# Leptin, a therapeutic avenue for the treatment of vascular disease, focus on congenital and antiretroviral therapy-associated lipodystrophies

> **NIH NIH R00** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $244,464

## Abstract

PROJECT SUMMARY
Lipodystrophy is a congenital disorder or a condition acquired later in life, which can be caused by antiretroviral
therapies (ART). Lipodystrophy is characterized by a total or partial absence of adipose tissue resulting in drastic
reductions in leptin levels, metabolic disorders and cardiovascular disease (CVD). However the molecular
mechanisms whereby lipodystrophy causes CVD are still unclear. In addition, although the FDA recently
approved the use of leptin as a therapy to minimize the metabolic dysfunction in lipodystrophic patients, whether
leptin replacement therapy improves lipodystrophy-associated CVD remains unknown. The goal of the present
application is to combine the use of genetically engineered animal models and pharmacological approaches with
cell cultures to identify the molecular mechanism whereby lipodystrophy induces endothelial dysfunction and
determine whether leptin treatment restores lipodystrophy associated endothelial dysfunction. Preliminary data
for this application report that reduction in adipose mass and leptin levels in mouse models of congenital and
ART-induced lipodystrophy is associated with impaired endothelium-dependent relaxation. Furthermore, we
show that lipodystrophy increases vascular oxidative stress, elevates endothelial Nox1 expression in the
vasculature, reduces vascular peroxisome proliferator-activated receptor gamma (PPARγ) and promotes
vascular inflammation characterized by elevated RANTES/CCR5, IL-1β, MCP-1, F4/80, and GATA-3 levels. We
also show that ROS scavenging with tempol or the Nox1/Nox4 inhibitor restores endothelial function and Nox1
lack prevents lipodystrophy-induced endothelial dysfunction and vascular inflammation. Moreover, we find that
leptin supplementation, restores endothelial function, increases PPARγ, reduces Nox1 in aortae and freshly
isolated endothelial cells, reduces RANTES/CCR5 expression and reverts vascular inflammation. Finally, we
report that increasing leptin sensitivity in endothelial cells specifically prevents lipodystrophy-induced endothelial
dysfunction and vascular inflammation. Based on these findings, we hypothesized that the reduction in
endothelial leptin signaling impairs endothelium-dependent relaxation and promotes vascular inflammation via
Nox1 dependent mechanisms, in lipodystrophy. This hypothesis will be tested with the three following aims: K99:
Aim 1: lipodystrophy triggers endothelial dysfunction via Nox1-mediated, PPARγ-dependent mechanisms.
K99/R00: Aim 2: reduction in endothelial leptin signaling impairs endothelial function in mouse models of
lipodystrophy. R00: Aim 3: leptin reduces vascular immune cell infiltration via decreasing endothelial
RANTES/CCR5 expression.

## Key facts

- **NIH application ID:** 9990881
- **Project number:** 5R00HL140139-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Thiago Bruder
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $244,464
- **Award type:** 5
- **Project period:** 2019-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990881

## Citation

> US National Institutes of Health, RePORTER application 9990881, Leptin, a therapeutic avenue for the treatment of vascular disease, focus on congenital and antiretroviral therapy-associated lipodystrophies (5R00HL140139-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9990881. Licensed CC0.

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