Tuning fat cell size and obesity through SWELL1

 描述(申请人提供)：肥胖是一个主要的世界性公共卫生问题。几十年来，有一种观点认为，肥胖的代谢性疾病更多地与脂肪细胞的大小有关，而不是与数量有关。此外，最近的研究强调了脂肪细胞大小、膜张力和脂肪生成之间的联系--导致一些人假设脂肪细胞自主的脂质稳态机制。到目前为止，还没有这种假想的脂肪细胞膜拉伸传感器的候选分子，也没有人提出可测试的模型。由于一些离子通道可以对膜拉伸做出反应，我们将膜片钳技术应用于新鲜分离的成熟脂肪细胞，并鉴定出一种新的拉伸/膨胀激活的离子电流SWELL1(LRRC8a)。SWELL1在细胞质体积调节中起重要作用，可通过PI3K/Akt信号通路传递信号。本研究的目的是阐明SWELL1对脂肪细胞功能的作用机制。我们的假设是，新型机械传感器SWELL1可以感知脂肪细胞的大小，并通过Akt介导的对脂肪分解和细胞葡萄糖摄取的影响来调节脂滴的生长。这些研究的基本原理是，描绘一个新的SWELL1信号通路，将脂肪细胞大小感知与胰岛素信号和脂质稳态联系起来，将促进我们对脂肪细胞生物学的理解，并为肥胖症的治疗提供创新的治疗方法。为了验证上述假设，我们提出了以下三个具体目标：目标1：研究瘦小、肥胖和禁食小鼠脂肪细胞的SWELL1电流。目的2：探讨脂肪细胞中SWELL1-PI3K-Akt信号转导机制。目的：探讨SWELL1对肥胖大鼠脂代谢和肥胖的调节作用。这一建议的贡献是重大的，因为它描绘了一个新的SWELL1信号通路，调节胰岛素信号和脂肪细胞的生长，从而促进了我们对脂肪细胞生物学的理解。这一建议是创新的，因为离子通道天生就是“可用药的”，SWELL1可能会为肥胖的治疗提供一个新的药理靶点。

 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.