Introduction and Objective: Activating and expanding brown adipose tissue (BAT) offer promising strategies to counteract obesity and cardiometabolic diseases. Due to their high metabolic activity, brown adipocytes act as a metabolic sink and improves glucose and lipid metabolism. Adipose depots are highly vascularized and innervated, containing an extensive network of capillaries and sympathetic nerves that support and regulate their function. As adipose tissue adapts to physiological stimuli such as cold exposure or overnutrition, coordinated growth and remodeling of its neurovasculature help maintain adequate oxygen and nutrient supply while preserving sympathetic and sensory regulation. We recently identified the axon guidance protein Slit3 as a critical regulator of BAT neurovascular development and thermogenesis. We showed that full-length Slit3 undergoes proteolytic cleavage to generate two secreted ligands: a large N-terminal (Slit3-N) and a shorter C-terminal (Slit3-C), which engage distinct receptors to promote angiogenesis and sympathetic innervation, respectively. Methods: Using a combination of biochemical assays, structural modeling, and in vivo approaches, we identified PlexinA1 (Plxna1) as a key receptor for Slit3-C. This interaction is essential for sympathetic innervation and thermogenic activation of BAT. Results: Plxna1 is selectively expressed on sympathetic neurites. Selective deletion of Plxna1 in sympathetic neurons results in a marked reduction in sympathetic nerve density and norepinephrine levels in BAT and leads to impaired cold-induced thermogenesis. Together, these findings establish Plxna1 as a critical mediator of sympathetic network development and cold-induced expansion in BAT. Conclusion: More broadly, this work identifies Plxna1, a canonical receptor for Semaphorins, as a central integrator of multiple axon guidance cues, including Slit3, and highlights a new regulatory node through which sympathetic innervation and thermogenic fat function may be therapeutically enhanced to improve systemic metabolism. Disclosure T. Duarte Afonso Serdan: None. H.E. Cervantes: None. F. Shamsi: None. Funding American Diabetes Association (1-26-PDF-0863)
Serdan et al. (Sat,) studied this question.