# Dichotomous Effects of MT1-MMP on Adipose Tissue Remodeling

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $385,000

## Abstract

Abstract
 In rapidly expanding adipose tissue (AT), pervasive hypoxia stimulates massive induction of Hypoxia Induced
Factor 1 α (HIF1α), which in turn initiates fibrosis and local inflammation ultimately leading to insulin resistance.
AT responds to the fibrosis by up-regulating MMPs, a family of endopeptidases that cleave collagens. MT1-MMP
(MMP14) is the major collagenase in AT that is up-regulated in obese fat pads. How MT1-MMP is up-regulated
and what are the functional consequences of the activation of MT1-MMP remain largely unknown. Interestingly,
we recently identified a novel collagen 6 digestion product (we refer to it as endotrophin) which stimulates fibrosis
and inflammation locally in unhealthy AT. However, the participating MMPs and detailed digesting event still
remain largely unknown. Based on the preliminary observations, it is hypothesized that MT1-MMP is responsible
for the digestion event to produce endotrophin. MT1-MMP might have dichotomous effects based on different
metabolic contexts in obese AT: On the one hand, at early-stage of AT expansion, MT1-MMP cleaves ECM
proteins to release the high pressure on fat cells, thus attempting to maintain healthy conditions; On the other
hand, at the late-stage of obese AT remodeling, it digests abnormally accumulated collagen 6α3 and produces
endotrophin which further enhances fibrosis and inflammation, ultimately leading a microenvironment highly
unfavorable for metabolic flexibility. To test the hypothesis, the current study has three specific Aims: 1). To
investigate the role of HIF1α in upregulation of MT1-MMP in obese AT; 2). To determine whether MT1-MMP
exerts anti-fibrotic and pro-angiogenic activity at early-stage of obesity development; and 3).To determine
whether MT1-MMP produces endotrophin by digesting abnormal accumulating collagen 6α3 to shape unhealthy
fat pads in late-stage of obesity development. Both gain-of-function and loss-of-function of HIF1α models will
be applied to achieve Aim 1. Diet-induced obese and doxycycline (Dox)-inducible AT specific MT1-MMP
transgenic mouse models will be used for Aim 2 and 3. Specifically, the overexpression of MT1-MMP will be
induced in AT during both “early-stage” and “late-stage” of obesity development. Endotrophin production, fibrosis
and inflammation in AT will be detected and metabolic phenotypes in the transgenic mice will be characterized
under different metabolic contexts. To further study the role of endotrophin in shaping unhealthy
microenvironment, both AT specific endotrophin overexpression and anti-endotrophin neutralizing antibody
treated mouse models will be utilized. The molecular mechanism by which endotrophin stimulates the local
fibrosis and inflammation will be further investigated in the mice.
 Findings from the study will enhance the general understanding of the complexity of AT physiology and
highlight the central role of MT1-MMP in the dynamics of AT remodeling during obesity development. Therefore,
inhibitio...

## Key facts

- **NIH application ID:** 9870790
- **Project number:** 5R01DK109001-04
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Kai Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870790

## Citation

> US National Institutes of Health, RePORTER application 9870790, Dichotomous Effects of MT1-MMP on Adipose Tissue Remodeling (5R01DK109001-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9870790. Licensed CC0.

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