Tuning fat cell size and obesity through SWELL1

通过 SWELL1 调节脂肪细胞大小和肥胖

• 批准号: 9917773
• 负责人: Rajan Sah
• 金额: $ 43.11万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-14 至 2021-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917773
• 关键词: Address; Adipocytes; C-terminal; Cell Line; Cell Size; Data; Diabetes Mellitus; Diet; Fasting; Goals; Growth; Health; Health Care Costs; Heart Diseases; Homeostasis; Human; Hypertrophy; Insulin; Ion Channel; Knockout Mice; Leucine-Rich Repeat; Link; Lipids; Lipolysis; Malignant Neoplasms; Measures; Mechanics; Mediating; Membrane; Membrane Proteins; Metabolic Diseases; Mind; Mission; Modeling; Molecular; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Obese Mice; Obesity; Obesity associated disease; Patch-Clamp Techniques; Pathway interactions; Persons; Pharmacology; Phosphatidylinositols; Phosphotransferases; Protein Family; Protein Kinase Interaction; Proteins; Proto-Oncogene Proteins c-akt; Public Health; Regulation; Research; Role; Signal Pathway; Signal Transduction; Societies; Stretching; Techniques; Testing; Therapeutic; Thinness; adipocyte biology; base; experimental study; glucose uptake; in vivo; innovation; insight; insulin sensitizing drugs; insulin signaling; knock-down; knowledge base; leucine-rich repeat protein; lipid biosynthesis; lipid metabolism; loss of function; member; novel; obesity prevention; obesity treatment; public health relevance; response; sensor; therapeutic target

 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.

 描述（适用提供）：肥胖是全球范围内的主要公共卫生问题。几十年来，已经有一条通知，肥胖症中的代谢疾病与脂肪细胞大小相比更多的是数字。此外，最近的研究强调了脂肪细胞大小，膜张力和脂肪形成之间的联系 - 导致一些人假定脂质稳态的脂肪细胞自主机制。迄今为止，对于这种假设的脂肪细胞膜拉伸传感器，还没有分子候选者，也没有人提出可测试的模型。由于某些离子通道可以响应膜拉伸信号，因此我们将斑块钳技术应用于新鲜分离的成熟脂肪细胞，并鉴定出一种新型的拉伸/溶胀离子电流Swell1（LRRC8A）。 Swell1对于细胞质体积调节很重要，并且可以通过磷酸肌醇3-激酶（PI3K）/AKT途径发出信号。当前建议的目的是阐明Swell1作用对脂肪细胞功能的机制。我们的假设是，新型机制Swell1感受到脂肪细胞的大小，并通过Akt介导的对脂肪分析和细胞葡萄糖摄取的作用来调节脂质液滴的生长。拟议的研究的基本原理是，描述了一种新型的Swell1信号通路，将脂肪细胞尺寸敏感性与胰岛素信号传导和脂质稳态联系起来将提高我们对脂肪细胞生物学的理解，并为肥胖治疗提供创新的治疗方法。为了检验上述假设，我们提出以下三个特定目的：目标1：表征来自瘦，肥胖和禁食小鼠的脂肪细胞中的Swell1电流。 AIM 2：确定脂肪细胞中Swell1-PI3K-AKT信号的机理。目标3：确定Swell1对肥胖症中脂质代谢和肥胖的调节作用。该提案的贡献很重要，因为它描绘了一种新型的Swell1信号通路调节胰岛素信号传导和脂肪细胞生长，从而促进了我们对脂肪细胞生物学的理解。该提案具有创新性，因为由于离子通道本质上是“可药物”的，因此Swell1可能为治疗肥胖症提供新的药物靶标。