Extracellular matrix-adipocyte metabolic crosstalk and diabetes

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PROJECT SUMMARY ABSTRACT Obesity and associated metabolic disease, including type II diabetes, is a public health crisis, the risks of which are elevated in military Veterans. Adipose tissue metabolism is dysregulated in obesity and is a central mediator of diabetes pathogenesis, but underlying mechanisms are not well-defined. The extracellular matrix (ECM) is an understudied component of adipose tissue, and our preliminary data demonstrate that that ECM regulates adipocyte metabolic dysfunction in the context of diabetes. These observations suggest adipose tissue ECM as a novel therapeutic target for diabetes. The scientific goals of this proposal are to define the role of the ECM in regulating adipocyte metabolism, and to develop novel in vitro engineered ECM-based adipose tissues as therapeutic vehicles to manipulate systemic insulin resistance. Our central hypothesis is that in diabetes, Advanced Glycation End-products (AGE)-modified adipose tissue ECM engages in crosstalk with adipocytes, with detrimental effects on tissue and systemic metabolism, contributing to disease pathogenesis. The rationale for this hypothesis is based on extensive literature linking alterations in adipose tissue ECM and metabolism to obesity and diabetes, and preliminary data confirming ECM regulation of adipocyte metabolism and implicating AGE and AGE-receptors in ECM-adipocyte crosstalk. Aim 1 will define the role of AGE in regulating human adipose tissue AGE- receptor signaling balance in diabetes, and perform detailed proteomics analysis to define diabetes-specific alterations in the human adipose tissue ECM proteome. Aim 2 will study the role of AGE and AGE receptors in regulating human adipose tissue metabolism in standard 2D culture and in sophisticated in vitro human 3D- ECM-adipocyte culture models. Aim 3 will study the role of adipose tissue ECM in regulating systemic insulin resistance using an innovative murine ECM-adipocyte transplant model. This project is significant because it will define mechanisms of ECM-adipocyte crosstalk in diabetes, bridging an important knowledge gap and advancing an understanding of ECM control of adipose tissue and systemic metabolism. This project also studies transplant of engineered ECM-based adipose tissue in murine obesity, a novel treatment strategy for diabetes with significant translational potential. The PI of this project Robert O'Rourke, MD, is a VA clinician-scientist with extensive experience in adipose tissue biology and metabolic disease research. This proposal will establish a unique obesity-research program within the VA system.