# SLIT3 fragments orchestrate neurovascular expansion and thermogenesis in brown adipose tissue

## TL;DR

This study reveals how brown fat expands blood vessels and nerves during cold exposure through fragments of a protein called SLIT3.

## Contribution

The study identifies SLIT3 fragments as key regulators of neurovascular coordination in brown adipose tissue.

## Key findings

- SLIT3 fragments SLIT3-N and SLIT3-C independently promote angiogenesis and sympathetic innervation.
- PLXNA1 is identified as a receptor for SLIT3-C in sympathetic innervation of brown adipose tissue.
- BMP1 is revealed as the first SLIT protease in vertebrates.

## Abstract

Brown adipose tissue is an evolutionary innovation in placental mammals that regulates body temperature through adaptive thermogenesis. Cold exposure activates brown adipose tissue thermogenesis through coordinated induction of brown adipogenesis, angiogenesis, and sympathetic innervation; however, how these processes are coordinated remains unclear. Here, we show that fragments of Slit guidance ligand 3 (SLIT3) drive crosstalk among adipocyte progenitors, endothelial cells, and sympathetic nerves. Adipocyte progenitors secrete SLIT3, which is cleaved into functionally distinct SLIT3-N and SLIT3-C fragments that independently promote angiogenesis and sympathetic innervation. We identify PLXNA1 as a receptor for SLIT3-C and demonstrate its essential role in sympathetic innervation of brown adipose tissue. Moreover, we identify BMP1 as the first SLIT protease described in vertebrates. Coordinated neurovascular expansion mediated by distinct SLIT3 fragments provides a bifurcated yet integrated mechanism that ensures a synchronized brown adipose tissue response to environmental challenges. Finally, this study reveals a previously unrecognized role for adipocyte progenitors in regulating tissue innervation.

Brown adipocytes are embedded within an intricate network of blood vessels and sympathetic nerves that support their development and thermogenic function. This study shows that adipocyte progenitor cells control blood vessel growth and nerve wiring in brown fat during cold exposure. They do so by releasing Slit3, which is cleaved into fragments that coordinate angiogenesis and sympathetic innervation.