# Determining the Cellular Mechanisms of Catecholamine Resistance in Obesity

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $65,310

## Abstract

Project Summary
Obesity is a major risk factor for numerous diseases and has reached epidemic proportions
worldwide. It is accompanied by a reduction in adipocyte responsiveness to epinephrine and
norepinephrine, termed catecholamine resistance. Catecholamine signaling in adipocytes is governed
by - and -adrenergic receptors. In mice, the 3-adrenergic receptor (ADRB3) is expressed at
hundred folds higher levels than other ADRBs and can regulate whole body metabolism.
Subsequently, ADRB3 agonists have been explored clinically to treat obesity; however, they have had
limited success due to low durability of their effects. Interestingly, ADRB3 is resistant to classical
desensitization but may become desensitized by regulating its own expression, which we hypothesize
is important for the limited effects of ADRB3 agonists in obese patients. My preliminary data suggest
that activation of inflammatory pathways or direct activation of ADRB3 dramatically downregulates
ADRB3 mRNA and protein in adipocytes. In both cases this downregulation is dependent on EPAC, a
guanine exchange factor for the small G-proteins RAP1/2. This proposal will investigate the novel
hypothesis that resistance to catecholamines produced physiologically during obesity (heterologous
desensitization) and pharmacologically during adrenergic agonist administration (homologous
desensitization) results from EPAC/RAP-dependent downregulation of ADRB3. I will utilize
sophisticated techniques including mass spectroscopy, RNAseq, adipocyte-specific knockout mouse
models, primary pre-adipocytes differentiated in vitro, as well as molecular biology, biochemistry,
small molecule/siRNA, and physiological assays to test this overarching hypothesis. I will determine
the signaling pathways and transcriptional regulators responsible for downregulation of ADRB3
during homologous and heterologous desensitization in adipocytes. This project represents an
excellent training opportunity for me, because it will not only expose me to cutting edge ideas and
technologies in metabolism/adipocyte biology, but also in career development (grant writing,
communication, lab management, etc) that will prepare me for the transition to independence.

## Key facts

- **NIH application ID:** 10141141
- **Project number:** 1F32DK124947-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Joseph Marco Valentine
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 1
- **Project period:** 2020-09-03 → 2022-04-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10141141

## Citation

> US National Institutes of Health, RePORTER application 10141141, Determining the Cellular Mechanisms of Catecholamine Resistance in Obesity (1F32DK124947-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10141141. Licensed CC0.

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