# Role of Endothelial Regulation of Fatty Acid Uptake in Metabolic Dysfunction

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $528,560

## Abstract

Abstract
Cardiovascular complications of diabetes continue to remain a huge burden on the health care system. Of all
the currently approved anti-diabetic therapies, only one class to date has demonstrated any significant
improvement in cardiovascular outcomes. Novel therapeutic strategies that can couple improvements in
glycemic control with reduction of cardiovascular complications would represent a significant advancement in
how we manage these challenging patient population. To this end, we propose to investigate an exciting novel
strategy to target the endothelial based signaling cascade driven by the G protein coupled receptor APLNR, as
we characterize the mechanistic basis of its anti-glycemic and atheroprotective effects. A key mechanistic basis
for this strategy, as outlined in this proposal, is to exploit its function as the metabolic transport barrier that
actively regulates the transport and uptake of fatty acid in target organs such as skeletal muscles, which in turn
determines insulin sensitivity and glucose utilization. Our exciting preliminary data, including: : 1) demonstration
of marked impairment of glycemic control in conditional, endothelial specific Aplnr deleted mice, 2) discovery of
FOXO1, a key metabolic transcription factor, as a novel signaling target of apelin, whereby apelin induces its
inactivation via phosphorylation and cytoplasmic translocation, 3) demonstration that the negative regulation of
FOXO1 by apelin in the endothelium leads to suppression of FABP4 (AP2) expression, which regulates trans-
endothelial FA transport, and 4) identification of novel endothelial based crosstalk between apelin/APLNR and
insulin/insulin receptor (IR) signaling. Based on these provocative preliminary data, we will address the
hypothesis that endothelial APLNR signaling is an essential regulator of the endothelial function as a gatekeeper
of FA uptake and transport. Aim 1 will utilize in vivo and in vitro approaches to determine the mechanism of
crosstalk between apelin-APLNR signaling and insulin-IR signaling. Aim 2 will determine the metabolic role of
elabela, the recently identified second APLNR ligand. Aim 3 will push forward the translational application of
these findings by testing the efficacy and mechanistic basis of novel APLNR agonists in experimental diabetes
and atherosclerosis models. Overall, our studies will significantly expand our knowledge of a novel endothelial-
based signaling paradigm that regulates energy resource utilization, with multiple implications in the context of
the worldwide epidemic of diabetes and its associated cardiovascular complications.

## Key facts

- **NIH application ID:** 9964528
- **Project number:** 5R01HL142818-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Hyung Joon Chun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $528,560
- **Award type:** 5
- **Project period:** 2018-07-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964528

## Citation

> US National Institutes of Health, RePORTER application 9964528, Role of Endothelial Regulation of Fatty Acid Uptake in Metabolic Dysfunction (5R01HL142818-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9964528. Licensed CC0.

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