76-OR: Axon Guidance Molecule Slit3 Is Essential for Cold-Induced Remodeling of BAT Neurovasculature and Thermogenesis

Abstract

Brown adipose tissue (BAT) is primarily responsible for regulating body temperature through adaptive thermogenesis. Enhancing energy expenditure through the activation of BAT thermogenesis is a promising strategy to prevent and reverse obesity and its cardiometabolic sequelae. Brown adipocytes are embedded in a dense network of blood vessels and sympathetic nerves that supports their thermogenic activity. Increasing the density of blood vessels and sympathetic innervation is essential for enhanced thermogenesis in cold. However, how these distinct processes are spatiotemporally regulated is not clear. To define the mediators of intercellular crosstalk in the BAT, we used single-cell transcriptomic analysis of BAT to build a network of ligand-receptor interactions. We identified Slit guidance ligand 3 (Slit3) as a new adipokine that mediates the crosstalk among adipocyte progenitors, endothelial cells, and sympathetic nerves. Using a combination of in vivo gain and loss of function studies, we showed that Slit3 is essential for cold-induced angiogenesis and sympathetic innervation in BAT. Loss of Slit3 reduced the density of blood vessels and sympathetic neurites in BAT. Consequently, mice lacking Slit3 expression in BAT exhibited severe cold intolerance, increased lipid accumulation and whitening of BAT, and reduced expression of thermogenic and mitochondrial genes in BAT. Conversely, the overexpression of Slit3 enhanced cold-induced BAT thermogenesis. Our mechanistic studies identified the key regulatory events that control Slit3 signaling in BAT. Collectively, these findings established the essential role of Slit3 signaling in regulation of BAT thermogenesis and introduced Slit3 as a new niche factor that promotes adipose tissue health. These studies introduced a potential node of intervention for improving systemic metabolism through the expansion of thermogenic fat. Disclosure T.Duarte afonso serdan: None. H.E.Cervantes: None. F.M.Neto: None. Y.Tseng: Consultant; Cellarity, LyGenesis. F.Shamsi: None. Funding National Institutes of Health (K01DK125608)