# Endothelial lipid droplet turnover and regulation of metabolic function

> **NIH NIH K01** · YALE UNIVERSITY · 2021 · $152,874

## Abstract

Project Summary
 Accumulating evidence demonstrates that the vascular endothelium plays an important role in the
regulation of metabolic homeostasis. In accordance, endothelial dysfunction contributes to metabolic
derangements associated with obesity and insulin resistance. Our laboratory provided the first evidence that
endothelial cells (ECs) have the capacity to form lipid droplets (LDs) in vivo and demonstrated that LD turnover
(i.e., synthesis and degradation) is necessary for maintaining EC quiescence and function. Specifically,
pharmacological inhibition of key enzymes in the LD synthesis pathway, diacylglycerol acetyl transferase (DGAT)
1 and 2, led to endoplasmic reticulum (ER) stress. Alternatively, endothelial specific deletion of adipose
triglyceride lipase (ATGL), the rate-limiting enzyme in LD hydrolysis, led to a profound reduction in endothelial
nitric oxide synthase (eNOS) protein levels and nitric oxide (NO) bioavailability in standard chow fed mice.
Indeed, these vascular perturbations have been linked to derangements in whole-body metabolism, but the role
of EC LD turnover as it relates to the control of vascular and metabolic function is unknown. Therefore, in this
proposal, I will define the specific role of endothelial LD turnover in maintaining vascular and metabolic
function during normal physiology, DIO and in response to acute and chronic exercise. To achieve these
ends, I will generate inducible, endothelial specific ATGL knockout (iECKO), DGAT1-iECKO and DGAT2-iECKO
mice as tools to dissect the molecular mechanisms by which LD turnover controls vascular and whole-body
metabolic homeostasis. In aim 1, I will dissect the cellular mechanisms by which disruption in LD turnover leads
to endothelial dysfunction under normal physiology and DIO via rigorous and meticulous molecular and metabolic
characterization. In aim 2, I will decipher the importance of endothelial LD turnover in maintaining insulin
sensitivity in normal physiology and DIO via comprehensive in vivo metabolic studies and ex vivo tissue analysis.
Lastly, in aim 3, I will establish the role of endothelial LD turnover in the regulation of adaptations in response to
an acute bout of exercise bout and chronic endurance training using a similar approach as aim 2. Collectively,
these studies will address a heretofore unknown role of EC LD turnover in whole-body metabolism. Results from
these studies will provide a better understanding of the interrelationship between vascular and metabolic function
during normal physiology and in the setting of obesity and type II diabetes. In addition to these research aims,
this proposal describes a five-year intensive mentored training program with the goal of developing the Principal
Investigator (PI, Nabil Boutagy, Ph.D.) into an independent and high impact, scientist in the fields of vascular
biology and metabolism under the supervision of his primary mentor, Dr. William Sessa, and co-mentor, Dr.
Gerald Shulman. Furthermore,...

## Key facts

- **NIH application ID:** 10221679
- **Project number:** 5K01DK124441-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Nabil Boutagy
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $152,874
- **Award type:** 5
- **Project period:** 2020-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10221679

## Citation

> US National Institutes of Health, RePORTER application 10221679, Endothelial lipid droplet turnover and regulation of metabolic function (5K01DK124441-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10221679. Licensed CC0.

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