Regulation of Adipose Tissue Remodeling Through Axon Guidance Molecule Slit3

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Project Summary Brown adipose tissue (BAT) is a specialized type of adipose that is primarily responsible for regulating body temperature. Once activated by cold, BAT dissipates the chemical energy as heat in a process called adaptive thermogenesis. Activating and expanding the thermogenic adipose tissue are attractive ways to increase energy expenditure and offer promising strategies to combat obesity and cardiometabolic diseases. A critical barrier to harnessing the potential of BAT to enhance cardiometabolic health in humans is the lack of understanding of the full range of pathways involved in the activation of BAT thermogenesis. Chronic cold exposure stimulates BAT thermogenesis through the coordinated stimulation of brown adipogenesis, angiogenesis, and sympathetic innervation. However, how these distinct processes are spatiotemporally coordinated is not known. Using single- cell transcriptomic analysis of BAT, we have recently identified the network of cellular interactome in the thermogenic adipose niche. This proposal is built on our recent discovery of Slit guidance ligand 3 (Slit3) as an essential regulator of BAT thermogenesis through controlling both angiogenesis and sympathetic innervation in BAT. This proposal examines the mechanisms by which Slit3 fragments stimulate vascular endothelial cells and sympathetic neurites to promote angiogenesis and sympathetic innervation. We hypothesize that the N-terminal and C-terminal fragments of Slit3 (Slit3-N and Slit3-C) bind to distinct receptors on endothelial cells and sympathetic nerves to stimulate angiogenesis and sympathetic innervation. In aim 1, we will use AAV-mediated gene delivery to overexpress Slit3 fragments in BAT and determine the effects of each fragment on angiogenesis and sympathetic innervation. In aim 2, we will use a panel of in vitro and in vivo models to identify the specific receptors responsible for mediating the effects of Slit3 fragments in vascular endothelial cells and sympathetic nerves. The proposed studies will provide a broad and deep understanding of how Slit3 regulates the two essential processes involved in BAT thermogenesis, angiogenesis, and sympathetic innervation. These studies will identify new potential nodes of intervention for obesity and metabolic diseases by stimulating the healthy expansion of thermogenic fat.