SLIT3 fragments drive neurovascular expansion and thermogenesis in brown adipose tissue, and SLIT3 expression in human visceral adipose tissue negatively correlates with HbA1c.
Adipocyte progenitor-derived SLIT3 is cleaved by BMP1 into distinct fragments that independently drive angiogenesis and sympathetic innervation in brown adipose tissue, which is essential for cold-induced thermogenesis.
Effect estimate: r = -0.092
p-value: p=<0.001
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.
Serdan et al. (2026) studied Obesity (n=1,480). SLIT3 was evaluated on Correlation of SLIT3 expression in omental visceral white adipose tissue with HbA1c (r = -0.092, p=<0.001). SLIT3 fragments drive neurovascular expansion and thermogenesis in brown adipose tissue, and SLIT3 expression in human visceral adipose tissue negatively correlates with HbA1c.