Effect of weight loss on intermuscular adipose tissue (IMAT) signaling

减肥对肌间脂肪组织 (IMAT) 信号传导的影响

• 批准号: 10735418
• 负责人: BRYAN C BERGMAN
• 金额: $ 65.75万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-05 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735418
• 关键词: Achievement; Adipose tissue; Age; Attenuated; Bathing; Biopsy; Body Weight decreased; Body mass index; Clinical; Closure by clamp; Data; Development; Diabetes Mellitus; Eicosanoids; Ethnic Origin; Extracellular Matrix Proteins; Fibronectins; Future; Glucose Clamp; Health; Human; Hyperinsulinism; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Intervention; Life; Magnetic Resonance Imaging; Marble; Measures; Metabolic; Metabolic dysfunction; Mission; Muscle; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Outcome; Paracrine Communication; Play; Positioning Attribute; Public Health; Research; Risk; Role; Sampling; Signal Transduction; Signaling Molecule; Skeletal Muscle; Techniques; Testing; Tissues; United States National Institutes of Health; Visceral; adipokines; combat; cytokine; disability; experimental study; improved; innovation; insulin sensitivity; lifestyle intervention; new therapeutic target; novel; obese person; obesity risk; prevent; response; sex; therapeutic target; therapy development; ultrasound; weight loss intervention

Intermuscular adipose tissue (IMAT) is marbled within skeletal muscle and appears to play a key role in the obesity-induced risk of type 2 diabetes. What is not known is how IMAT promotes decreased muscle insulin sensitivity. There is a critical need to understand how IMAT contributes to the risk of obesity-induced diabetes, and how to intervene to minimize IMAT-induced muscle metabolic dysfunction. The overall objective for this project is to determine the impact of weight loss on IMAT secretion of fibronectin and inflammatory cytokines and eicosanoids. Our central hypothesis is that IMAT secretion of fibronectin promotes muscle insulin resistance, and IMAT secretion of inflammatory cytokines and eicosanoids causes muscle inflammation, both of which are diminished by weight loss. The rationale that underlies the proposed research is that clarifying the extent to which weight loss alters the IMAT secretome will inform development of interventions to modify IMAT and improve muscle insulin sensitivity in obese individuals. We propose two specific aims: Specific Aim 1. Evaluate the impact of weight loss on IMAT secretion of fibronectin and the role of fibronectin in the IMAT secretome to decrease insulin sensitivity in vitro. Preliminary data inform our working hypothesis that IMAT secretes fibronectin that decreases muscle insulin sensitivity and is attenuated after weight loss in humans. In vitro experiments will measure the extent to which IMAT fibronectin secretion explains IMAT-induced muscle insulin resistance. We will study individuals with obesity before and after a 12-week weight loss intervention. IMAT will be sampled using an ultrasound guided IMAT biopsy technique, insulin sensitivity measured using insulin clamps, and IMAT content measured using MRI. Specific Aim 2 – Determine the influence of weight loss on IMAT secretion of pro-inflammatory cytokines and eicosanoids and potency to cause inflammation and decrease insulin sensitivity in vitro. We hypothesize, again based on preliminary data that the IMAT secretome is less inflammatory after weight loss in obese individuals, with decreased potency to promote muscle inflammation and insulin resistance. Muscle inflammatory response and insulin sensitivity with IMAT secretome exposure will be compared before and after weight loss in vitro. The proposed research is innovative because it represents a new and substantive departure from the status quo by testing specific IMAT secreted paracrine signals rather than clinical associations with IMAT content. These contributions will be significant by identifying the first IMAT paracrine signals that impact muscle and revealing the plasticity of IMAT through weight loss, providing proof of concept that IMAT is a therapeutic target to combat muscle metabolic dysfunction.

肌间脂肪组织（IMAT）在骨骼肌内呈大理石花纹，似乎在骨骼肌的形成过程中发挥着关键作用。 肥胖引起的 2 型糖尿病风险目前尚不清楚，IMAT 如何导致肌肉胰岛素下降。 迫切需要了解 IMAT 如何增加肥胖引起的糖尿病的风险， 以及如何进行干预以尽量减少 IMAT 引起的肌肉代谢功能障碍。 该项目旨在确定减肥对 IMAT 分泌纤连蛋白和炎症细胞因子的影响 我们的中心假设是纤连蛋白的 IMAT 分泌促进肌肉胰岛素。 抵抗力和 IMAT 分泌炎症细胞因子和类二十烷酸会导致肌肉炎症，两者 这项研究的基本原理是澄清体重。 减肥改变 IMAT 分泌组的程度将为改变 IMAT 的干预措施的制定提供信息 我们提出了两个具体目标：具体目标 1。 评估减肥对 IMAT 分泌纤连蛋白的影响以及纤连蛋白在 IMAT 中的作用 初步数据告诉我们 IMAT 的工作假设。 分泌纤连蛋白，降低肌肉胰岛素敏感性，并在人类体重减轻后减弱。 体外实验将测量 IMAT 纤连蛋白分泌在多大程度上解释 IMAT 诱导的肌肉 我们将研究肥胖个体在 12 周减肥干预前后的情况。 将使用超声引导的 IMAT 活检技术对 IMAT 进行采样，使用以下方法测量胰岛素敏感性 胰岛素钳夹和使用 MRI 测量的 IMAT 含量 具体目标 2 – 确定体重的影响。 促炎细胞因子和类二十烷酸的 IMAT 分泌丧失，以及引起炎症和炎症的效力 再次基于 IMAT 分泌组的初步数据，我们在体外降低胰岛素敏感性。 肥胖个体减肥后炎症较少，促进肌肉的效力降低 IMAT 分泌组的肌肉炎症反应和胰岛素敏感性。 这项研究的创新之处在于，将在体外对减肥前后的暴露进行比较。 通过测试特定的 IMAT 分泌的旁分泌，它代表了对现状的新的实质性偏离 信号而不是与 IMAT 内容的临床关联，通过识别这些贡献将是重要的。 第一个影响肌肉的 IMAT 旁分泌信号并通过减肥揭示了 IMAT 的可塑性， 提供了 IMAT 是对抗肌肉代谢功能障碍的治疗靶点的概念证明。