The Role of IMAT Inflammatory Secretome on Muscle Insulin Resistance

IMAT 炎症分泌组对肌肉胰岛素抵抗的作用

• 批准号: 10749725
• 负责人: Colleen McKenna
• 金额: $ 6.91万
• 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: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749725
• 关键词: Address; Adipose tissue; Bathing; Biological Assay; Biometry; Body mass index; Cardiometabolic Disease; Clinical; Clinical Sciences; Colorado; Data; Endocrine; Endocrinology; Fascia; Funding; Goals; Health; Human; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Institution; Insulin; Insulin Resistance; Intervention; Investigation; Knowledge; Life; MAPK8 gene; Measures; Mediating; Medical; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Methods; Mission; Mitogen-Activated Protein Kinases; Muscle; Muscle Fibers; N-terminal; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Outcome; Paracrine Communication; Parents; Pathology; Phenotype; Phosphotransferases; Positioning Attribute; Postdoctoral Fellow; Prediabetes syndrome; Proteins; Proteomics; Public Health; Research; Role; Severities; Signal Transduction; Skeletal Muscle; Small Interfering RNA; Testing; Thinness; Tissue Donors; Tissue Therapy; Training; Translational Research; United States National Institutes of Health; Universities; Viral; Visceral; Work; cardiometabolic risk; cytokine; diabetes risk; disability; in vivo; insulin sensitivity; insulin signaling; knock-down; metabolic phenotype; nutrition; p38 Mitogen Activated Protein Kinase; paracrine; pharmacologic; skeletal muscle metabolism; skills; subcutaneous; transcriptome; translational scientist; vastus lateralis

PROJECT SUMMARY/ABSTRACT Skeletal muscle insulin resistance with type 2 diabetes (T2D) is, in part, caused by adipose inflammation and endocrine signaling. Intermuscular adipose tissue (IMAT) is a particularly problematic adipose depot as it resides under the muscle fascia and between myofiber bundles. Thus, it is uniquely situated for paracrine-mediated signaling towards muscle. Total IMAT content and its pro-inflammatory transcriptome relate to insulin resistance in humans, with the obese IMAT secretome milieu inhibiting myotube insulin sensitivity in vitro. However, it is unknown if the pro-inflammatory IMAT secretome is dynamic, contributing to muscle insulin resistance with obesity and T2D. There is a critical need to address this gap in knowledge in order to provide the framework for interventions to minimize IMAT-induced muscle metabolic dysfunction. The overall objective of this project is to quantify the IMAT secretome across BMI and insulin sensitivity and evaluate the importance of mitogen-activated protein kinase (MAPK) signaling in IMAT-induced muscle insulin resistance. We will utilize IMAT from the vastus lateralis of individuals with obesity or obesity and prediabetes/T2D in comparison to lean controls through a currently funded R01 (under the sponsor Dr. Bryan Bergman) to achieve the following specific aims. Aim I: Evaluate the extent to which intermuscular adipose tissue pro-inflammatory secretion differs across BMI and insulin sensitivity in humans. Based on our preliminary evidence that IMAT with obesity has a more potent pro-inflammatory secretome compared to other adipose depots, our hypothesis is that IMAT secretome scales to BMI and insulin resistance. A high-throughput quantitative proteomic assay will measure inflammatory proteins in IMAT conditioned media. Aim II: Elucidate the importance of MAPK signaling in intermuscular adipose tissue-induced skeletal muscle insulin resistance. Our preliminary evidence demonstrates that obese IMAT paracrine milieu upregulates c-Jun N-terminal Kinase (JNK1) and p38 activity, and downregulates insulin sensitivity, in human myotubes. Our hypothesis is that inhibition of MAPK signaling will help to alleviate IMAT- induced muscle insulin resistance. This will be tested by evaluating IMAT conditioned media-induced insulin resistance with either JNK1 or p38 inhibition through either viral siRNA knockdown or pharmacological inhibition in human myotubes. Our expected contribution is significant because IMAT is positioned as a strong candidate to explain the pathology of muscle insulin resistance that is central to T2D. This training plan includes sponsorship by Dr. Bergman at the University of Colorado Anschutz Medical Campus (CUAMC). The proposed research will enhance the skillset of the postdoctoral fellow in both clinical and in vitro methods. The postdoctoral fellow will complete additional training in endocrinology, obesity metabolism, and biostatistics through the Nutrition Obesity Research Center and Clinical and Translational Sciences Institute at CUAMC. This research, sponsor, and institution will collectively position me as an independent translational scientist investigating the role of skeletal muscle insulin resistance in T2D risk and progression.

项目概要/摘要 2 型糖尿病 (T2D) 的骨骼肌胰岛素抵抗部分是由脂肪炎症和 内分泌信号。肌间脂肪组织（IMAT）是一个特别有问题的脂肪库，因为它存在 位于肌肉筋膜下方和肌纤维束之间。因此，它对于旁分泌介导的 向肌肉发出信号。总 IMAT 含量及其促炎转录组与胰岛素抵抗相关 在人类中，肥胖的 IMAT 分泌环境在体外抑制肌管胰岛素敏感性。然而，它是 未知促炎性 IMAT 分泌组是否是动态的，从而导致肌肉胰岛素抵抗 肥胖和 T2D。迫切需要解决这一知识差距，以便提供框架 减少 IMAT 引起的肌肉代谢功能障碍的干预措施。该项目的总体目标是 量化跨 BMI 和胰岛素敏感性的 IMAT 分泌组，并评估有丝分裂原激活的重要性 IMAT 诱导的肌肉胰岛素抵抗中的蛋白激酶 (MAPK) 信号传导。我们将利用广大的 IMAT 肥胖或肥胖和糖尿病前期/T2D 个体与瘦对照者相比，通过 目前资助 R01（在赞助商 Bryan Bergman 博士的资助下）以实现以下具体目标。目标一： 评估不同 BMI 下肌间脂肪组织促炎分泌的差异程度 和人类的胰岛素敏感性。根据我们的初步证据，IMAT 对肥胖有更有效的作用 与其他脂肪库相比，促炎分泌组，我们的假设是 IMAT 分泌组规模 BMI 和胰岛素抵抗。高通量定量蛋白质组学测定将测量炎症蛋白 在 IMAT 条件培养基中。目标 II：阐明 MAPK 信号在肌间脂肪中的重要性 组织诱导的骨骼肌胰岛素抵抗。我们的初步证据表明，肥胖的 IMAT 旁分泌环境上调 c-Jun N 末端激酶 (JNK1) 和 p38 活性，并下调胰岛素 人类肌管的敏感性。我们的假设是，抑制 MAPK 信号传导将有助于缓解 IMAT- 诱发肌肉胰岛素抵抗。这将通过评估 IMAT 条件培养基诱导的胰岛素进行测试 通过病毒 siRNA 敲低或药物抑制对 JNK1 或 p38 抑制产生耐药性 在人类肌管中。我们的预期贡献是巨大的，因为 IMAT 被定位为强有力的候选者 解释对 T2D 至关重要的肌肉胰岛素抵抗的病理学。本次培训计划包括 由科罗拉多大学安舒茨医学院 (CUAMC) 的 Bergman 博士赞助。拟议的 研究将提高博士后研究员在临床和体外方法方面的技能。博士后 研究员将通过以下方式完成内分泌学、肥胖代谢和生物统计学方面的额外培训 CUAMC 营养肥胖研究中心和临床与转化科学研究所。这项研究， 赞助商和机构将共同将我定位为一名独立的转化科学家，研究 骨骼肌胰岛素抵抗在 T2D 风险和进展中的作用。