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 骨骼肌胰岛素抵抗合并2型糖尿病(T2D)，部分原因是脂肪炎症和 内分泌信号。肌间脂肪组织(IMAT)是一个特别有问题的脂肪库，因为它存在于 在肌筋膜下和肌纤维束之间。因此，它是旁分泌介导的独特位置。 向肌肉发出信号。总IMAT含量及其促炎转录组与胰岛素抵抗的关系 在人类中，肥胖的IMAT分泌体环境在体外抑制肌管胰岛素敏感性。然而，它是 尚不清楚促炎症的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。迫切需要解决知识方面的这一差距，以便为 减少IMAT引起的肌肉代谢功能障碍的干预措施。这个项目的总体目标是 通过BMI和胰岛素敏感性量化IMAT分泌组，并评估丝裂原激活的重要性 蛋白激酶(MAPK)信号在IMAT诱导的肌肉胰岛素抵抗中的作用。我们将使用股骨头的IMAT 肥胖或肥胖症和糖尿病前期/T2D患者与瘦身对照组的侧向比较 目前为R01(在发起人布莱恩·伯格曼博士的资助下)提供资金，以实现以下具体目标。目标I： 评估肌肉间脂肪组织促炎症分泌在不同BMI间的差异程度 以及人类对胰岛素的敏感性。根据我们的初步证据，IMAT与肥胖症有更强的 促炎性分泌体与其他脂肪库相比，我们的假设是IMAT分泌体具有鳞片 体重指数和胰岛素抵抗。一种高通量的定量蛋白质组分析将测量炎性蛋白 在IMAT条件培养液中。目的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氨基末端酶1和p38活性，下调胰岛素 敏感性，在人体肌管中。我们的假设是，抑制MAPK信号将有助于缓解IMAT- 诱导肌肉胰岛素抵抗。这将通过评估IMAT条件培养液诱导的胰岛素来进行测试 通过病毒siRNA敲除或药物抑制而抑制JNK1或p38的耐药性 在人体肌管中。我们的预期贡献很大，因为IMAT被定位为一个强有力的候选者 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 由科罗拉多大学安舒茨医学院(CUAMC)的伯格曼博士赞助。建议数 研究将提高博士后在临床和体外方法方面的技能。博士后 FLOW将完成内分泌学、肥胖症新陈代谢和生物统计学的额外培训 中国农业大学营养性肥胖研究中心和临床与翻译科学研究所。这项研究， 赞助商和机构将共同将我定位为一名独立的翻译科学家 骨骼肌胰岛素抵抗在T2D风险和进展中的作用。