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）在骨骼肌内大理石，似乎在 肥胖引起的2型糖尿病风险。尚不知道的是IMAT如何促进肌肉胰岛素减少 灵敏度。迫切需要了解IMAT如何促进肥胖引起的糖尿病的风险， 以及如何干预以最大程度地减少IMAT诱导的肌肉代谢功能障碍。总体目标 项目是确定减肥对纤连蛋白和炎症细胞因子IMAT分泌的影响 和类花生酸。我们的中心假设是纤连蛋白的IMAT分泌促进肌肉胰岛素 抗炎性细胞因子和类花生素的抗性和IMAT分泌引起肌肉感染，均引起肌肉感染 其中的体重减轻减少了。拟议研究的基础的理由是使 体重减轻在多大程度上改变了IMAT分泌组将告知开发干预措施以修改IMAT 并改善肥胖个体的肌肉胰岛素敏感性。我们提出了两个具体目标：特定目标1。 评估体重减轻对纤连蛋白IMAT分泌的影响以及纤连蛋白在IMAT中的作用 分泌体内降低胰岛素敏感性的分泌组。初步数据为我们的工作假设提供了IMAT的工作假设 分泌纤连蛋白，可降低肌肉胰岛素敏感性，并在人类体重减轻后减弱。在 体外实验将测量IMAT纤连蛋白分泌的程度解释IMAT诱导的肌肉 胰岛素抵抗。我们将研究12周减肥干预前后的肥胖者。 IMAT将使用超声引导的IMAT活检技术进行采样，并使用胰岛素灵敏度测量 使用MRI测量的胰岛素夹和IMAT含量。特定目标2 - 确定体重的影响 促炎性细胞因子和类花生素的IMAT分泌损失以及引起感染的效力 降低体外胰岛素敏感性。我们再次基于初步数据来假设IMAT秘密 肥胖个体体重减轻后的炎症较少，促进肌肉的效力降低了 炎症和胰岛素抵抗。肌肉炎症反应和胰岛素敏感性与IMAT分泌组 体外体重减轻之前和之后将比较暴露。拟议的研究具有创新性，因为 它通过测试特定的IMAT分泌旁分裂来代表与现状的新事物差异 信号而不是与IMAT含量的临床关联。这些贡献将通过确定 第一个影响肌肉并通过减肥来揭示IMAT的可塑性的IMAT旁分泌信号， 提供概念证明IMAT是对抗肌肉代谢功能障碍的治疗靶标。