Mechanisms of slits3 signaling in thermogenic adipose tissue - Project Summary The regulation of body temperature, thermoregulation, is a fundamental homeostatic process in warm-blooded organisms. Brown adipose tissue (BAT) plays an important role in the control of body temperature by generating heat in cold environments. BAT is functionally distinct from white adipose tissue (WAT) which is the primary site of energy storage. 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. Notably, studies in humans and rodents show that the biological significance of thermogenic adipose tissue extends far beyond enhancing energy expenditure. Due to their high metabolic activity, thermogenic adipocytes act as a metabolic sink to improve glucose and lipid metabolism and thus exhibit anti-diabetic and lipid-lowering effects. The major challenge in targeting BAT as an anti-obesity therapy is the limited amount of active BAT in most adult humans. Although using chronic cold exposure as a preventive or treatment strategy is not feasible, understanding the mechanisms of cold adaptation presents a unique opportunity to exploit these pathways and develop strategies to increase BAT thermogenesis and improve systemic metabolism. Using single-cell transcriptomic analysis of BAT and analyzing the cell-type-specific transcriptional changes in BAT from mice housed at different temperatures, we have recently revealed that thermogenic adaptation involves the multi- layered and coordinated remodeling of all adipose resident cells to enhance thermogenesis. Through extensive analysis of ligand-receptor communications, we have constructed the intricate network of intercellular crosstalk within the thermogenic adipose niche. Within this framework, we identified the axon guidance ligand Slit3 as an essential regulator of BAT thermogenesis. Our functional studies demonstrated the role of Slit3 in the regulation of angiogenesis and sympathetic innervation, firmly establishing Slit3 as a key player in the control of BAT thermogenesis. However, the mechanisms by which Slit3 signaling influences these processes remain unknown. Building on our recent discovery and exciting preliminary data, we propose a series of innovative strategies to determine the contribution of Slit3 proteolytic processing to its function in BAT (Aim 1), identify the molecular mechanisms of Slit3 signaling in endothelial cells and sympathetic neurons (Aim 2), and address the potential of Slit3 to ameliorate the detrimental effects of diet-induced obesity by promoting angiogenesis and preserving the sympathetic innervation in BAT and WAT (Aim 3). Successful completion of the proposed studies will provide a mechanistic understanding of an entirely new pathway that regulates adipose tissue function and will have an important and sustained impact on the field.
