# Extracellular matrix-adipocyte metabolic crosstalk and diabetes

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## 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 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
metabo...

## Key facts

- **NIH application ID:** 10909789
- **Project number:** 5I01CX001811-06
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** ROBERT W O'ROURKE
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-01-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909789

## Citation

> US National Institutes of Health, RePORTER application 10909789, Extracellular matrix-adipocyte metabolic crosstalk and diabetes (5I01CX001811-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10909789. Licensed CC0.

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