# Extracellular matrix-adipocyte metabolic crosstalk and diabetes

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2021 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 9856881
- **Project number:** 5I01CX001811-02
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** ROBERT W O'ROURKE
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856881

## Citation

> US National Institutes of Health, RePORTER application 9856881, Extracellular matrix-adipocyte metabolic crosstalk and diabetes (5I01CX001811-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9856881. Licensed CC0.

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