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.

项目摘要/摘要 2型糖尿病（T2D）的骨骼肌胰岛素耐药性部分是由脂肪炎症和 内分泌信号传导。肌间脂肪组织（IMAT）是一个特别有问题的脂肪仓库 在肌肉筋膜下和肌纤维束之间。因此，它位于旁分泌介导的独特位置 向肌肉发出信号。 IMAT的总含量及其促炎性转录组与胰岛素抵抗有关 在人类中，肥胖的IMAT分材秘密环境抑制体外肌管胰岛素敏感性。但是，是 未知的促炎性IMAT分泌组是否动态，导致肌肉胰岛素抵抗 肥胖和T2D。在知识上解决这一差距，以提供框架 干预措施以最大程度地减少IMAT诱导的肌肉代谢功能障碍。该项目的总体目标是 量化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。我们将利用大量的IMAT 与通过A的精益控制相比 目前，R01（在赞助商Bryan Bergman博士的领导下）资助了以下特定目标。 AIM I： 评估肌间脂肪组织促炎性分泌的程度在多大程度上不同 和人类的胰岛素敏感性。基于我们的初步证据，表明肥胖具有更有效的 与其他脂肪仓库相比，促炎性分泌症状，我们的假设是IMAT分泌量表 抗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条件媒体中。 AIM II：阐明MAPK信号在肌间脂肪中的重要性 组织引起的骨骼肌胰岛素抵抗。我们的初步证明表明肥胖 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 敏感性，在人体肌管中。我们的假设是，抑制MAPK信号传导将有助于减轻IMAT- 诱导肌肉胰岛素抵抗。这将通过评估IMAT条件培养基诱导的胰岛素来测试 通过病毒siRNA敲低或药理抑制作用JNK1或P38的抗性 在人类肌管中。我们的预期贡献很重要，因为IMAT被定位为强大的候选人 解释肌肉胰岛素抵抗的病理，这是T2D的核心。该培训计划包括 科罗拉多大学安索斯大学医学校园（Cuamc）的伯格曼博士赞助。提议 研究将在临床和体外方法中提高博士后研究员的技能。博士后 研究员将完成内分泌学，肥胖代谢和生物统计学的其他培训 Cuamc的营养肥胖研究中心以及临床和转化科学研究所。这项研究， 赞助商和机构将共同将我定位为一名独立翻译科学家，调查 骨骼肌胰岛素抵抗在T2D风险和进展中的作用。