# Endothelin-1 in Obesity and Insulin Resistance

> **NIH NIH R01** · UNIVERSITY OF MISSISSIPPI MED CTR · 2021 · $407,650

## Abstract

Project Summary
Insulin resistance (IR) is a major health problem in the U.S. It precludes type II diabetes and is often present in
patients suffering from obesity, both being major risk factors for cardiovascular disease. Currently,
mechanisms leading to IR are not fully understood. ET-1 is a vasoactive peptide primarily released by
endothelial cells. It is increased in patients with obesity and associated with IR. ET-1 is elevated in response to
hypoxia, which occurs in individuals with obesity. It activates two receptors, ETA and ETB, which typically
oppose each other physiologically. Our preliminary data indicate that inhibiting ETB receptors in rodents, either
genetically or pharmacologically, improves insulin tolerance and reduces fasting blood glucose. This
improvement in glucose control is associated with an increase in plasma adiponectin and adipose adiponectin
and peroxisome proliferator-activated receptor gamma (PPAR-γ) mRNA. In addition, adipocyte specific ETB
gain of function mice have exacerbated glucose intolerance in response to high fat feeding, while adipocyte
ETB knockout mice have improved glucose and insulin tolerance compared to floxed control littermates. These
data suggest the adipose tissue as a possible target for ET-1 induced reduction 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 improves insulin sensitivity in a rodent model of sleep apnea.
These data suggest that increased ET-1 observed in patients with obesity may promote IR via the ETB
receptor. Thus, we hypothesize that that obesity induced tissue hypoxia promotes ET-1/ETB receptor
activation in adipose leading to IR on adipocytes, PPAR-γ inhibition and reduced Adiponectin release
by adipocytes thereby causing IR in muscle and liver tissue. To test this hypothesis, we will utilize both in
vivo and in vitro techniques. First, using cultured adipocytes, we will determine whether activation of ETB
receptors inhibits PPAR-γ, reduces adiponectin secretion, and causes insulin resistance on adipocytes. Next,
we will used clinically approved inhibitors of ET-1 receptors in a model of diet induced obesity and IR, and we
will utilize two novel mouse models that were produced by our lab that allow us to over-express or knockout
the ETB. To test this hypothesis, the following specific aims will be tested:
Specific aim 1: To test the hypothesis that ETB receptor activation directly inhibits insulin signaling on
adipocytes and reduces adiponectin production by inhibiting PPAR-γ.
Specific aim 2: To test the hypothesis that ETB receptor activation on adipocytes promotes insulin resistance
by inhibiting PPAR-γ and reducing adiponectin release in mice.
Specific aim 3: To test the hypothesis that ETB receptor blockade increases plasma adiponectin and improves
insulin resistance in obese mice.

## Key facts

- **NIH application ID:** 10211313
- **Project number:** 1R01DK124327-01A1
- **Recipient organization:** UNIVERSITY OF MISSISSIPPI MED CTR
- **Principal Investigator:** Joshua S Speed
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $407,650
- **Award type:** 1
- **Project period:** 2021-04-09 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10211313

## Citation

> US National Institutes of Health, RePORTER application 10211313, Endothelin-1 in Obesity and Insulin Resistance (1R01DK124327-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10211313. Licensed CC0.

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