# Nuclear hormone receptors in adipocyte differentiation

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $425,539

## Abstract

A major goal of this laboratory is to understand the molecular mechanisms by which the nuclear receptor
peroxisome proliferator-activated receptor γ (PPARγ) regulates metabolism. PPARγ is the master regulator of
adipocyte biology and has important metabolic and anti-inflammatory effects in macrophages. It is also the
major target of thiazolidinedione (TZD) drugs that have unique abilities to reverse insulin resistance. A major
goal of the present proposal is to understand how PPARγ and TZDs function at the nexus of dietary and
genetic influences on adipocyte and macrophage biology in obesity and diabetes. Specific Aim 1 is to
understand the role of adipose PPARγ in metabolic dysfunction and its treatment by mining the
convergence of diet, antidiabetic drugs, and genetics. We will use state-of-the-art genome-wide
approaches and mutational analysis to determine the mechanisms of convergence of diet, drugs, and genetics
in metabolic disease. Specific Aim 2 is to determine the transcriptional and cellular mechanisms by
which PPARγ in adipose macrophages contributes to the antidiabetic effects of TZDs. We will elucidate
the PPARγ-dependent effects of TZDs on oxidative metabolism of peritoneal and adipose tissue macrophages
(ATMs), and determine whether these effects on ATMs occur in vitro and in vivo. The mechanism of these
effects will be determined using genome-wide approaches and mutational analysis. Specific Aim 3 is to
delineate genomic modulators of TZD action and PPARγ function in human adipose tissue and
macrophages. We will determine individual-specific effects of natural genomic variation on adipocyte TZD
responsiveness, and the underlying molecular mechanisms. This approach will also be applied to human
macrophages, including ATMs, to determine the extent and importance of natural genetic variation in
determining the actions of TZDs and PPARγ in macrophages. Together, using innovative approaches, we will
address major questions about the molecular mechanisms underlying gene-environment interactions that are
implicated in individual differences in obesity, diabetes, and the response to antidiabetic drugs. Our focus on
adipose tissue and macrophages is appropriate given the established importance of these tissues in obesity
and diabetes, and the effects of TZDs on these tissues. Our innovative genome-wide and systemic
approaches will also provide fundamental insight into the molecular mechanisms underlying tissue-specific and
individual-specific effects of transcription factors. Studies of human adipocytes and macrophages will
determine the extent of translatability of the mouse findings, and provide insights that will inform strategies for
personalized and precision approaches to the treatment of metabolic and inflammatory diseases. This
knowledge will thus shed new light on the transcriptional and epigenomic control of adipocyte and macrophage
biology and organismal metabolism, with translational relevance including the potential to lead to...

## Key facts

- **NIH application ID:** 9938550
- **Project number:** 5R01DK049780-26
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** MITCHELL A. LAZAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,539
- **Award type:** 5
- **Project period:** 1995-07-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938550

## Citation

> US National Institutes of Health, RePORTER application 9938550, Nuclear hormone receptors in adipocyte differentiation (5R01DK049780-26). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9938550. Licensed CC0.

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