Tuning fat cell size and obesity through SWELL1

通过 SWELL1 调节脂肪细胞大小和肥胖

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：几十年来，人们一直认为肥胖中的代谢疾病与脂肪细胞大小的关系大于与数量的关系。此外，最近的研究强调了脂肪细胞大小之间的联系。、膜张力和脂肪生成——导致一些人假设脂质稳态的脂肪细胞自主机制迄今为止，还没有这种备受追捧的脂肪细胞膜拉伸传感器的候选分子，也没有人提出。由于一些离子通道可以响应膜拉伸而发出信号，因此我们将膜片钳技术应用于新鲜分离的成熟脂肪细胞，并确定了一种新型拉伸/膨胀激活离子电流 SWELL1 (LRRC8a)。用于细胞质体积调节，并可通过磷酸肌醇 3-激酶 (PI3K)/Akt 通路发出信号当前提案的目的是阐明 SWELL1 的作用机制。我们的假设是，新型机械传感器 SWELL1 可感知脂肪细胞大小，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。将脂肪细胞大小传感与胰岛素信号传导和脂质稳态联系起来将增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。为了检验上述假设，我们提出以下三个假设。具体目标：目标 1：表征瘦、肥胖和禁食小鼠脂肪细胞中的 SWELL1 电流。目标 2：确定脂肪细胞中 SWELL1-PI3K-Akt 信号传导的机制。目标 3：确定 SWELL1 对脂质代谢和肥胖的调节作用。该提案的贡献是显着的，因为它描绘了一种调节胰岛素信号和脂肪细胞生长的新型 SWELL1 信号通路，从而增进了我们对脂肪细胞的理解。该提议具有创新性，因为离子通道本质上是“可成药的”，SWELL1可能为肥胖症的治疗提供新的药理学靶点。