# Endothelin in obesity induced insulin resistanceInvestigate the effects of the endothelin receptor type B in visceral adipose and mechanisms by which it can drive insulin resistance in obesi

> **NIH NIH F31** · UNIVERSITY OF MISSISSIPPI MED CTR · 2020 · $25,704

## 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 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 increased in obese patients and associated with insulin
resistance. ET-1 is elevated in response to hypoxia, which is thought to occur in adipose of obese
individuals. ET-1 activates two known receptors, ETA and ETB, which typically oppose each other
physiologically. Our preliminary data indicates 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, loss
of ETB function reduces adiposity. These data suggest the adipose tissue as a possible target to
improve insulin tolerance by inhibiting the endothelin system. 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 that obesity induced tissue hypoxia promotes ET-1/ETB receptor
activation in adipose leading to 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. Next, we will utilize two novel mouse models that were produced by our lab that allow us
to alter the balance of ETB receptors on adipocytes in vivo. We will over-express the ETB receptor and
knockout the ETB receptor in adipocytes. The following specific aims will be tested:
Specific aim 1: To test the hypothesis that ETB receptor activation inhibits insulin signaling in
adipocytes and reduces adiponectin production by inhibiting PPAR-γ.
Specific aim 2: To test the hypothesis that adipocyte specific ETB receptor activation causes IR in
mice.

## Key facts

- **NIH application ID:** 10068991
- **Project number:** 1F31DK125035-01A1
- **Recipient organization:** UNIVERSITY OF MISSISSIPPI MED CTR
- **Principal Investigator:** Osvaldo Rivera Gonzalez
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $25,704
- **Award type:** 1
- **Project period:** 2020-09-15 → 2021-07-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068991

## Citation

> US National Institutes of Health, RePORTER application 10068991, Endothelin in obesity induced insulin resistanceInvestigate the effects of the endothelin receptor type B in visceral adipose and mechanisms by which it can drive insulin resistance in obesi (1F31DK125035-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10068991. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*