# The Role of IRX3 Neurons in the Regulation of Body Weight Homeostasis

> **NIH NIH F31** · UNIVERSITY OF IOWA · 2024 · $35,771

## Abstract

PROJECT SUMMARY / ABSTRACT
Obesity results from an imbalance of energy that is driven by both environmental and genetic factors. While
many genomic loci are associated with obesity, several non-coding single nucleotide polymorphisms (SNPs) in
the first intron of the fat mass and obesity (FTO) gene have the strongest association with obesity in humans.
The obesity-associated region containing these SNPs forms functional long-distance connections in the adult
mouse brain with the promoter of a neighboring gene iroquois homeobox protein 3 (IRX3), but NOT FTO,
suggesting that IRX3 may be a regulator of body weight gain. Interestingly, the obesity-associated SNP,
rs1421085, is highly associated with increased IRX3 expression in human brain samples and has been proposed
to increase IRX3 expression directly through interfering with the binding site of a transcriptional repressor of
IRX3. However, the mechanism and relevant brain region(s) of IRX3 function have never been reported. Thus,
there is a critical need to better understand the potential underlying mechanisms contributing to the obesity
epidemic. The overall objective of this proposal is to investigate the central circuits and mechanisms by which
IRX3, and by extension obesity-associated SNPs, influences body weight homeostasis. To accomplish this, we
have developed a novel mouse model harboring the human rs1421085 SNP (OB-SNPrs142/rs142). Importantly, OB-
SNPrs142/rs142 mice under humanized thermoneutral and high-fat diet conditions recapitulate phenotypes
associated with humans possessing the rs1421085 SNP including increased fat mass percentage and an
approximately 5% increase in bodyweight. Our preliminary data also reveals that OB-SNPrs142/rs142 mice exhibit
increased Irx3 mRNA expression in the brain in a dose-dependent manner, similar to what was reported in the
brain samples of humans harboring the risk-allele. Using a novel Irx3-CRE mouse crossed to a tdTomato reporter
mouse, we have determined that IRX3 expression in the hypothalamus is primarily expressed in neurons in the
ventral premammillary nucleus (vPM). This and additional preliminary data has led us to hypothesize that
increased IRX3 expression in the vPM of the hypothalamus alters body weight homeostasis and increases body
weight gain. This hypothesis will be evaluated through the following aims: In Aim 1, we will evaluate the
contribution of vPM IRX3 to metabolic phenotypes, by utilizing a viral vector to increase IRX3 levels in the vPM
and then monitor energy parameters. In addition, using chemogenetic activation of IRX3(+) neurons in the vPM,
we will explore the role of IRX3 neurons to regulate metabolism. In Aim 2, we will investigate potential
electrophysiological and transcriptional mechanisms through which increased expression of IRX3 in vPM
IRX3(+) neurons impacts metabolism using patch-clamp recording, single cell RNA sequencing, and chromatin
immunoprecipitation. This proposal is significant because it is the first t...

## Key facts

- **NIH application ID:** 10874445
- **Project number:** 5F31DK137587-02
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Andrew Sullivan
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $35,771
- **Award type:** 5
- **Project period:** 2023-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10874445

## Citation

> US National Institutes of Health, RePORTER application 10874445, The Role of IRX3 Neurons in the Regulation of Body Weight Homeostasis (5F31DK137587-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10874445. Licensed CC0.

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