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

基本信息

  • 批准号:
    10749725
  • 负责人:
  • 金额:
    $ 6.91万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
项目总结/摘要 2型糖尿病(T2 D)的骨骼肌胰岛素抵抗部分是由脂肪炎症引起的, 内分泌信号肌间脂肪组织(IMAT)是一个特别有问题的脂肪库,因为它驻留在 在肌筋膜下和肌纤维束之间。因此,它是唯一位于旁分泌介导的 向肌肉发出信号IMAT总含量及其促炎转录组与胰岛素抵抗的关系 在人类中,肥胖IMAT分泌体环境在体外抑制肌管胰岛素敏感性。但据 尚不清楚促炎性IMAT分泌蛋白组是否是动态的,导致肌肉胰岛素抵抗, 肥胖和T2 D。迫切需要填补这一知识空白,以便为以下方面提供框架: 干预措施,以尽量减少IMAT诱导的肌肉代谢功能障碍。该项目的总体目标是 在BMI和胰岛素敏感性之间量化IMAT分泌蛋白,并评估促分裂原活化的重要性。 蛋白激酶(MAPK)信号转导在IMAT诱导的肌肉胰岛素抵抗。我们将利用来自宇宙飞船的IMAT 肥胖或肥胖和前驱糖尿病/T2 D个体的外侧肌与瘦对照相比, 目前资助R 01(在赞助商Bryan Bergman博士的领导下),以实现以下具体目标。目标一: 评估肌间脂肪组织促炎性分泌在不同BMI之间的差异程度 和胰岛素敏感性的关系。基于我们的初步证据,IMAT与肥胖有更有效的 促炎分泌组相比,其他脂肪仓库,我们的假设是,IMAT分泌组规模 BMI和胰岛素抵抗的关系。高通量定量蛋白质组学检测将测量炎症蛋白 在IMAT条件培养基中。目的II:阐明肌间脂肪中MAPK信号传导的重要性 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(JNK 1)和p38活性,下调胰岛素 敏感性,在人类肌管中。我们的假设是,MAPK信号的抑制将有助于减轻IMAT- 诱导肌肉胰岛素抵抗。这将通过评价IMAT条件培养基诱导的胰岛素 通过病毒siRNA敲低或药理学抑制对JNK 1或p38抑制的抗性 在人体肌管中。我们的预期贡献是显着的,因为IMAT被定位为一个强有力的候选人 来解释T2 D的核心肌肉胰岛素抵抗的病理学。该培训计划包括 由伯格曼博士在科罗拉多大学安舒茨医学院(CUAMC)赞助。拟议 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定位我作为一个独立的翻译科学家调查 骨骼肌胰岛素抵抗在2型糖尿病风险和进展中的作用

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