Slit3 Fragments Orchestrate Neurovascular Expansion and Thermogenesis in Brown Adipose Tissue

Area of Science:

• Cell Biology
• Physiology
• Developmental Biology

Background:

• Brown adipose tissue (BAT) enables adaptive thermogenesis in placental mammals for thermoregulation.
• BAT function relies on a dense network of blood vessels and sympathetic nerves.
• Cold exposure triggers coordinated brown adipogenesis, angiogenesis, and sympathetic innervation in BAT.

Purpose of the Study:

• To identify factors coordinating angiogenesis and sympathetic innervation in BAT.
• To elucidate the role of Slit guidance ligand 3 (Slit3) in BAT adaptation.
• To understand the molecular mechanisms of neurovascular network expansion in BAT.

Main Methods:

• Identification of Slit3 as a niche factor secreted by adipocyte progenitors.
• Analysis of Slit3's role in regulating angiogenesis and sympathetic innervation in BAT.
• Investigation of Slit3 proteolytic cleavage into Slit3-N and Slit3-C fragments.
• Identification of bone morphogenetic protein-1 (Bmp1) as a Slit protease.

Main Results:

• Slit3 secreted by adipocyte progenitors is essential for BAT thermogenesis in vivo.
• Slit3 regulates both angiogenesis and sympathetic innervation in BAT.
• Slit3 fragments (Slit3-N and Slit3-C) activate distinct receptors to stimulate angiogenesis and innervation.
• Bmp1 is identified as the first vertebrate Slit protease.

Conclusions:

• Slit3-mediated neurovascular network expansion is critical for cold-induced BAT adaptation.
• Co-regulated expansion of neurovasculature by Slit3 fragments ensures synchronized BAT response to environmental challenges.
• Adipocyte progenitors regulate tissue innervation, revealing novel cellular interactions within adipose tissue.