# Endothelin - Mechanisms in Hypertension and Obesity

> **NIH NIH R00** · UNIVERSITY OF MISSISSIPPI MED CTR · 2020 · $70,973

## Abstract

PROJECET SUMMARY
Insulin resistance is a major health problem in the U.S. It precludes type II
diabetes and is often present in obese patients, both being major risk factors for
cardiovascular disease. Currently, mechanisms associated with insulin
resistance aren't fully understood. ET-1 is a vasoactive peptide primarily released
by endothelial cells that is associated with insulin resistance and increased in
obese patients. ET-1 activates two receptors, ETA and ETB. We have previously
shown that inhibiting ETB receptors in rodents, either genetically or
pharmacologically, improves insulin tolerance and reduces fasting blood glucose.
In addition, loss of ETB function reduces adiposity, suggesting the adipose tissue
as a possible target for ET-1 induced alteration in insulin signaling. It has been
previously shown that activation of ETB receptors on cultured adipocytes inhibits
the anti-lipolytic effects of insulin. Furthermore, blockade of ETB receptors
reduces fasting blood glucose in the GK rat model of type II diabetes and
improves insulin sensitivity in a rodent model of sleep apnea. These data suggest
that increased ET-1 observed in obese patients may promote insulin resistance
via the ETB receptor. Thus, we hypothesize that activation of the ET-1/ETB
receptor promotes IR and impairs glucose metabolism in adipocytes. To test this
hypothesis, we will utilize both in vivo and in vitro techniques using two novel
mouse models. One will allow us to over-express the ETB receptor, and another
that will allow us to knockout the ETB receptor specifically in adipocytes. We will
test the following specific aims:
Specific aim 1: To test the hypothesis that ETB receptor activation inhibits insulin
signaling in cultured adipocytes.
Specific aim 2: To test the hypothesis that ETB receptor activation causes insulin
resistance in vivo.

## Key facts

- **NIH application ID:** 10057015
- **Project number:** 3R00HL127178-05S1
- **Recipient organization:** UNIVERSITY OF MISSISSIPPI MED CTR
- **Principal Investigator:** Joshua S Speed
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $70,973
- **Award type:** 3
- **Project period:** 2016-01-15 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10057015

## Citation

> US National Institutes of Health, RePORTER application 10057015, Endothelin - Mechanisms in Hypertension and Obesity (3R00HL127178-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10057015. Licensed CC0.

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