# Fibrin(ogen) control of metabolic inflammation and obesity

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $376,526

## Abstract

PROJECT SUMMARY/ABSTRACT
Obesity-driven metabolic dysfunction is a driver of cardiovascular disease, type II diabetes, fatty liver disease,
thrombosis, and numerous cancers, and thus underlies substantial morbidity and mortality in the United States.
In obese humans with metabolic syndrome, and in mouse models of obesity, pathologic outcomes are driven
by a chronic inflammatory state of “metabolic inflammation,” in which immune cells (eg, macrophages) and
immune modulators (eg, cytokines) hijack normal metabolic function. Coagulation cascade activation is a
conspicuous feature of obesity in humans and is similarly prominent in high fat diet (HFD)-challenged mice.
Compelling published and new findings from our research team suggest that fibrin deposits in adipose are an
important, yet largely unappreciated driver of metabolic inflammation, and a powerful determinant of adipose
and liver pathologies in the obese state. The scientific premise for the proposed research is that fibrin(ogen),
factor XIII (fXIII), and β2 integrins have all independently been implicated in the pathogenesis of obesity
sequelae in experimental obesity. However, the precise mechanism(s) by which fibrin promotes inflammation,
including the molecular form of the molecule and the precise cell-surface receptors mediating inflammatory cell
activities, remains largely undefined. The central hypothesis framing these studies is that stabilized
extravascular fibrin deposits in adipose exacerbate macrophage-mediated metabolic inflammation by engaging
leukocyte integrin receptors αMβ2 and αXβ2. The principal objective of this study is to determine the
mechanisms whereby shifts in fibrinogen deposits in adipose and liver trigger local inflammatory cell activation
and dysfunctional metabolism in experimental obesity Specifically, we will: (i) determine whether the
conversion of fibrinogen to crosslinked fibrin matrices and the engagement of the leukocyte integrin receptor
αMβ2 are mechanistically coupled to the development of diet-induced obesity and metabolic dysfunction (AIM1);
(ii) determine the contribution of immobilized fibrinogen, fibrin, and crosslinked fibrin to β2 integrin-dependent
changes in macrophage phenotype as well as macrophage-mediated adipogenesis and lipid accumulation
within cells (AIM2); and (iii) determine the systemic and tissue-based changes in metabolism (specifically
glucose handling) mediated by fibrin(ogen). (AIM3). The insights gained will significantly advance the current
understanding of obesity development and highlight novel therapeutic opportunities centering on fibrin(ogen) in
the treatment of obesity-driven metabolic pathologies.

## Key facts

- **NIH application ID:** 10065070
- **Project number:** 7R01DK112778-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Matthew J. Flick
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,526
- **Award type:** 7
- **Project period:** 2018-12-20 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065070

## Citation

> US National Institutes of Health, RePORTER application 10065070, Fibrin(ogen) control of metabolic inflammation and obesity (7R01DK112778-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10065070. Licensed CC0.

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