# Regulation of Adipose Tissue Remodeling Through Axon Guidance Molecule Slit3

> **NIH NIH R03** · NEW YORK UNIVERSITY · 2024 · $115,920

## Abstract

Project Summary
 Brown adipose tissue (BAT) is a specialized type of adipose that is primarily responsible for regulating body
temperature. Once activated by cold, BAT dissipates the chemical energy as heat in a process called adaptive
thermogenesis. Activating and expanding the thermogenic adipose tissue are attractive ways to increase energy
expenditure and offer promising strategies to combat obesity and cardiometabolic diseases. A critical barrier to
harnessing the potential of BAT to enhance cardiometabolic health in humans is the lack of understanding of the
full range of pathways involved in the activation of BAT thermogenesis. Chronic cold exposure stimulates BAT
thermogenesis through the coordinated stimulation of brown adipogenesis, angiogenesis, and sympathetic
innervation. However, how these distinct processes are spatiotemporally coordinated is not known. Using single-
cell transcriptomic analysis of BAT, we have recently identified the network of cellular interactome in the
thermogenic adipose niche. This proposal is built on our recent discovery of Slit guidance ligand 3 (Slit3) as an
essential regulator of BAT thermogenesis through controlling both angiogenesis and sympathetic innervation in
BAT. This proposal examines the mechanisms by which Slit3 fragments stimulate vascular endothelial cells and
sympathetic neurites to promote angiogenesis and sympathetic innervation. We hypothesize that the N-terminal
and C-terminal fragments of Slit3 (Slit3-N and Slit3-C) bind to distinct receptors on endothelial cells and
sympathetic nerves to stimulate angiogenesis and sympathetic innervation. In aim 1, we will use AAV-mediated
gene delivery to overexpress Slit3 fragments in BAT and determine the effects of each fragment on angiogenesis
and sympathetic innervation. In aim 2, we will use a panel of in vitro and in vivo models to identify the specific
receptors responsible for mediating the effects of Slit3 fragments in vascular endothelial cells and sympathetic
nerves. The proposed studies will provide a broad and deep understanding of how Slit3 regulates the two
essential processes involved in BAT thermogenesis, angiogenesis, and sympathetic innervation. These studies
will identify new potential nodes of intervention for obesity and metabolic diseases by stimulating the healthy
expansion of thermogenic fat.

## Key facts

- **NIH application ID:** 10833664
- **Project number:** 5R03DK135786-02
- **Recipient organization:** NEW YORK UNIVERSITY
- **Principal Investigator:** Farnaz Shamsi
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $115,920
- **Award type:** 5
- **Project period:** 2023-04-27 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10833664

## Citation

> US National Institutes of Health, RePORTER application 10833664, Regulation of Adipose Tissue Remodeling Through Axon Guidance Molecule Slit3 (5R03DK135786-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10833664. Licensed CC0.

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