Tuning fat cell size and obesity through SWELL1

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 DESCRIPTION (provided by applicant): Obesity is a major world-wide public health problem. For decades there has been a notion that metabolic disease in obesity is associated more with adipocyte size than numbers. Moreover, recent studies have highlighted a connection between adipocyte size, membrane tension and adipogenesis - leading some to postulate adipocyte-autonomous mechanisms of lipid homeostasis. To date, there are no molecular candidates for this hypothesized adipocyte-membrane stretch sensor, nor has anyone put forth a testable model. As some ion channels can signal in response to membrane-stretch, we applied the patch-clamp technique to freshly isolated, mature adipocytes and identified a novel stretch/swell-activated ionic current, SWELL1 (LRRC8a). SWELL1 is important for cytoplasmic volume regulation and can signal via phosphoinositide 3-kinase (PI3K)/Akt pathway. The objective of the current proposal is to elucidate the mechanisms of SWELL1 action on adipocyte function. Our hypothesis is that the novel mechanosensor, SWELL1, senses adipocyte size and regulates growth of the lipid droplet via Akt-mediated effects on lipolysis and cellular glucose uptake. The rationale for the proposed studies is that delineating a novel SWELL1 signaling pathway linking adipocyte size sensing to insulin signaling and lipid homeostasis will advance our understanding of adipocyte biology and provide innovative therapeutic approaches for the treatment of obesity. To test the above hypothesis we propose the following three specific aims: Aim 1: Characterize SWELL1 current in adipocytes from lean, obese and fasted mice. Aim 2: Determine the mechanism of SWELL1-PI3K-Akt signaling in adipocytes. Aim 3: Determine the regulatory effect of SWELL1 on lipid metabolism and adiposity in obesity. The contribution of this proposal is significant because it delineates a novel SWELL1 signaling pathway regulating insulin signaling and adipocyte growth, thereby advancing our understanding of adipocyte biology. This proposal is innovative because, as ion channels are inherently "druggable", SWELL1 may provide a new pharmacological target for the treatment of obesity.