Extracellular matrix-adipocyte metabolic crosstalk and diabetes

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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 and identify Advanced Glycation End- products (AGE) modification of the ECM as a mechanisms of adipose tissue dysfunction in 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 and AGE in regulating adipocyte metabolism, and to develop novel adipose tissue-based vehicles to manipulate systemic insulin resistance in vivo. Our central hypothesis is that in diabetes, adipose tissue ECM regulates adipocyte cellular metabolism via an AGE-integrin-cytoskeleton signaling axis triggered by increased matrix stiffness in DM, and that manipulation of matrix stiffness can be exploited to modulate adipocyte cellular metabolism and the effects of ASC on systemic insulin resistance. The rationale for this hypothesis is based on extensive literature linking alterations in adipose tissue ECM and metabolism to obesity and diabetes, and our preliminary data confirming ECM regulation of adipocyte metabolism and implicating AGE- mediated regulation of the adipocyte cytoskeleton in ECM-adipocyte crosstalk. Aim 1 will define the role of AGE-integrin-cytoskeleton signaling in regulating human adipose tissue dysfunction in vitro in the context of diabetes in a human ECM-adipocyte culture system. Aim 2 will study the role of AGE in regulating human adipose tissue metabolism in an in vitro human 3D-adipocyte hydrogel culture model that permits manipulation of matrix mechanics. Aim 3 will study the role of adipose stromal cells and matrix in regulating systemic metabolism using a murine xenograft transplant model in which human adipose tissue stromal cells are transplanted into mice in engineered hydrogel vehicles to ameliorate systemic insulin resistance. 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 human adipose tissue stromal cells delivered in engineered artificial matrix in murine obesity addressing an important knowledge gap that will study the role of human cells in regulatinging system metabolism, and serving as a first step towards development of novel treatment strategies for diabetes with significant translational potential. The PI, Robert O’Rourke, MD, is a VA clinician-scientist with extensive experience in adipose tissue and metabolic disease research. Our research team includes co-investigators Andrew Putnam, PhD, a bioengineer with expertise in matrix-cell engineering, and Carey Lumeng, MD, PhD, an adipose tissue biologist with expertise in murine models of obesity. This proposal extends an already unique, robust obesity-research program within the VA system established by the PI that has been in place for nearly a decade. This diverse team and infrastructure maximizes the likelihood of this proposal generating novel, clinically relevant findings.