The Role of IMAT Inflammatory Secretome on Muscle Insulin Resistance

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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.