# Mechanism of Gdf3 action to limit insulin sensitivity in obesity

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $636,249

## Abstract

Project Summary
The thiazolidinediones (TZDs) are powerful anti-diabetic drugs whose use in treating type 2 diabetes is limited
by adverse side effects. The goal of this proposal is a biochemical investigation into the mechanism that
separates the positive metabolic effects of TZDs to lower glucose from their well-characterized negative side
effects. PPARγ, a molecular target of the TZDs, regulates systemic insulin sensitivity by promoting formation of
new adipocytes. However, we show that the TZDs have a second biochemical function on PPARγ, to block
phosphorylation of serine 273 (pS273). We find that phosphorylation of PPARγ at serine 273 promotes insulin
resistance without affecting adipogenesis. Reversing this phosphorylation with pharmacological or genetic
inhibition is sufficient to promote insulin sensitivity and increase thermogenic responses to cold. We propose that
one of the main mechanisms by which phosphorylation of PPARγ at serine 273 promotes insulin resistance is
through increased expression of growth differentiation factor 3 (Gdf3). Gdf3 is a secreted protein in the TGF-
/BMP superfamily and a negative regulator of BMP signaling. In adipose tissue, BMP proteins contribute to
insulin sensitivity and thermogenesis. We therefore propose that elevated levels of Gdf3 in obesity are the cause
of insulin resistance mediated by PPARγ S273 phosphorylation. Indeed, we show that ectopic expression of
Gdf3 is sufficient to cause insulin resistance in lean mice. In this proposal we examine the contribution of Gdf3
to the pathogenesis of obesity and insulin resistance. We predict that blocking Gdf3 levels or activity will restore
whole-body insulin sensitivity and promote thermogenesis. We will interrogate the role of Gdf3 on glucose
homeostasis and obesity using both acute gain-of-function and loss-of-function models. We will utilize innovative
new wireless continuous glucose monitoring technology concurrently with indirect calorimetry to achieve high-
precision measurements of insulin resistance, energy balance, and circulating nutrient availability. We will
determine whether Gdf3 is the mechanism linking PPARγ S273 phosphorylation and insulin resistance. We will
also determine whether Gdf3 requires BMP signaling through SMAD1/5/8 proteins. Finally, we will perform an
unbiased investigation into the pathways required for Gdf3 signaling using a genome-wide CRISPR/Cas9
knockout screen. This hypothesis suggests a new therapeutic modality which harnesses a specific beneficial
aspect of TZD treatment which is independent of TZD-associated side effects. The results from this proposal will
definitively determine if Gdf3 is a suitable target for promoting metabolic health.

## Key facts

- **NIH application ID:** 10295286
- **Project number:** 2R01DK107717-06A1
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** ALEXANDER BANKS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $636,249
- **Award type:** 2
- **Project period:** 2016-02-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10295286

## Citation

> US National Institutes of Health, RePORTER application 10295286, Mechanism of Gdf3 action to limit insulin sensitivity in obesity (2R01DK107717-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10295286. Licensed CC0.

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