# Nuclear Receptors in Metabolic Tissues

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $427,011

## Abstract

Project Summary
A major goal of this laboratory is to understand the molecular mechanisms by which nuclear receptors (NRs)
regulate metabolism. Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte
biology and the target of thiazolidinedione (TZD) drugs that uniquely reverse insulin resistance. Clinical use of
TZDs has been hindered by side effects, making it critical to better understand the functions of PPARγ. There
are two PPARγ isoforms, and a glaring unanswered question is whether they subserve different functions which
could be harnessed to more specifically target insulin resistance. Specific Aim 1 is to elucidate the unique
cistromes, interactomes, and physiological functions of PPARγ isoforms γ1 and γ2. Little is known about
the two major isoforms of PPARγ. We hypothesize that PPARγ1 and γ2 have isoform-specific functions that
differentially contribute to both therapeutic and adverse effects of PPARγ ligands. To test this, we generated
novel mouse models of isoform-specific deletion, as well as mice with epitope tags knocked into the endogenous
isoforms. Preliminary data reveal isoform-specific metabolic phenotypes, as well as differential genomic binding
and transcriptomic regulation. The underlying mechanisms will be evaluated by determining isoform-specific
interactomes in the basal state and upon TZD treatment. Molecular factors that mediate isoform-specific effects
will be manipulated to specifically target the metabolic functions of PPARγ1 or γ2. Specific Aim 2 is to
determine individual-specific functions of glucocorticoids in humans. The glucocorticoid receptor (GR) is
another NR that is a major drug target with untoward side effects; glucocorticoids (GC) are widely prescribed for
inflammatory conditions, but cause obesity, diabetes, and lipid disorders. There is presently no way to predict
which patients will suffer from adverse effects of GCs, nor which will most benefit from therapy. We hypothesize
that SNPs function in adipocytes to control GR binding and GC effects on metabolism and inflammation in a
predictable, patient-specific manner. Preliminary data demonstrate individual-specific GR binding and GC effects
on gene expression and metabolism in multiple patient stem cell-derived adipocytes and hepatocytes, which will
be related to single nucleotide polymorphisms (SNPs) controlling the binding of GR. The mechanisms underlying
the function of these SNPs will be determined, as will their effects on metabolic functions of the cells as well as
predicting adverse metabolic effects of GC in patient populations. We also hypothesize that SNPs will control
individual differences in anti-inflammatory potency due to individual differences in GR binding and function that
will be tested in stem cell-derived macrophages from multiple patients. Together, our innovative genome-wide
and systems approaches will provide fundamental insights into molecular mechanisms underlying tissue- and
individual-specif...

## Key facts

- **NIH application ID:** 10854774
- **Project number:** 5R01DK049780-29
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** MITCHELL A. LAZAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $427,011
- **Award type:** 5
- **Project period:** 1995-07-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10854774

## Citation

> US National Institutes of Health, RePORTER application 10854774, Nuclear Receptors in Metabolic Tissues (5R01DK049780-29). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10854774. Licensed CC0.

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