# GLUCOCORTICOID RECEPTOR POST-TRANSLATIONAL MODIFICATIONS IN INSULIN RESISTANCE

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $343,125

## Abstract

Abstract:
There is a global epidemic of metabolic syndrome, characterized by insulin resistance, hypertension, and
central obesity. Although the etiology of metabolic syndrome is still an active area of investigation, one leading
hypothesis is that it is caused by elevated glucocorticoid (GCs) levels in key insulin responsive tissues such as
liver and fat. GCs are stress hormones produced by the adrenal gland. GCs bind to the GC receptor (GR) a
nuclear hormone receptor that alters transcription of target genes by multiple mechanisms including direct
binding to DNA (transactivation) as well as protein-protein mediated repression. GCs are also effective
therapies for many inflammatory diseases including chronic obstructive pulmonary disease, inflammatory
bowel disease and rheumatoid arthritis, but their use is limited due the adverse metabolic effects including
weight gain, insulin resistance and hypertension. Recently, several groups have identified GR post-
translational modification (PTM) in cell lines, and these PTM events alter GR transcriptional activity. However,
the role of GR PTM in physiologically relevant paradigms in vivo is unknown. Based on preliminary data, I
hypothesize that GR PTM, specifically phosphorylation, mediates the complex effects of GC on the liver in
vivo. This hypothesis will be tested in three Specific Aims: 1) We will determine the role of GR phosphorylation
on hepatocyte metabolism and gene expression. This will be done by adding back wildtype or phosphomutant
GR isoforms to GR knockdown hepatoma cells 2) We will determine the role of GR phosphorylation in
mediating heaptic metabolism, gene expression and GR occupancy in the livers of mice. This will be done by
analyzing metabolism, gene expression and chromatin immunoprecipitation with antibodies to GR. We have
created novel GR knockin phosphomutant mice using CRISPRS. These S211A mice have a key
phosphorylated serine residue mutated to alanine. We will determine which GC mediated changes in hepatic
lipid metabolism, gene expression and GR occupancy are phosphorylation dependent. 3) We will determine if
GR phosphorylation is associated with hepatic insulin resistance in samples from obese patients undergoing
Roux-en-Y gastic bypass surgery. This will be done by staining liver biopsies from these patients (as well as
controls) with phosphoGR specific antibodies. Currently selective GR modulators are being developed for the
treatment of metabolic diseases as well as safer anti-inflammatory medications. Therefore, understanding the
role of GR PTM in mediating effects of GCs should shed light on novel treatments for metabolic disease as
well as common inflammatory conditions.

## Key facts

- **NIH application ID:** 9980364
- **Project number:** 5R01DK106083-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Clay F. Semenkovich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,125
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980364

## Citation

> US National Institutes of Health, RePORTER application 9980364, GLUCOCORTICOID RECEPTOR POST-TRANSLATIONAL MODIFICATIONS IN INSULIN RESISTANCE (5R01DK106083-05). Retrieved via AI Analytics 2026-09-08 from https://api.ai-analytics.org/grant/nih/9980364. Licensed CC0.

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