susheel K.
AU - Xie, Litao
AU - Sah, Rajan
N1 - Funding Information:
Obesity ion channel insulin caveolae mechano-transduction National Institutes of Health 10.13039/100000002 1R01DK106009-01A1 American Diabetes Association Innovative Basic Science Award (#1-18-IBS-229), and Roy J. Carver Charitable Trust (01-224). Obesity is a major public health problem, predisposing to high cholesterol, diabetes and hypertension and inflicting health-care costs over 100 billion dollars in the US alone. It is characterized by a tremendous increase in adipose tissue that is in large part due to massive volumetric expansion of the constituent adipocytes [ 1 , 2 ]. This adipocyte expansion has been long associated with metabolic disease and insulin resistance [ 1 , 3 – 6 ], implicating adipocyte-size dependent regulation of insulin signalling and growth. Studies in cultured adipocytes show that lipid droplet growth increases local tissue stiffness to mechanically-stimulate lipogenesis, and adipocyte growth in neighbouring cells via MEK signalling [ 7 – 9 ], suggesting that obesity may beget obesity in a positive-feedback, feed-forward manner [ 7 ]. Indeed, elegant studies in primary, mature, human adipocytes also reveal evidence of adipocyte mechano-signalling in human adipose tissue [ 10 ]. Taken together, this literature suggests that, in the setting of obesity, adipocyte expansion may activate an undiscovered mechano-sensitive molecule that modulates adipocyte growth and intracellular signalling. We recently discovered that SWELL1 (LRRC8a), a member of the L eucine R ich R epeat C ontaining protein family, is a required component of a volume-sensitive and putatively mechano-sensitive ion channel/signalling molecule that is activated in the setting of adipocyte hypertrophy and regulates adipocyte size, insulin signalling and systemic glycaemia via a novel SWELL1-PI3K-AKT2-GLUT4 signalling axis. Adipocyte-specific SWELL1 ablation disrupts insulin-PI3K-AKT2 signalling, inducing insulin resistance and glucose intolerance in vivo [ 11 ]. These data identify SWELL1 as a component of a cell-autonomous sensor of adipocyte size and a positive regulator of adipocyte insulin signalling, growth and glucose homeostasis, particularly in the setting of obesity ( Figure 1 ). Thus, SWELL1 may be a component of the molecular mechano-sensor responsible for the mechano-sensitive nature of adipocytes described by others previously [ 7 – 10 ]. Figure 1. Adipocyte SWELL1 is a positive regulator of insulin signalling and glucose homeostasis. LRR: Leucine Rich Repeat; Cav1: Caveolin-1; GSK3β: Glycogen Synthase 3β; GS: Glycogen Synthase. (Zhang Y. et al., Nature Cell Biology 2017).
Publisher Copyright:
© 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
PY - 2019/1/2
Y1 - 2019/1/2
N2 - Obesity is becoming a global epidemic, predisposing to Type 2 diabetes, cardiovascular disease, fatty liver disease, pulmonary disease, osteoarthritis and cancer. Therefore, understanding the biology of adipocyte expansion in response to overnutrition is critical to devising strategies to treat obesity, and the associated burden of morbidity and mortality. Through exploratory patch-clamp experiments in freshly isolated primary murine and human adipocytes, we recently determined that SWELL1/LRRC8a, a leucine-rich repeat containing transmembrane protein, functionally encoded an ion channel signalling complex (the volume-regulated anion channel, or VRAC) on the adipocyte plasma membrane. The SWELL1-/LRRC8 channel complex activates in response to increases in adipocyte volume and in the context of obesity. SWELL1 is also required for insulin-PI3K-AKT2 signalling to regulate adipocyte growth and systemic glycaemia. This commentary delves further into our working models for the molecular mechanisms of adipocyte SWELL1-mediated VRAC activation, proposed signal transduction mechanisms, and putative impact on adipocyte hypertrophy during caloric excess.
AB - Obesity is becoming a global epidemic, predisposing to Type 2 diabetes, cardiovascular disease, fatty liver disease, pulmonary disease, osteoarthritis and cancer. Therefore, understanding the biology of adipocyte expansion in response to overnutrition is critical to devising strategies to treat obesity, and the associated burden of morbidity and mortality. Through exploratory patch-clamp experiments in freshly isolated primary murine and human adipocytes, we recently determined that SWELL1/LRRC8a, a leucine-rich repeat containing transmembrane protein, functionally encoded an ion channel signalling complex (the volume-regulated anion channel, or VRAC) on the adipocyte plasma membrane. The SWELL1-/LRRC8 channel complex activates in response to increases in adipocyte volume and in the context of obesity. SWELL1 is also required for insulin-PI3K-AKT2 signalling to regulate adipocyte growth and systemic glycaemia. This commentary delves further into our working models for the molecular mechanisms of adipocyte SWELL1-mediated VRAC activation, proposed signal transduction mechanisms, and putative impact on adipocyte hypertrophy during caloric excess.
KW - Obesity
KW - caveolae
KW - insulin
KW - ion channel
KW - mechano-transduction
UR - http://www.scopus.com/inward/record.url?scp=85076137719&partnerID=8YFLogxK
U2 - 10.1080/21623945.2019.1612223
DO - 10.1080/21623945.2019.1612223
M3 - Comment/debate
C2 - 31112068
AN - SCOPUS:85076137719
SN - 2162-3945
VL - 8
SP - 223
EP - 228
JO - Adipocyte
JF - Adipocyte
IS - 1
ER -