# Adenosine receptors and metacolic homeostasis

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $535,901

## Abstract

Project Summary/Abstract
 White adipose tissue (WAT) is a key regulator of whole-body energy balance. During
feeding WAT enters an anabolic state facilitated by insulin by storing non-esterified fatty acids
(NEFA) in triglycerides (TG). During fasting WAT enters a catabolic state facilitated by
catecholamines and releases NEFA from TG. During pathogenic insulin resistance, excessive
NEFA accumulates in blood (lipotoxicity) and stimulates excessive hepatic glucose production.
There is a growing awareness that many of the defects in metabolism seen in obese and
prediabetic patients occur not under fasted conditions, but in the postprandial state of one to
four hours following a meal. Indeed, elevated postprandial NEFA partitioning to non-adipose
tissues clearly occurs in these patients and is strongly implicated in the induction of peripheral
insulin resistance. Our novel preliminary data shows that food intake causes a switch from A1R
to another adenosine receptor, Gs-coupled A2B receptor (A2BR), resulting in increased A2BR
and decreased A1R expression and function. The changes in adenosine receptor expression from
A1 to A2B reverse adenosine action. This switch in adenosine signaling reveals that adenosine
functions as a feedback metabolite to oppose dominant hormonal signals: opposing
catecholamines during fasting via A1R inhibition of lipolysis, and opposing insulin in response
to feeding via A2BR stimulation of lipolysis. Obesity shifts the adenosine receptor balance
toward A2BR expression characteristic of feeding and this shift provides an explanation for the
known obesity-induced impairment in postprandial NEFA storage. This proposal undertakes a
rigorous and comprehensive examination of how A2B adenosine receptor (A2BR) signaling
changes between fasted and postprandial conditions and the functional consequences of genetic
deletion or pharmacological manipulation of A2BR signaling. We will also determine how food
intake promotes adenosine signaling via A2BR in fat during the postprandial period.

## Key facts

- **NIH application ID:** 10812248
- **Project number:** 1R01DK136126-01A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Thurl E. Harris
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $535,901
- **Award type:** 1
- **Project period:** 2024-03-12 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812248

## Citation

> US National Institutes of Health, RePORTER application 10812248, Adenosine receptors and metacolic homeostasis (1R01DK136126-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10812248. Licensed CC0.

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